SUBSTANCE. ABUSE

SUBSTANCE . 

ABUSE 

A COMl'REHENSIVE TEXTBOOK 

Second Editimz 

Editors 

JoyceH. Lowinson, 1VI.D . 

Professor of Psychiatry 

Director, Division of Substance :Abuse 

Albert Einstein College ofMledicine 

Bronx, New York 

Pedro Ru2z,1Vl.D . 

Professor of Psychiatry 

Baylor College of Medicine 

Houston, Texas 

This, ma,'er, ~ ~ . G 

.I IIIG ~1 

'fllaill ~d`11~ 

CORS~ - 

Robert B ..1ll illman, M.D . 

Saul P . S'teinberg, Distinguishedl Professor of Psychiatry and Public Health 

Cornell University Medical College 

New York, New York 

Affoau'ate Editor 

John G. Langrod, Ph.D . . 

Division of Substance Abuse 

Albert Einstein College of Medicine 

Bronx, New York 

WILLIAMS & WILKINS . 

lWLIIMONIE • HiONG . KONG .• EONDON'• MUNICH 

PNIU'OflPH/A • SYONEY .- IIOKYO 

http://legacy.library.ucsf.edu/tid/xbd67d00/pdf

7 

BRAIN REti?VARD .MECHANISIWIS' 

Eliat L. Gardner, Ph:D. 

Among the social and medical illss of the 20th century, 

substance abuse surely ranks as one of the most devastating 

and .cosaly . Although totallyaccurate data on the cost to society 

are difficult too arrive at, currment well-informed estimates 

of the yearly cost to the United States alone are in the range 

of $250 ~ to 300. billion (1,2) . Of course, substance abuse : is 

nornew: Indeed, dhscriptions of drntg abuse arc as old .as nlie 

written word, with a particularly ancient one to be found in 

the Bible in the :book of Genesis (chapter 9 ; .verses 20-23)y 

in which Noah is described as becoming drunk with winc 

and being,found lying in a dmnken stupor in his tent . At 

present, though, this age-old human scourge has taken on .a 

new and frightening dimension with the realization that intravcnotu 

use ofcocaine and heroin now constitutes tbeprincipal 

vector for.tihe spreactofac9uioed immunodeficiency syndiome 

(AI DS) in North America and Europe (3-5) . 

A question .obviouslyarises-why do human beings initiate 

and persisrinsuch obviously self-destmctive :and'.aberrant 

bchavior.as substance abuse? As with all aberrant behavior 

patterns, compulsive dmg-seeking and drug-taking 

behavior poses two fvmdamentallquestaons, one for the scientist 

.and onefor tlle clirtician : Forahe scicntist, ohe question 

is ~'vhat causes and perpetuates such patently self«destructive 

behavior?"Forthe 

:d'utician{ the question is "how can suchbchavtor be modified or curbed to the tdtimate benefit of the 

patient?"' In the absencte of purely accidental or fontuitousdi 

.scoveries of effective treatment methods forpathologic drugseeking 

anddrug-taking, tlhe scientific question becomes par-amount, because from an understanding of the causes of dmg 

scl6admiiuistrationn can come rational hypodncsis-drivcn 

treatment modahties : . 

Obviously, the causcss of substance abuse are complex and 

multifactorial, including .profoundly important social; cco 

; nomic; and educational factors. Att die same time, the fact 

that laboraoory animals, .on whom social, economic, and ed 

ucational variablesare inoperative, .will .voluntanily (indeed ~ 

avidly) selfad}ninistcr the same drugs that human beings use 

and abuse (6-9), and will satsdf-administerothcr drugs (see 

below for more complete discussions of drug sclf-adminir 

tration in lafooratory animals),, arguns connpelli n gliythat there 

is a profoundlyimportant core .of basic biology to the phe-nomcnon of substance abuse 

:. Also,, the fact that .laboratory 

anintals will voluntarily selfadminister these same drugs into 

70 

hig(dy selective and specific brain loci, and not into other 

brain loci (again, see below for fttrther discussion)„argucs 

that this core of basic biologic causation for substance abuse 

is nerrvnbiologicc in nature . 

F),istorically ; .explanatorypostulatcsof the neurobiologic - 

motivating forces behind the specific behavioral pattern of 

substance.abuse have tended to parallel nce more .general explanarcory 

postulates put forth byneurabehavioral theorists 

for the motivating forces behind all behavior. Early general - 

theories of motivation, .especially those of the 19th century, 

posited that behavior results primarily from subconscious 

"instincts" coded in the brain thacimpel certain .behaviors to 

occur (10) . Other early general theories of motivation, especially 

those popular dbring the first four decades of the 

20th century, posited that io is the activation of internal homcostatic 

brain,mechanisms(e .g ;, hunger) that "drive" beliavior 

(e .g ;, eating) to occur (10) .'Thus, both concepts hold 

that .behavior isprintarily the result of activationiof internal 

ncuropsychobiologic states witltiin .the organism, and the re< 

sulting behavior serves too relieve or reduce such internal ae 

tivation, Inqui6e parallel fashion ; an early explanation for 

substance abusepositedlnhat compulsive dmgusers : had a 

preexisting,"psyehic" disturbance (the sm•called "addict" personality) 

that impelled drtng-taking behavior ( :11) . Although 

certainly true to a limited extent, such "instiiuct satisfaction" 

on "drive reduction"'thcoriesdo not cxplainwhycenain behaviors 

are preferred over.others with presumably equivalent 

"instinct satisfaction" or "drive reduaion"value (e .g :, why 

some foods .are preferred over others), and the postulation of 

a .a precoded "heroin drive " or"cocaine . drive" in the central . 

nervous system has seemed far-fetched toeventfte m!osndyed 

iin-the-wool instinct or drive reduction tlheorists .lherc 

; :isalsoan unplcasing element of circularity i tosuchconcepts .e .,, a 

drug addict uses .drugs because heor she is predisposed ttN~ 

do so. .Tme in soniczases, noo doubt, but hardlya riclilvsat(y`I 

isfying explanation of the underlying neurobiologic or psy-Nchobiologic nurlaunimu 

. W 

DWning .the nniddl6 decades of the 20th eentury,,analter-+ Pb 

native cxplhnation canic to: dominaec motivational theory inN 

both psychology and i psydniatry- This view, termed reinforce-r 

mcnt tJfeory, ( :10;12), explains bchavior in ternts ofcontingent r 

assoctationsbetwccn ioitially random bdiavioral elements and' ~ 

ctnvironmental stimuli . That is, ifcertain enviionmental stim- 

,-,, . o ~ 

"-','^,' ., , .>? 


7 / 1{RA4N PtEWAdtU 1v1EcILAN15M5 7 1 

ulij termed reinferocrs, are contingentlypaired with bchavior, 

the fumre probability of that same bchaviorincreases . Thus, 

rcinforccment theory lioldsdnarbehaviur ispriimarilyahe result 

of tlnee presence of salient cnviionnrental stimuli thatt act 

on the central nervous system im .such a way as' .to alter nlte 

future probability, of bchavior occurring in their presence 

(10,12) . The . "reinforcement tlneory"explanation for substance 

abuse posits that compulsive substancee abusers use 

drugs because these same drugs have been positive reinforccrs 

on previous occasions. Once again,, as with "instinct" and 

"drive reduction"'thcories, .tlnere is an .unpleasitng circularity 

to such an explanation, i .e .,, a drug addict uses drugs becattsc 

drugs have previousH/ been "reinforting."' All verytrue in 

most cases, nodoubt,,but sinccreinforcement theory makes 

no attempt to descrille .the .neurophysiologic processes that 

occur in'tht.poesence .of reilnforcers, the "reinforcement" explanationfor 

substance abuse is as unsatisfying ;withrespect 

to underlying neumbiologic or psychobiologic substrates and 

mechanisms as are "instinct" and "drive reduction" explanations 

. 

Seemingly more gqnnane to thescissues is the notion of 

"incentive stimulation" or "incentive motivation," a more 

modervrconcept in motivational,theory (10) . .This view attempts.to 

describe rcinforcers as having the :abilicy to .activate . 

internal sensory or affectiive processes within the organism 

that are itaherently pleasurable or rewarding (i .e ., subjectively 

pleasant) : and that : then organize andd influence bchaviorr tooccur (10,13-15) 

. For example, if an organism ingutsheroin 

or cocaine and finds that pleasure .orreward ensues, thee 

likelihood of future ingestion of heroin or cocaine increases . 

This position is, of course, strikingly close to the "common 

sense" hedonustic ecplanation fbr motivation which, as Yotmg, 

(13) notes, "implies .that subjec2ivefeelungs of pleasantnesss 

andunpleasammess influence behavior." 

That drugs of abusee are positive reinforcers is, of course, 

clear . As early as . 1940, Spragg's pioneeringg workdemon-strated 

. (26)) rhatt laboratoryanirttalsy will voluntarily engage 

in .thehaviors that lead .to the injection of habit-formung dFtngs . 

Indeed, in Spragg's studies the .animals (chimpanzees) would 

drag the researcherto: the cupboard' where : the morphine, 

syringes ; and'mcedlcss were stored and,voluntarily assume : thee 

proper position to rcceive : theinjettions . .In 1962, Weeks (6) 

demonstrated that animals will volmttamlyself-administer 

habit-forming drugs if placed in a Iaboratorysetting in which 

the animal'sresponsc omn aa mamipulandutu activates an automatic 

infiision system that deliverss a preset amount of drug 

through a~ surgicallyimplanted venouss catheter . . Thus„ the 

human researclicr is .totadliy ourof tlnc loop ; drug delivery or 

nondelivery is totally under the voluntaryconorol of dee .anitmai 

. Thisworkscr du stage for the now widely used, para-digm of drug seVF-administration in laboratory animalsas a~ 

tool for smdyingdntg-induced reinforcement processes(sce . 

bclow for{urthcr discusssion ) ;. One important ancillaryresuln 

of tlxdiscovcry of voluntary drugself-adtninistration in amimalsis 

thatit .turned scientific attention away from hypol thctical 

.internallstates withinsubstancc abusers (i!e-, the"ad= 

dict" Ixrsonaliry),that supposedly "drovc" tdtcmto abuse dinigs„ 

and focused attention uistcad on .the drugs thennselUcs and 

on the connmon neuropharmacologic properties .thcy migbt 

possess that makctluctm .positive oeinforccrsfors humans and 

animals aEikc. - 

As .noted above, "incentive motivation"dreory holds that 

positive ncinforcersactivate internal neural processes .thatare 

inherentlypleasurable or rewarding (10,1!3 :-15) . Thcstudy 

of the nature of these processes was advanced dtamatically, in 

1954with the seminal discovery by James Olds and Peter 

Milner that laboratoryanimals will voluntarily (indccd,, avidly) 

self-administerr electrical stimulation .delivered through 

electrodes deep in .the brain . (16) ;. Thiss finding was of grcart 

importance for many reasons- First, such .brainstimulation 

appears to actprecisclyas other positive reinforcers .do, and 

can be used toselectively strengdten any behavior linked contingently 

to it(16), Second, thefinding that only a limited 

number .of brain sites support such brain stimulationreward 

(17)) strongl)•y implies that there arc anatomically specific circuits 

in the brain dedicated to the neural mediation of reward 

or pleasure (18-20) . Third„the lhct rhatelectrical stimulation 

of braii7, reward sites can also evoke natural consurnmatorybchaviorssuch 

as eatingand .drinking (21-25)implies 

.that sucheleetrical stimulation activates neural systems 

involved in natural reward'and motivation . 

Evidence that habit-forming drugs.might derive theirrewardingproperties 

byaaivating such brain reward circuitswas presented less than 3 years after thediscovery ofthe brain . 

stimulation reward phenomenon (27) and has been amplyconflirmed inthe more dianthree decades since 

.(see below) . 

This acute enhancement of brain reward mechanisms now 

appears oo be the single essential pharmacologic commonality 

of akusable substances; androhe hy,potlnesis .uhat abusable substancesaet 

on these brain mechanisms to produce thee subjective 

reward that constitutes the reiiaforcing "high" or "tush°or 

."hi2' sought bysubstance abusers :is, at .present, the mostt 

compellingg hypothesis available on the ncurobiology of sub-stance abuse 

. (28 :-31) 

.Theretnainderaf this reviewaddrecsesvarious :aspects of 

this .unifying,conception of the neural nature of the :positsvc 

reinforcement engendered by sclf-adntinistration of abusable 

substances . 

DRUG REWARD MODELS-SELF- 

ADMINiSTRATI~ONIOF ABUSABLE 

SUBSTANCES BY LABORATORY ANIMALS 

As stated above, untilapproxirnately 200 yearsagq ;s thee 

standard explanation foo compulsive substance abuse emphasiud 

predisposing internal .drives within thrsubstancc ~ 

abuser that drove himurher to abuse drugs . Additionally, a ~~ 

second' aspect to the standard l 1950s attd 1960s explanation . WJ 

forsubstaneeabuse was that substance abuscrs, .driven to .dntg : ~ 

use byy prcdiisposing internal states, soonbccamecauglit upin a vicious cyclrof drug adntinistration, 

.tolerance, phvsical CA '. 

dLpcndence; withdrawal, and ncadtntinistrationi Driven bythis r 

vicious.cycle, the substance atruser was .bclieved to scll'ad- W 

miitister abusaklu substances primarily, to ward off the um N 


ofdtug 

72~~ Part II: . Derrmtirurnts~s of SulJaranee Abtse 

pleasant cornsequencess of witladrawad- The cntphasis of thisexplanatory,ruliric was thus negative-oo ward off the ncgative 

physical consequences .ofdrug withdrawal . No .etmphasiso 

was placed ondie possibility that abusablc substances mightt 

have powerfial pacitivdy rcurforcingg properties . 

It was the demonstration that laboratory animals .wild voluntarilq 

and often avidly . self-adintinster abusable substances 

(6-9)that .decisivelyreoriented scientific attention to the 

positively rewarding properties of the drugs themselves . 

The Self-A'drnilnistration Paradigm ; 

orr against operant responding for saline .or veliicle admihis> 

tration . .For.somc abusable substances, acquisition of operant 

res .ponding .for sclf-adntinistratioo-.israpid and facile-the 

caaheterized laboratory animal,is siinplyy placed into :the .operant 

chamber and allowed to explore . Normal curiosity,and 

exploratoryoehavior soonresutt in an initiallyrandom'response 

on the manipulandum that deliversa drug injection : 

With the appropriate drug„dose, attd reinforcement :contingency, 

the animal experiences subjective reward, with resulting 

"selfshaping"of behaviorr to the motorr response thatt 

dchvers the drug . Self-administration of the . abusablec substance 

ensues, w ;th a c.haracteristic learning curve and char-acteristic 

.asymptottc self-adhunistration behavior . .For other 

abusable substanires (presurnabhy substances with a lowerimitial 

reward pote4cy), such "sdfleaming"doesnot~ tesultt in . 

reliableself-adrty{tistrationbehavior . In such cases, other experimental 

procF4dures are followcdl to obtain reliable selfadministration 

btllavior . These procedures include : (a) trainingaheanimal'ftrsotorespondforatraditionalreinforcersuch 

- 

as food'.and thensubstimtting the drug reinforcer for the food 

(60) ; (b)) trainingthe animalfirst 

.to respond foranodnerdrugwith presumably higher initial rewardpotency and then substituting,thedrug 

under investigation for the original ditrg 

(52,65,84) ; (c) deliberately shaping the animal's operant behavior 

toward the manipulandum thatadministersdmtgs (65) ; . 

(d) usingnoneontiugent drug adhunistranion during the initial 

stages of the animal's exposure to the drug self-administrationaituation 

(85) ; (i) using an aversive stimulussueh .as 

footshock to initiate the operant responding for drug adntinistratiom 

(38) ; (f) using food .or water deprivation to encourage 

: responding on the drug-administering manipulan- 

Abusable substances can be .self-admiinistered by laboratory 

animals using a variety of administration routes : The 

intravenous, intramuscular, intraperitoneal, and intraccro 

bral injection routes have'all been used, as havc the oral iimgesrion, 

intragastric,, and inhalation routes : . The typical diug 

self-administration paradigm uses the intravenouss mute, im 

laboratory animals surgically implanted with chronic indwelliitgintravenous 

catheters. (6-9,32,33) . Most typically,, 

rats .(34',35),or rhesus mon krys (36--40) :are uscd, although 

other mammalian species have also been successfully used . 

(41I-43): Strikingly, animals will self-administerabusable 

substances in the absence of tolerance, physical dependence, 

withdrawal, or indeedlany prior history of drug taking :,The 

importance of this fact can hardly be overstated, because it 

clearly shows that drug-takiing behavior cannot be explained 

simply in terms of the abiliry of abusable drugs to ameliorate 

the withdrawal discomfort associated with abstinence from 

prior administration of such drugs . In addition, the use of 

operant conditioning,procedures .has s hown that animal behavior 

can be controlled by abusable substances in much the dum~(86) : 

; and (g) fustrnaking the animal physically depcndcnt upon dne 

same mamterthat food or water can control the .behavior of 

a hungry or thirstyanimal (e.g .,39)„with dte obvious caveats that 

drugs can produce nonspecific increases or.decreasesinr 

motorr behavior and that undcrcertain operant schedules 

self-administration (e :g ;, low fixed-ratio sehedules) .suc 

cessive dosesmay accumulate rapidly within the body, resultingin 

limitations on the rate of response (32) . With ratio 

schedules of operant: rcinforcement, responding by laboratory 

animalsfordtug selfadministration has .been demonstratedlfbr 

cocaine (39,44-47) ; amphetanvnes (39,43,4'8- 

54) ., ., other stimulants (55-56), caffeine (36), opiates 

(6,36,4'.1,45,57-64), ethanol (65-66), sedatdvo-hypnotics 

(36,44,67-70), dissociative anesthetics (71-72), and other 

abusable substances (9,33) ~ With interval .schcdulesofopcrant 

ncinforcement, respondingby laboratoryanirualsfor 

drug self-administration has bectudemonstrated for cocaine 

(47,73-77) ; opiates (7$-81), cthanol (80,8Z-83), scdarivchypnotics 

(70), and othcr abusable .substances (9,33) . As with 

human substance abuse, drug sdf administration in laboratory 

anirnalss is profoundly influenced by the subjeco's pnc- 

saline or vehicle forr the active drug and seeing 

vious experience wit lr drugand by the environmental context 

in whiclndte dtagadtninistration takes place (32) . 

Typically,, operant responding fordrug self admiitistmtion 

in laboratory animals is comparedwithoperant respondingon 

a control mattipulhndutn that docs not adnwtistcr drugs, 

.dmg byprogpammed drug delivery and thervallowingthc 

animal to .respond for dtug .injeetions after the .terminationof 

programmed delivery(6)1 Some .authorities have 

argued that the use of such procedures constitutes less rigorous 

demonstrationss thatt a drug can serve as a reinforcer 

(3a),. Such arguments are debatable. So long .as~dte final drug 

sdf administratidnbehavior obtained is reliablyhigher than 

operant rapondijtg on .a control manipulattdum that does 

not administer .dr(tgs, or .higher than operant responding .fior ` 

saline orr vehicle a4trtinistration, .tlne laboraoory "tricks" used 

to initiate or faci+itatee initial operanr responding for drug 

reinforcement:wo(~Id seem more related to initial reward .potency„ 

whichean 6ave significant pharmacokinetic as .well as 

pharmacodynamu components, than So basic reinforcement 

value. No:mattcnltow the .drugsclfadnunistrationis inioiatcd, 

it can casily be determined whether the contingent drug 

administrationn is truly reinforcing the operant behavior by simply disabling the drug delivcrysystemor by substituting 

.whenher bc-~havioral extinction (cessation of responding) occurs ., lf the ~ . 

drugg is scrving,asla reinforcer, cxtincuon ensucs . If the drug CA 

is not serving as a~ ~ reinforcer, die behavior continues una- )& 

batcd . Extinctton'of drug-rcinforced responding follows a r6 

highly characterisoic patrccrncssuntially identical tothat .ofw, 

extinction of food- or watcr-reinforced .belnaviord an initial ~ . 


7 / 6a .vN REwA¢m Mecwnrusnts 73 

i?i.;'; 

iincrease in, response rate (frustrative nonrcwardl bchavioral 

augmcntation ), followedd by decreasedd responding attd! tdtimate 

.totallccssation of resprrnding~ Recent demonstrationss 

tlhat .extinction .of responding for direct intracranial electrical 

oraiin .stimulation reward .follows :tfie same hiighlycharacteristic 

behavioral pattern as extinction of drug-reinforced re< 

sponding( ;87 ; see :also discussion of this point below) . arc an 

important element of the argument that drug self-adminisn oration activates the same braimreward mechanisms activated 

by electrical brain stimulation reward . 

Characteristic Patterns of'Drug Intake in the 

Self-Administration Paradigm 

Patterns of drug intake in the self-administration paradigm 

in laboratoryanituals vary with drug class (33) and are 

provocativclysintilar to intake patterns seen in humans : With 

unlimited access to :opiates, self-administration is quite uniform 

and constant, characterized by moderate and measured 

self.administrattion of modest dosess without voluntary abstinence 

periods. (36,88) . Ih contrast, unlimited self-adtninistration 

of stunulants . (coeaine, .amphctacrtines, methylphenidate, 

caffeine), is charaeterized'bya4terrtating periods of drug 

intake.and .dmg abstinence (36,50,52,89-91) . Duringdmg 

intake periods theself-administration behavior often reaches 

frenzied levels,accompanied .by characteristic dopaminergic 

behavioral stereorypes„markedlyreduced food and water intake, 

and total lack ofslecp . During drug abstinence periods ; 

a seminlance of normal eating,drirtking,,and sleeping returns . 

The alternating drug intake and drug abstinence .periods can 

continue for months and markedly resemble the alternating 

tiinge and abstinence pattern of human stimulant abuse (925, 

Unlinnited ethanol self-administration in anirmals :is also.characterized 

by alternatting binge and abstinence periods (6S)~ 

Unlimited barbiturate and dissoeiative~anesthetic (e .g ., phcncyclidine) 

: self-administration in animals is dtaracterizedlby 

maxiinumself-administrationaf available dmg, .witlnout abstinence 

.periods (3Yrz~68,93) :. Unliinitedlban.odiazepine sel[ 

administration is characterized by very modest intake pattcros 

. (68) : . .Given the right reinforcement schedule and dose, 

nearly alllintravenously,self-administered dmgscan be consumcd 

bvlaboratory animalsto rhe point of toxicityand/or 

dcath,(36,52',65,88) . The death .rate from unlimited stimulant 

self-adnwiistratiorvis veryhigh ;,that :from opiates, ethanol, 

and barbimrates is :considcrably Itvwer, .although still signif 

icanc . When drugavailability, is litnited!toa preset daily session 

; drug :intake .temds to be stable from sessiomtoscssion . 

Within each session, drug intake patternvariesn with drug 

class . Opiate self-administration is measured andsvcady,, .whilc 

stimulant self-adntinisuation is .clnatac[eriacd .by "mini-binges" 

at the start of tcso sessimns followed by more measured selfadnniinistratiomforr 

the remainder of the session : WithdifEcrcntdoses 

available during different test sessions, drug intake 

appears to be regulated by the animal to produce fairly uniform 

aaual dmg,intakc.overa broad range of doscs, a plicnomenon 

that has becn interprcted as supportingvhe concept 

that laboratoryanunals self-administer dmgsto~nuirntain a 

constant blood :and .braiinlevel (94) . 

Essential Commonalities of Substamces5eif- 

Admilnistered by Laboratory Animals 

Ah}nou,gt CboniinlAbmsrdr lists millions ofdifferent known, 

chemicals ; rhe number of chemicals voltmtarilyself-adtnin-istered by laboratoryanimals is 

.onlya startlingly tiny fraction, 

of that number-in facr no :more than a fewscore com-pounds (8-9,33) 

. 

. Also, the chemicals~s voluntarily selfad-ministered'by laboratory animals differ strikinglyfromeadu 

otherr in chemical structure and pharmacologic class 

: (a) what .do these . The fol-lowing questions obviously arise s41M=administered 

compounds have in common, and (b), whatt distinguishes 

these compounds from the millions of other known 

compounds? The answers appear to be :threefold First, atthough 

there are inexplicable exceptions (33), by and large 

the substancess that .t are voluntarily self-administered by laboratory 

animals are the same ones : that human beings also 

voluntarily self-administer (8 ;9;33;95-99)„and by and large 

the same drugss that are .eschewed by animals are also es, 

chewed byhumans. Second, virtually all adequately studied 

abusable substances (including opiates, cocaine, amplnetatninas; 

dissociative anesthetics, barbiturates, benzotllazepines, 

alcohol{ and marihuana) enhance brain stimulation reward 

or lower brain reward thresholds in the mesotelencephalic dopamine (DA) 

.system .(28-3'1,100-110)~(also:see .further 

discussiomof this topic below), 

. Tlnird, virtually all adequately studied abusable substances enhance basail neuronal' Gring, 

and/or basal ncurotransmitter release in reward-relevant brain 

circuits ( :102,1111-121) (alsoo see : further discussion of thistopic below) 

. These essential commonalities of substancess 

self-administered byy laboratory animals are important ele-ments in the theorythaty drug self-administration activates 

the same brain reward mechamisms activated by electrical braio 

stimulation reward and that these mechanisms include a me-sotclencephalic DA component that runs through the medial 

forebrain bundle (see below) : In thislast regard, it is 

.com-pelling that animalsvolhntarily self-administer dte DA 

;122- 

.rcup-take blockcrs bupropion, mazindol, and nomifensine (55 

127),, as well as1-{2-[ bis(4-fluorophenyl)me[hoxy]cthyl),4- 

(3-phenylpropyl)piperazine (G6R 12909), a higlrly selective 

DAreuptakc blockcr (1;28-129), It is similarly compelling 

in this regard that animals also voluntarily self-administer direct 

DA receptor agonists .suchas apomorphine and piribedil 

(84,130-133) . 

An interesting varianr .of the drug self-administration paradignn 

in laboratory aniiatals isonc in which tlnedmg infusion 

is delivered automatically and the animal can voluntarily rea 

spond to:renninare the infusion (134) . )ustas the volluntary 

sclf-administration paradigm .assesses the positivc rewa~rd'of 

drugs, thiss voluntary tennination-of-infusion paradigm as: 

sesses the ncgativc reward valuc or avcrsive property ofdrugs . 

Interestingly, sonic drugs doo act as negative tciinforcersiin 

this paradigm (134 ; l35) :. Most such drugs,,which may thus 

be iinfirred to have negative rcwardlvalue, are DA antagonists 


74 Purr IL. Dci~niaun+fi . uf Subttanrc Aibusc 

sucL aschlbrprontazine :and perphenazine (134,135) . Most 

humans find such drugs dysphorigenic (136-137) . -17ncse . 

findings are additional important elements im dic tlteorythat 

the brain reward mechanisms 

.activared by drug self-adnnin-istration include a crucial DA component (see below) . 

Altesation of Drug SeUf-AdFninistration by 

Pharmacologic :on Neurobiologic Manipudations 

One of dne many approaches usedlto unravel the ncuroan . 

atomic, neurophysiologic, and neurochetnical substrates of 

drug-induced reward hasbeen to attempt to, alter systemic 

drugg self-administrationn iit laboratory animals by pharmacologic 

manipulations or specific braimltsions . Obviously, 

when attempting to alter drugself-administration by adtninistering 

anotherphatanacolbgicagent, one hasto :be alert to 

the possibility of nonspecific drug effeceson behavior . Tlius, 

a compound theoretically could inhibit an, animal's lever 

pressing or bar pressiitg for drug injections simply by being 

so powerful a sedative as to inhibit all motor behavior in a 

nonspecific fashion .,The key, then, to inferring a specific ef-fect on 

.drug-inducedaeward is .to look for specific cffectss on 

behavior maintaiined .bydrug reward (33) . Thus, pharmacologic 

manipulations that augment the reinforcing properties 

of a self-administered drug will selectivelysuppressdrug, 

responding . (similar to increasing the unit dose of the 

:self-adn»nistcred drug) without altering other behaviors, whik 

pharmacologic manipulations that diminish the reiioforcing, 

properties of a self-administered drug will sclecdvelyincrease 

drug responding (to compensate for the reduced effectivencss 

ofdte self.adminisucred drug)) withoutalteriiug other 

behaviors . Amanipulationtlhatcomplctelyabolishes dte reinforcingg 

value of a self-administered drug should produce 

characteristic extinction of drugqreinforced responding-ann 

initiall increase in responsee rate. (frustratdve nonreward behavioral 

augmentation) followed by decreased respondutgg 

and, finally„ cessationn of responding . Not unexpectedly, 

administration of opiate antagonists (e .g., naloxonc,naltrcxone) 

too animals :sdf-admiiuistering morphine or heroin produccs 

characteristic extinction of the dtugresponding(57,81,138-140) L Provoutively,, antibodiesto 

. monphinee also . 

produce a paroialkxrinerion•likc increase iniheroiit intake (141) . 

Pharmacologic challenges that specifically dismpt individ-ual 

.ncurotransmirtcr .systcros obviously can yield impot¢antt 

information on dxe 

neurochemical substrates of drug-in-ducedlreward 

. Iot the many reports in which such neurotransmitter-specif[c 

plnammacologic manipulations have been paired 

with drug sclf-administration in laboratory animals, a striking 

conumon thread stands out-pharmacologic challenges 

that disrupt brain DAsysocros interfere wiah the reward value 

of sclf.administcred dmgs :Thus„ a-methyl-para~tyrosine 

(aMPT), aDA snmtlicsis inlnibitor„initially produces a partial-cxtinction-likc 

incrcasc in cocainc .or amphetamine sclf 

adntinistration, folloi .ved byfull extinction of thc sdF administcation 

behavior as tdte a1w1pT dose increascs(142'-144) . . 

Similarly, gradually inrcasingdoses g of the D1'\ antagonis t 

pimozide produce an iioitial dose-dependent increase in selfadministered 

antphetatnine intake, followed,at higher dosesa 

nycessation of sclC adttunistration ( 

:145)~- The stcrcoisomers (+)butaclamol (possessing potent DAA antagonism)~ and . 

(-)butaclamol (dcvoid of DA antagonism) ; have also .been 

used toassrss DAsubstratcs of drug-induced reward (146) . 

In these studies, (+)butaclamol produced pattiall and then 

complete extinction of amphetamine self-administration while 

(-)butaclamol had no. effect on amphetamine self administration 

(146) . Similar patterns of increased drug self adnninistration 

after low-dose DA blockersfollmwed by decreased 

drug sellf-administration after higher doses have also been 

reported frotn adarge .numberof laboratories for.animalksdf 

adrtunistering a wide : range of abusable substances, including 

cocaine, amphetamine, and morphine (130,139,147- 

160) . In contrasr, noradrenergic blockers havee noo effeat on 

drug self-administmaion in laboratory animals (e .g ., 

144,14(u,147;150,152) . In humans, DA antagpnisrs and DA 

synthesis inhibitors mltvttt the euphorigenic effects of atleast 

some abusable substances ( L61-164) . 

Anotherapproach to pharmaeologic manipulationofdrug 

scllf-administration in laboratory animals is the administra-tion of neurotransmitter-specific agonists 

: Therationale for 

thiss approach is tliat of substitution-just as noncontingent 

adrninisration of amphetamine temporarily decreasa 

. am-phetamine self-administration, so too should a, neurotransmitter-specifac 

agonist thatt activatess the: same brain rewardd 

substrates tetnporardydecnease dlntg self-adminisnarion . Such, 

in fact, is die case . Noncontingent administrations oftheDAf agonists apomorphine or piribedil 

. dose-depend'cntly decrease 

amphetamine sellfadministratdon (84) . 

A further .approach to elucidatingthe .neurochert>;cal sub• 

stmtea ofdmg-inducedlrewardlis toarudl/ the effect on drug 

self-administration of selective lesions, induced eidterr surgically 

on pharmacologically, ofspccific neurotraumirctersystems 

in the brain . .Obviously, suchstudies .also help, toducidate 

the neuroanatomic substrates ofdrug-induced reward . 

Such studies typically are oftwo rypes . One type has assessed 

the effects of brain lesions on stable, previously acquired drugg 

selfadministrati©n, while the second type has assessed the 

cffect of brain lesions on acquisioion of drug self=adininistra-tion (165) 

. In such studies, the use of neurotransmitter-spe-- 

cific ncurotoxins to produce the desii-ed Iesion is generally 

preferable to nonncurotransmitter-specifuc knife cuts, electrolytic 

lesions, orthermoeoagplative Iesions(165) . Whem 

the catechoiamine-specific ncurotoxin 6-hydroxydopamine 

(6-OHDA) is .uscd to selectively produce :lesions of the IDArich 

nuclcusaccurnbcns, cocaine self-administration is : disrupted 

but self-adininistrarion of the direct DAreceptor agonist 

apomorphine in the same animals is unaffected (166) . 

Similarly, when 6,OHDA .is used to producelcsions of the 

DA-ricli ventral tegmental arca„cocainct.self administration 

is disrupted' burt apomorphinc . sclfadministratiom is unaffecrcd 

(1~67) : 6-OHDA lesions.of otlnerbrain sites doo not 

affect cocaine sclf-administration (165-167) . These data argue 

that cocaine sclf-administration, is critically dependenr 

upon a highlvspecificy subset of the DA wiring.of the mammalian 

brain-thc mesolimbic DA systemy .which originatu . 

2023451138 


7 / BSIAIN REwARDMECnANISMS 75 

in the.ventral tegmental'area .and,projects totlte .nucleus ac- even endurepain ta.reacli the lever that delivers brain .stimcumbcns(168) 

. In .animals with 6 :-OHDA .Icsionsofeither mlarionreward Response .ratesofanimalssclf-stimulatingfor 

of these two DA lociy tlleexocnt .of 6-OHDiA-indlrced DAelectrical brainreward arc extrcmely,higln, often in excess of 

dcpletioninthenucleusaccmatbemsishighlyprcdictivcofdle 11001everpresses .pernuinute .Insllort, 

.self«adntimistrationL The ulation reward is .ones of the most powerful .eltctricalbrains[im-druratiwn of currtailnlent of cocaine rewards ktoown 

greaterthe .DAdeplction;thelongerthealtitnal .takes.oore- to .biology; .rivaledonlybydxrewartengendtredbythemost 

cover drug sdf-ad}ninistratiorn behaviory and animalk .wiifi powerfulself-adtninistereddrugs(e .g .,cocaine) 

. DA .loss(more than 90%) , often fail to recover man studies of'electrical stimulation of brain reward .Theftwhu-the greatest areas~ 

atall( .165) .6-OHDAlesionsofthcnudeusaccumbensal .ko confiruudiis ;thehumanexperiicnce .beingoneofiotensesubblockacqpisitionofamphetantineself-administration(1169)i 

jective pleasureorcuphoria (176)- 

Heroin and, morpHiine self adrninistration in laboratoryani . With simple operant schedules of reinforcement,, lever 

tnalshave been similarly demonstrated tobe critically dt :pen, pressiing fbrelectrical brain stimulation reward extinguishes 

dentuponahefiunctionaliintegrityofthe .mesolimbicDAsys- usentiallyimmediately upon* terminatiomof the reward, 

tem~(170-172) . It is compellingthatg the mesolamliic DttA without the normal . frustrative nonreward increase in resystem~constitutesacriticalcotmponent', 

ofthe .rewardsystcltnf sponding .thateharaeteriustheearlystagesofextinctionto 

ofthemammalianbrain(29 ;3L,110.1,102;see .also.discussionf lever pressing for food, water, ordrug,reward . For many 

below). Ih .this regard, the above-reviewed data suggcst that years, this was a major conundrum, with some workers arfunctional 

blockade ; either pharmacologicallyind'uced or Ic- guing .that this distinction between electrical' brain stimulasion 

. induced, of brain reward substrates is the important tion reward and drugsclf-administration reward implied that 

comtnonality of manipulations that block systcmic drug self- different brain substrates are activated by the two types of 

administration . .Hence, .studies in which alteration of drug reward . Recently, however, Franklin and Lepore, .in .an ex 

:-sdf-administration hasbeen achieved by pharmacologic or trcmeliy important study„haveshown that the rapid extinc-neurobiologic manipulationsare important elementss in the tion of brain stimulation reward behavior on low-ratio retheory 

tHe drug ;self: administration activates the same brain- inforcement schedules is essentially an artifact of the immediacy 

reward mechanismss activated by electrical brain-stimulation of the electrical brain stimulation reward and of tHe operantt 

remvard and that these brain-reward .mcchanismsinclude the behavioral schedulestypically used' in~brain stimulation remesoliinbic 

DAsubsystem thatruns throug(i the medial fone- ward studies (87) . The paradigm develbped by Franklin and 

brain bundle (see belbw) . Lcpore, termed sdf-adminisrration ofbrain-rtfmulation, delivers 

rewarding electrical brainstimulation in amanner dt:lio- 

T'HE UNDER'LYING NEUIROBIIOLOGY OF eratelydesignedtomimicthepharmacokineticsofdmgxlf- 

DRUG REWARD-ELECTRICAL $ELF- administration as closely as possible . The animal's first re- 

OF BRAIN REWARD CIRCUITIS sponse on tltebrain stimulation reward lever turns on the 

$TIJv4ULATION 

brain stimulator, wlnichthen stapss penmaneutly on for the 

The Electrical BYaini$timulatiomiRevwarcli durateonofthetcsnscssion,delivering ;acontinuoustraimof 

Parad igfm biphasic pulse-pairs of reward Ing stimulation . However, the . 

frequency of the pulse-pairs decreases with time, in much the 

To .smdy electrical brain .stimulation reward„animals are samewaye that brain and .blood levels of a self-administeredd 

frrstsurgicallyimplantedwithchronicindwellingintracranial drugdecreasewithtime .Successiveleverpressesinereasethestimulhting electrodes in specific 

.brain .loci, allowed to re- stimulationfrequencybyapresetamount.Sinceforanygiven 

coverfromthesurgery„andthemtrainedtoselfadminister setofelectricalstintudationparanreters .(puLse 

.pressingorlever eoc .)tlnere.isaraltgeofstimulationfrequencies .widtlt,current,t tlnerewardingelectricallstimulationbybar .tlnat .is :optipressiing 

in a .standard operant chamber. The trainingteclt- mallyretvarding, animals in this paradigm typically press the 

niques typically used arc essentially identical too those em- lever enough timuto bringntte frequency into the optimal 

ployedtotrainanimalsfordmgselfadmunistration(sceabove)d rangeandlthcnwait.whileitslowlydeeays(inmuchthcsame 

Acquisition of lever-pressing for braimstimulation reward .is fashion that animalson dntgself-adnunistration wait for drug 

vcq rapid, .wirh hig/t asymptotic.operant levcls . Volitional reward to .decayaffer taking a few"hits°) . When the stimu 

self-administraoion of the rewarding electrical stimulation 

; lation, frequatcy hass decayed cnoughrto bring it out of the No&cntcrmcd''Iirstrarnaui,alrey-rrimul'ntiun,iseasilymaintained rewardingrange,theanimalstypicallytakcafcwmore"hits" C'by sinnplce operant schedules of reinforcement 

. . Thee reward on the lever to : bringg the stimulation back once agaiin .oo the 

engendered by such,stimulatibn, and tlie brainsubstrates that optitnal rangr . .ln this paradigm, whichso deGberatelymodelS C03 

support it,, have been much studied and well characterized the pliarmacokinetics of drug self-administration, extinction N 

overtlnclast35.years(173!-175) .Withdectnoder.inThe :proper is essentiallv identical to extinction of'~drug-reinfiorced be- ~ 

braiin loci (see below), such direct brain stimulation reward haviior, ecomplete with am initial fuilstrativee nonreward in- ~ 

is intensely powerful . Hungry animals ignore food too get it crease in responding .followed'by aslowdecrcase .andultintate Ca 

andthirstyatnintalsignorewatcrtoget.it,instrikinglysimilar cessationofresponding :Theimtponanceofthis"srlf-admin- ~ 

fasliion to .the way in wbicivcocaine self-administering ani- istration ®fbrain stimulation"paradigtn can hardly be .overmals 

ignorc food and water during a drugbingc . B.nimals statsd,for-itshowstlnatonccthe"pharmacokincaies"ofclechttp://legacy.library.ucsf.edu/tid/xbd67d00/pdf

mutitlationteward aremade to emulate ttaose of 

lr` 

drug(xeivard,'tlne 

'YOr!^+- 

diffcrence between the two rcwardparag¢rsdisappears 

. In view of tluse recent developments, th e hypothesis that drug reward and brain stimulation rcwar 

activate ducsame brain rcwardisubstrates appearsmorc cotnpelliing 

than ever- 

The Neuroanatorny and Neurochemistry of Brain 

Stimulation Reward 

The neuroanatomic substrates of direct electrical brain 

stimulartiou reward initially were unclear . Early anatomic 

mapping,stttdiesof the brain for positive brain stimulation 

reward sites, carriedout in the 1950s and 1960s, demons2rated1tltatelcetricalibrainreward 

could benhcited in laboratory 

rats, cats, and monkeys from a wide variety of brainstem, 

midbrain, and forebrain loci, induding the ventral 

tegmental area,substantia nigra, hypothalamus, medial Iforebrain 

bundle, scptum, amygdala, neostriatum, nudeus accvmberus, 

ventral forebrain olfactory nuclei, and portions of 

the cingulzte cortex .andfrontal'coroex (17,177-182) . Such 

a~ liodgepodge of sensory, motor, limbic, midbrain, dicncephalic, 

and cortical dbmaiias made littlescnse at the .time; 

although even the early workers noted that the vast majority 

of brain sites positive for electrical brain stimulation reward 

correspond to the aggregate of ascending and descending, 

traets that comprise the medial forebraim bundle, the nudei 

and projections of which extend from brainstemrto cortex . 

Then, in the mid-1960s„pioneeringScandinavian neuroanatomists 

began to illuminate the monoaminergic anatomy of 

the brain using the newk, developed .neurotransnuoter map 

-ping technique of hisroFluorescence microscopy (183-186),, 

and a striking correspondence was noted'between sites positive 

for brain stimulation reward and themesotdencephalic 

DAsystem, the major portions of whichare carried through 

the medial forebruin bundlefromthe ventral meseneephalbn 

totlne liinbic and cortical forebrain (168) ~ 

Guided by this anatomiccorrespondence, workers in many 

laboratories began to study the effcctsof pharmacologic ma 

.neurotransmission on brain stimulation re--nipulation of DA 

ward. In 1969, the author and his colleagues found that se- 

Iccrive irdaibioionof tyroslne hydtoxyl4se profoundly inhibited 

brain reward in monkeys, but thatsclective inhibition ofDA 

p-hydroxylase did not„promptingthem topostulate that brain 

reward was critically dependent upon the functuonal iintegrity 

of DA rneurotrarnsmission . In 1972, Crow suggested thar~ dirca 

activation of the ccll bodies or axons of thcmcsolimbic 

and mesosttiatal DAsvstcros was rewarding, andthat DA 

was the crucial ncurotransmtrter of at least one major reward 

system in the braim(187) . In.19810, Corbcttand Wise, using 

movable electrodes to map brain reward substrates in : the 

vcntral mcsencephalon, showcd.that brainstimulation rcward 

tliresholds were afunctiom of the density of DA clcments 

surrounding the electrode tip (188) . Also.compclling 

in this regard arc the factsdnat DA blockade disrupts brain 

stimulation rcward .atall brain sites adequatelytcsted (189! 

191)„ and that„following DA dcncrvation that abolishes ncostriaral! 

brain stimulation .reward„direco electrical brain re 

can be restored intite denervated tneostriattmr by DA-ward 

reinnervardon front cmbryoniesubst antia nigra transplants 

(:192).From these studies and literally hundheds ofother experinucnts 

.(31,102,191,193-195) . it hasbeconnc abundhrttly 

clear that brain reward is, in fact, critically dependent upon 

the futtcuonal integrity ofDA .ncurotransntission within the 

mesotelenccphalic IDA systems ; with the mesolimbic DA system 

constituting a particularly impo rtant focal point within , 

these Urain n-ward systetns . Compcllutgly,DA blockade mimic 

ricallinocnsi ty ofthe reward-ing brain stimulatiorv(190) . 

the effect of decreasing the clett 

Howeveq the original supposition of many researcher 

s ethat electrical brain stimulation reward dancrlyactivates th 

DA fibers ofthemcdial forebrain bundleis very muchopett 

to question„with the preponderance of evidence being contrary 

to that supposition. This evidence d'erives from the elegant 

electrophysiologic studies ofGallistel, Yeomans, Shizgal, 

and their colleagues (196-200), whi&argue persuasively 

onelccorophysiolbgic groumdsthatdte primarytnedial fmrebrain 

bundlesubstrate directly activated byeiectrdcal brain 

stimulation reward is a myelinated,caudallyrvnniitg fiber 

systcm whosc neurons have absoluterefractoryperiods of0 .5 

to 1.2 msec and localpotencialdecay time constants of approximatelip 

0 .1 msec. Since none of these neurophysiologic 

properties agrees with those of the ascending mesoteleucephalic 

DA neurons ofthe medial forebrain bundle, Wise and 

his colleagues have argued that the DA neurons cannot be 

the `Yirst stage° reward neurons preferentially activated by 

electrical brain stimulation reward, but must instead constitute 

a crucial "second stage" anatomic convergence witlnim 

the reward circuitry of the brain, upon which the "frrst stage" 

neurons (those prcferentiallh7 activated by rewardingelectri 

-cal stimulation) synapse to form an "in series" reward-relevant 

neural circuit (29,1101-102) . It is on this °sccond stage" 

DAconvergence that abusable substances appear toaa to 

enhance brain reward and produce the eupltorigenic effect 

stharconstitutc the "h igh" or "rush" soughtby substance abusers 

(29-31,101,102,191 ; see also discussion below) . Fur 

-thermore, itseems likely that onlya smalllsubset of theseDA . 

ncuronsare specialized for carry,ingreward-relevant infor- - 

mation (102) . Although apparently preferentially activated 

by abusable substances, these DA substrates also appear capable 

of direct activation by electrical brain stimulationreward 

under the properiaboratory conditions (201) . Figure 

7.1 illustrates some of the DA circuitry of the forebrain involved 

inthcse reward mechanisms . 

E(fects of Abusable Substances on Brain 

Stimulat'ion Reward 

Anumber of paradigms ofelectrical brain stimulation neward 

have been used in thc laboratory to study,dte effects of 

abusablesubstanceson .thcsebrain rewardrrtechanisms (sce 

102,202 for revicws and discussions) : Unfortumatcly,most 

carly,smdics (innost6y inthe1950sy 1960s,and earlyP970s) 

used simple response rare measures for braiin stimulationo f 

Z023i45114Q 


7 / BantN RewnttID Mr.cnnnusntS77 

Prelrontal 

conex 

Anterior 

dngulale contex 

Corpus 

callosum 

Hippocampus 

©Maciory 

tutlerae 

Pyriforrn 

cortex 

Locus 

\coeruleus 

laleral parabrachial 

Central ~ \ nucleus 

nuGeus Enlorhinal 

amyqdala uortex' . 

Figune 7-1 . The nnesolelencephalie dopamine (DA) cincuitryo( the mam, 

maliam (lafioratoryy rat) ) brain. The primarybrain.reward-relevant .ponion 

appears to .be a subset of themesolimbii'.projections'.origihating,in the 

ventral tegmental area pDAnucleus AhOi .and terminating,in the .nucleus 

accumbens . (Fromfooper JR ; Bloom FE . Roth RH . The bioahemica4 basisof neuropharmacology 

with permission .)) 

: .5lh ed . New York : Oxford UniversityPress, 1986, 

fixed voltage orr aurent .and fixu ed stimulation frequency : Such 

simple response rate studies were inadequate on many grounds, 

uottlne least being that ruanyabusablc substances are strong 

sedative-hypnotics andhuany others are strong psychomotor 

stimulants . Such compounds may spuriously produce ded pressed or cntnanced 

.respondingfor brain reward in asimple 

response rate paradigm due simply to nonspecific motor effects 

. Asa result, much of the eardyliterature dcalingwith dle 

effects of abusablh.substancesonbrainreward is either very 

difficvlctointerpret or, worse still, leads to incotrectconclu, 

sions': For these reasons, attention in recent .years has shifted 

to threshold measu res, response pattern analyses, choice measures;' 

curveshift" raoe-frequency function measures analo : 

gous to rhe dosc response paradigm of traditional phatmacology„ 

andd a host of other conceptually similar but 

operationallyy distinct brain stuntdation .reward paradigms (see 

102,202~ forr excellent discussions andcomparisonsd among 

these paradigms) . The author's I'aboratory has used a number 

of variants oft,he dJ'crcmcntal tiirating-tlnreshold brain .reward 

pardigm, corrmionly known in the brain .reward literaturc 

asthe "autoti2ration" paradigm, which wasdeveloped 

bySocinand .Ray . (2'03) . .Imonr.of thc autotitration variants 

used (107',108r1110,204-207'), tloe animal presses a"rewardt' 

levcrto self-administcr'a~bnitf (300 msec) train of rewarding 

braiin .stimulaoion, which automatically decreases in intensity 

witli cach succrssiveievcr-press . When tlnis .decremental stimulation 

passus'.through the.tlnresholdlfbr activating the umderlyingncural 

substrarr.of reward, the animal presses a"nesct" 

ltvcr that does nor deliver any brain reward bute resets 

the brain reward inrensity'back to~its initial ll :vcl . An analysis 

of"restt" valuesprovidhs 

.a measure of the activation thresh-old (in microamperes of delivered current) of the neural systemsubservingbrain 

reward .ehat isindcpendenb of ruponsee 

rateamd diusindependernt of the incidental sedation or incidental 

psychomotor stimulaoion produced by many abusablesubstances 

. In another autotitration variant(208-209)y 

the "ieset" of bnain .reward intensity back to initial level is notn 

controlled by a second lever but rather by a time dtlaycircuit 

that'.tniggers only when the andmal stops responding on the 

"reward" lcvcr.for a~preset Icngth .of time (e.g ., 5sec) . Since 

animals will respond fbr even marginally rewarding brain 

stimulation rather than none at all, this paradigm tends to 

give a more accurate measure of truethreshold ratherdnan 

threshold of x preferred range . Usingthcse paradigms, tlie 

author has studied tlic effects on brain stimulation reward 

of a wide range of abusable substances, including cocaine„ 

amphetamines, opiares,, barbiturates, benzodiazc 

pincs, kctamiinc, pbcncyclidinc ; alcohol, and marihuana 

(107, I08,110 ;205:-207) . I n evcry . casc, :robust enhancement 

of brain stimulation'reward .is seen . Similar robust enhance- N 

mcnr of brain' stimulation reward by representative com- N 

pounds from virtually everyy known clhssof abusable sub- ~ 

stancc has alsobcen rcportedd frtonn a vcry largce number of ~ 

othcr .laboratories (fbr reviews, scc'.29-31,100,191,202 ; sce N- 

adso.107,1 190, 2'.10-22G ) L 

Arguing Iwrsuasivcly for the vicwthat all abusable sub- ~ 

~ 

stanccs act.by facilitating a comrnon brainreward substrate 

is tlie Gnding that abusable substances ofdiffarsnt pliarma- r 


78'Pari IL . Detrrntinant.r of Substantc Abtuc 

cologic categories (e .g-, opiatcsandstimndattts) have a synergistic 

effect onbraen stiinularion neward thresholds whenco-administercd (212 

;223) . 

Arguing persuasively forthe view th at facilitation of brainn 

reward mecltanisnus iss closely rclatedd to ~ abuse potcntiall are . 

fiiudingss with thee class of compounds knownn variously as 

opiate paroiat',agqnistsor mixed agonimantagonists . This.class, 

synthesized in large measure as part of a deliberate effort to 

develop effectivenarcotic analgcsics :withlittle or no abuse 

potential, contains some compoundss that in fact appearr to 

possess no abuse potential and others thatt do possess abusee 

potential (227) . .In this class, the brain stimulation .reward 

paradigm discriminates nicely betwecn those compounds 

having abuse pooential''.and those devoid of it . Specifically, 

the abusablc: substance pentazocine lowcrss brain rewardd 

thresholds while other mixed agonist amogonistslacking abuse 

potential (e :g, cydaaocine, nalorphine) do noc(220) . 

Am intriguing finding is that brain-stimul?ttion reward 

undergoes an age-related, decline (2116-217), which is reversed 

.by a single dose oftLamphcramine(21fi) .. It is :temptingto 

.conclude that this age-relatedldecGne in central reinforcement 

mechanismsmaycorrelatewith age-related declihee 

in central DA function (228), whichis temporarily . resroredl 

by acute amptietamine: 

A striking fundingof many different laborarories .is .that . 

DA antagonists, such as neuroleptics, irthibit electrical brain 

stimtilation reward of the medial forebra'tn bundle and associated 

DAloci (i .e ., raire brain neward thresholds) un a manner 

that appears diametrically opposite to the enhancement 

of brain stimulation rewardl(loauring of brain reward thresholds) 

produced by substances of abuse . This is arobust and 

rephcablt .finding, firso repcarted130years .agoby Stein and 

colleagues (203,211) and replicated many times since im a 

number of different laboratories (229-231 ; seealso .195e for 

a review of tliescand related studies andl Ibr ani impressive 

theoretical formulation .of the role of DAantagonismin .anhedonia). 

Such fundingsi coupled'with the hndings that amimals 

volitionally 2ernuinate infusionsof DA antagonists (see 

above), .and takenin the overall context of the fiindings .described 

above, are important elements in the theory that electrical 

.brain stimulation reward activates the .same DA brain 

reward .substraresactivated by drug self-administration, and 

that these substrates includNthe :mesollmbic DAreward systems 

of the medial forcbraiiun bundle . 

For some abusable substances, the dose ramgewirhirrwhich 

electrical Ibraiio stinmlation rcward enhancement is seen is relativcly 

narrow. Pltencyclidiiac and ketantinc, Ibr example, 

produce brainrewardlenhancement widtioa comparatively 

narrow range of low doses, .but they inhibit brain reward„in 

neunolepoic-like fashion,, at higher. doses (206), The author 

has .suggested that this Ibw-doser .brain reward enhancement, 

hig(i-dosebmin reward inhibition phenomenon in laboratory 

animals is homologous with thc"Iow-dose, good trip", 

"high-dbse, bad trip" phenomenon reported bystrcer .users 

of thcse .drugs . 

Provocatively, die author (107;108,205,206,213,23,2) and 

others (222,223,234 ; sec also 29,101) have lound that the 

brain reward cnhancement .produced by abusable substances 

(iiscludiing compounds in sudr differeno chemical and pharmacologic 

classes as opiates, amphetamines, cocaine, edianol, 

barbi tura tes„benaodiaaepiioes, . phcncyd id ine, and ketamine) . 

is in every case significantly attenuated by theopiaue antagonists 

naloxone or .naltrexomc . Naloxone not only attenuates 

thc .low-dose .enhancement of brain stimulation rewardlprodiuced 

by ket+atnine and phencyclidine but also attenuates the 

high-dbse inhibition of brain reward produced by these samedrugs (sec above) 

. 

.Naloxone also has been reported toaug-mcnr nemroleptic-induced inhibition of brain stimulation reward 

(231). .In view ofthe .naloxone-indueed attenuation of 

thee brain stimulauomneward enhancement produced by all 

knowirdasses ofabusable substances, it appears that :arrimportant 

anatomic and funceionall interrelationship exists between 

the crucial drug-sensi6ive "second stage" DA fibers of 

the neward system (29-31,102,191) and cndogenous opioid 

peptude circuitry„ andlfathetmore that thiss interrelationship 

is important for the brain rewardienhancement produced by 

aU substances of abuse, notjust opiates, and hence for their 

abuse liability . Anatomically, 

.there are many brain lbci where such a functional interaction between reward-relevant DiAA 

neuronss and endogenous opioid peptide neurons could :take 

place . Cell bodics„ axons„ and synaptic termiitals of enkephalinergic 

and endorphinergicneurons are found in profusion 

throughout the extent of the reward-relevant mesoteleneephalie 

DA circuitry (235, 236) . The author (237), and 

others (238,239) have shown that endogenous opioid peptide 

neurons :synapse directlvonto mesotclcocephahc DA axon 

terminals, fonrting .precisely the type of axo-axonic synapses 

one would expea .ofa system designed to modulate the flow 

of reward-relevant neural signals :through the DA circuitry . 

In addition to theDA axon terminal regions, other possible 

sites .of etilcephalimetgic-DAflunaional .interaction .utdude the 

DAcelllbody region of the ventral mesencephalon (194) and 

transsynaptic modulation via afferents to the ventral mcsencephalom 

from the region of the locus coenileus (29) . The 

author also believes that some DA neurons of the reward 

system may synapse directlyontoendogenous opioid pcpoide 

neurons located postsynaptically . in the .DA terminal regions, 

which may then carry the reward .signal .one synapsrtvrdter . 

The reasons for soo believingare threefold . First,, it hasbeem 

demonstrated (205) ~ thar naloxone significantly attenuates alie 

enhanced brain stimulation reward induced by chronic pharmacologic 

.up-regulauon of DA receptors in the mesolimbic 

DA system, suggesting .thaaa crucial naloxonc blbckable endogenous 

opioid peptide .link l ies efercnt torhe up-regulated 

DA .receptors. Second, it has .becn demonstrated (240) that 

naloxonesignificantly modulates behavioral responses induced 

bydirecrpostsynaptic IDA-rcceptor agonists in animals 

in which the presymaptic .DAGber system has been destroyed 

by selective lesions .of the .DA .mcsotdencepltalic system, again 

implicating a~crucial naloxonc-scnsitii+c cndogenousopioid 

peptide link effcraat to the ascending DA mesotelfneephalfc 

DA system . Third, Pickel and her colleagues havc recently 

presented evidence, from doublc-label electron .microscopy 

studies, suggesting,tltat a portion of the ascending mesoxc 

,i 

F 

Y 


7 / BrtAizJ lYSwnrtu Mccnraatsms 79 

lencepltalic DA.Eiberssynapsedirectlyonto endogenousopioid 

pepride neurons (241). Asinnilar.suggestion, again based on 

ultrastrucoural evidence .was made previously by Kubota .et 

al . (242)', Therefore, a likely site for tlne .interaction of abusable 

substances with thee endogcnouss brain opioidd mechanisms 

presumcd too functionally modulate the intensi[y, of reward 

.signalscarried through the DA reward system isin thc 

DAA termiinal regions of the reward-relevant ascending DA 

mesorelencephalic system, in reward-relevant synapses containing 

both an opioid-DAaxo-axonic link and aDA-opioid 

presynaptic-postsynaptic link 

THE CRITICAL NEUROANATOMY OF DRUG 

REWARD-INTRA'CRANIAL MICROINJECTION 

OF ABUSABILE SUBSTANCES 

Although it is possible to infcranatomieaites of drug vewardfrom 

studiessuch as these just described, there are other, 

more direct ways of studying the neuroanatomy of drug-induccd 

reward . Two.such ways involve direct intracranial .microinjeations 

of abusable substances, in the firsecasecoupled 

withh thee electrical! brain stimulationi reward paradigm and 

imm tlve second . case coupled with self-administrarion : methodologies 

. 

Effiects :oflntracranial Microinjections of 

Abusable Substances on Electrical Brain 

Stimulation Reward . 

When makingintracranial microinjectionss of chemical 

substances too infer localized sites of actionwithin the brraih, 

a number of potentially serious ancthodologic considerations 

arise. Thesew incllade die dangers of misinterpretationof data 

due .to diffiesion of die .injected substance, local anesthesia 

within the injection site, andinonspecific irritation within the 

injectimn site : .Alsoi local pressure effects and high local conccntrations 

of the injected substance can be problematic . For 

a review of t}iese :and otherimpottant :methodologic considerationss 

that :apply to paradigms that use direct intaacraniali 

rnicroinjectionsi the reader is directed to reviews by Routtenbcrg 

(243), Bozarrk (244), and Btoekkamp (245) . With 

due regard for these methodologic considerations, direct intracranial 

n»croinjections oCabusablc substances can be combined 

.with electrical inoracraniaPsclf-stimulation methods to 

infer the :local sitc(s) of rewarding efikcts : Using these techniques 

; Broekkamp and colleagues found that thefocal!arcae for morphine's enhancing effects on electrical brain stimulation 

reward lies :witihin the ventral tegmental area and caudal 

hypothalamus (24K,247), with microinjections into dteventral 

tegmcntal area producing more immediate enhancement 

than microinjcctions into the caudal hypothalatmus . (248)s In 

thesc studies, die latency tirnc for etthancement .of brain stimulhtion 

.rcward~wzs strongll/ corrclhted with , distance from 

the .DAccllsof the ventral mesencephalic DA nucleilohat give 

rise to thc mesotclcnccphalic DA fibcrs .of the medial forcbrain 

bundlr ( r=-0 .83, p< 0 .0001) (245,248') . These data . 

are compelling, given the evidence reviewed above from other 

experimental paradigms .and approaches for a focal .role ofdie . 

"second stage" DA neurons of the mesotelencephaloc DA sys-tem in mediating drug-induced reward 

. Using similar methods, 

.Broekkamp and,colleagucs found!thartlne focal area forr 

amphetamine's enhancing effects on electrical brainstimulation 

reward7ics within thc.nucll:us accumbcns and neostri 

atal forebrain DA terminal projection loci of die "second stage" 

mesotelencephalic DA .rcward-reltvant systems (249) . Mi~ 

aoinjeetions of the DA antagonisn haloperidohinto . these same 

DA .termiaal projection loci irthibited .brainstimulation reward 

(247) . 

Intracranial Self-Administration of Abusable 

Substances 

A direct way to study the neuroanatomy of drug-induced 

reward is :to meld inoracranial microinjection technology with 

the self-admiinistrationparadigm, so that animalsare allbwed 

to work for direct intracranial self-administration ofabusable 

substances into disrretebraiin loci. Although conceptually 

straightforward, this is .actually an extremely difficult laboratory 

paradigm (for reviews, see 243-244,250-252) . As 

noted by Old's(19)~ early work with intracranial self-adminimatnon 

was almost universally meahodologicallyfiawed . Even 

with .the mosrsophiscicated microinjection teetmol'togitss (253), 

many conceptual and iinterpretational'problerns still remain . 

For example, it is difRcult with microinjection procedures 

(which must :be kept to sufficiently small volumes and'forces 

as to preclude nonspecific neuronal responses) to duplicate 

the elose temporal . hnk between behavioral response and reinforcement 

oitaroccurs with natural .rewards„and!virttnaldy 

impossible toduplicatethco imtncdiary of electrical brain 

stimulation reward. Since a dclay'of rcinforcement of only a 

few seconds is often enough todismpcoperant behavior 

(245,255), this becomes aserious concern- .Similarly,, issues 

of drug diffusion, anatomic spccificiq,, pharmacologic specificity, 

and the multiple and distinct physiologic systems activated 

by most drugspose major conceptual .andlrnethodolbgic 

problems . Also, as noted in Boaarth's many iosigfitfull 

reviews of intracranial self-admutistration (244,250), the fact 

that a given brain site does . nott support self-administration 

does not eliminate that.site asa reward locus, since competing 

behaviors (e .g ., sedation) produced!by the intracranial diuginjection may mask the reward 

: behavior . . Additionally,, arnd 

again as~notcd by Bozatah(244),,succcssful intracrarnial self-adtministration only identifies a site 

.asbcing involved in the 

ini[iutian of drug :rcward, not neccssarily'inthe undoubtedly 

complex and multistepped ncurophysiologic eomponentsof ju 

the ovaradl sulbjectivc experience of drug-induced reward .orCr 

plcasure : In spite of itsmany mcthodologic and iinoerpretational 

problcros, due paradigm's seenilng face validity has madeW 

it.veryappcaling to researchers studying .thencurobiology16h 

and'ncuroanatomy o/ldrug-induccd reward„and in reccntCA 

decades a number of laboratoriesarounds the world have suc-r 

cccdcd in ovcrcomingg most of tloe paradigm's problunsand ~ 

using it to gcncoaa provocative and!compcllingdata :. ~ 


Bo PnrtZL. Dc~ninanrr ofSnbrthnuAbure . 

Thus, animalss will voliuttarily selfadutinister rnicroinjectionsof 

amphetamine iinto tlee.nudcus accumbensand .prefrontal 

cortex (256-258) :, both ofwlnich aremesolimbic 

THE CRITICAti NIEUROCHEMISTRY OF DRUG 

REVVAR'D-IN VIVO BRAIN CHEMISTRY 

MEASUREMENTS DURING ADMINISTRATION 

OF ABUSABLE SUBSTANCES 

If the . ascendingg mesoteienceplnalic DAsystenssplay the 

crucial rolc .iin .drug-induccd brain reward thart is currently 

ascribcd to thcm, one.would cxpect .abusablc substances to 

act, at least indircctlyor transsynapticadly, .in a~DA-agonistlike 

.fashion in thcse systems . For many years, this crucial dcrivativc 

o6thc thcory was untestable. I[c.-ccntl y, however, two 

laboratoryrechttiques have been developed that allbw in vivo 

real-tin .c nncasmrcments of neurotrausmitter release iin .discrctc 

brain loci .of living . (indeed, im many cases, conscious, ., 

frecly moving)'.animals . These techniques are :imvivo braim 

microdialysis and imeivoa .braimvoltammetric electrochetstis-try (273-275) 

.Dtrie terminal projection loci 

. 

.of ohe system (168) 

. At the tip of the probe, Ibcated in the brain 

; but not into other braimsites . Similarly, 

cocaintee is voluntarily selfadministeredd intoo thee prc-frontal',corocx (259) 

. Ivlorphitoeis self-admitnistered into the 

ventral tegmtental area (260,261)„ lateral . hypothalamus 

(262,263), and nuclcusaccumbens(264), alll of which are 

either nuclei or ocmtihal projection .loci mesolimbiaDA 

; but not unto other brain sites . Other opioidS„ 

both synthetic and cndatgenous, are also self-adininisteredd 

intracranially. Fentamyl iss self-administered into the ventral . 

regmentaliarea (265), met-enkcphalin .is self-administered into 

the nucleusaccumbens (266), 

.and the mct-enkephalin anac loguc d-ala'-met-enkephalinamide is self-administered into 

the lateral hypodtalamus .(267')~ A related and conceptual derivative 

of these kind's of studies is the finding by Britt and 

Wise .that microuojections of ahydrophilic opioid antagonist 

with liinitcd diffusion characteristics (diallyl-normorphinium 

bromide) into the ventral 

.aegmcntal area'block'intrave-nous opiate sdf-administration (268) . 

An important theme in .such .in¢acranial microinjection 

smtdies, .alteady alluded to„is the ability of such approaches 

to yield data showingwhich brain loci are responsible for the 

initiation of each separate pharmacologic acdon of any given 

abusable substance. So, for example, the analgesic effea of 

opiates is mediated by local action omenkephalinergic circuits 

within the periaqucductal attd periventricular gray matter oFl 

the brainstem (269-270)t and the thermoregulatory effect, 

by. action in the preoptie .area (271), while the rewardingg 

effects appear mediated by acoion on'the nudei, tracts, and'd 

terminal projpetion loci of the mesolimhic DA system (reviewed 

above) . Itnpottatntly; microinjcction'.studies have shownn 

that't physical dependence upon opiates is mediated by action 

on brainstem loci anatomically distinct and far removed fnom 

the mrsoliinbic DA .loci mediating :opiate-induced reward of the brain)) uhrough the probe at aalow'rate 

(272), .and tharrepeatedlmorphine injections .into the mcsolimbie 

site 

DA lbci icritical fordrug reward fail to .produce ptiys- 

to be measured)txtraccl-lularneurotrarnttttitters and metabolite molcailes 

ioltagic .dependence (272) . 

Despite the difficulties that rlte iiotracranial self-administration 

paradigm ~ poses, studies carried out with it add persuasively 

to 

.the hypothesis that the "second stage"DA neu-rons of the mesotrclencephalic DA system play a fmcal and 

essential rolei~n mediating drug-induced reward . 

. Both paradigms havc provedltltemselves to'be valid and srnsitive ways of measuring real-titme neurorransnuttcr 

release in discrete loci ofthe liviing brain, and both 

have now been applied to the qpestion of which neurotransmitter 

substrates are .activated Iby administration of abusable 

substances . Additionally, classical in vivasiitgle-ncuronelectrophysiologic 

recording techniques have aLsoo been applied 

tomhe same question . There is 

.also an extensive literature ontheuse of push-pull cannula perfusion (275) forstudyingther effects 

:of abusable substances .on imvivo neurotransmitter 

release in forebrain reward-relevant loci (276'-277) ., :but 

.this', literature is not reviewed separately here, since thcpush-pull 

cannula perfusion technique is conceptually and even meth. 

odologically analogous to in vivo brain microdialysis . Also, 

the effects ofabusablesubstanccson DAin forcbraint-cward 

loci as determined by in vivo push-pull perfiuion have .been 

Found'.to be essentially identical to those determined by in 

vivo brain tnicrodialysis . 

The Paradigrns of In Vivo Brain Microdialysiss 

and In Vivo Brain Voltammetric Electrochemistry 

Although in vivo brain microdialysis .(278-281)iis conceprually 

similar to the much older push-pull carmula pardigm 

(275), .it is technologicallysuperior . Foriio vivo microdialysis 

studics, a microdialysis probc . (282) ~is fabricated from 

miniature stainless steel andldialysis tubing'and surgicallyy implanted, 

by standard .stercotaxic'.technique, into~the desired 

brain locus . A pump isuscd to drive a solution (similar in 

ionic constituents and concentrations to the .ocvacellttlar fluid 

.dialyze aenoss the membrane and are carried out of thc probe in rheper- 

Fusate to an analytic biochemistry apparatus . Typically, the 

analytic biochemisaryapparatus is a high-penformance liquid 

chromatograph with clcct¢ochetttical dctecaion, alNtough other 

analytic d'evices are alsosometimesused . If high-performanee 

liquid chromatographywitrefectrochemical detection is used, 

tlu .neurotransmittersand ntetabolitesin thc dialysate arc farst 

separated .byreverse-phase column chromatography .and the 

eluting species are then measured with ann electrochemical 

detector . Thc .in vivo sensitivity of this paradigm is excellent, 

allowing .dctectionof basal DA' release imeven diffusdyy innervated 

DAtcrminal projection loci (e .g .,, prefFontal cortcx) 

. The selectivity of the paradigm is:aVso .cxcellent, becausc 

of ihe excellent.separation of chemical speciesaffordedbynce 

chromatography columns . Time resolution rypicallyis about 

one measurcment'.evcry 5 or l0~minutes . 

In vivo brain voltatmnetric clecvocheniistry'(279,275 ;283'- 

285) is basedlupon the fortuitous chemical coincidence that 

many neurotransmirtcrsof intcrest and their mctabolites'(in 

2!023451144 


7/' BnntN Ar:wAIru Mucnntutsius 81 

the present instance, DA) are capable .ofclccurooxidation. 

Such oxidation yieldsan oxidation current, whichcan be 

measured using electrodes and apparatus essentially identical 

to that usedd in axon-conduction voltagC-clantp measurements 

of traditional neuropltysiology : Themeurotransmitter 

moleeules .are idennified .bytheir characteristic oxidation potential, 

theirrcharacteristic electrochemcal signatures (e .g ., 

the shape of the voltanunogramwhen performing fast cyclic 

voltammetryor dce .characreristic oxidation-reduction ratios 

when . performing tiigh,speed chronoamperometry), and by 

altering the physical-chemical .naoure of the,electrodb working 

surface, at whiclt the electrochemical reactions take .place, 

to produce electrodes withhigh~selectivity for specific mol- 

- ecules(2815) . .Forin .vivovoltamruenricdecttochemistrystudies, 

.an electrochemical °working" electrode (so called because 

the .eltcorothemical reactions . °work"'at its surface) is .fabri« 

cared, typically from carbon fibers and .miniature glass tubing, 

andl then calibrated for sel6etivity,and sensitivity and 

characterized for response time . This working electrode is 

then surgically implanted, by standardlstereotaxic technique, 

into the desired brain locus . At the same time, reference and 

auxiliaryelecrrodNs .are implanted, typically at the brain surface. 

Electrochemical measurements arc then begNn and con, 

tinued for . the duration of the cxperiment :The in vivo sen . 

sitivity ofthis paradigmm is good„and the time resolutiomof 

high-speed versions (fast cyclic voltamrneery ; high-speed 

chronoamperomatry) is excellent, allbwing10 to 200 independent 

measurements of neurotransmittcr efElux per second. 

Both in vivo brain microdialysis and in vivo brain voltarnmetric 

electrochemistry, are markedly superior to older in,virro 

and ex vivoneuroclicmicaE paradigms„ because they are 

real-time neurochemica9 measurement paradigms allowing 

correlations with ongoing behavior and because .dteyeliminate 

the artifacaual elevaoions : in extracellularr neurotransrnitterconeentraaiotu 

seen .at death with .in vitro .and ex vivo 

paradigms (287) . hn .dreir most sophisticated usages, both in 

vivodarain microdialysis .and in vivo brain voltammcrric clccrrochemistryare 

carriedlout.in awake animals, to obviate artaifactsintroduced 

by anesthesia . 

In Vivo Brain Microdiialysis Studies 

Usingthc in vivo :brain microdialysis paradigm, a number 

of laboratories around the world have shown that cocaine 

producesa robust enhancement of cxoraceflular DAA in the 

ncostriatal and nuclcus .accumbens terminal projcrtion areas 

of the reward-relevatt mcsooelenceplialic DA system (e .g ., 

114,288-297) . This enhancementt of ext¢acellular DA is more 

pronounced in mhe nucleus accumbetu than in other forebrain 

DAdoci (288) and is dosedcpendcnt (297) . The extraccllular 

DA levels meastued in forebrain DA loci after cocaine adminstratiom 

closclyminror the extraccllular Ievcls of cocaine 

itself in the sarnc : brain locus (289,293,298) . The DA-cnhancingnfket 

is seen whether dte cocaine is exogenously administered 

by. dtrrcxpcrinxntcr or selFadministcrcdl by the 

animal (290,29'I) :. Rclativr.recvaluation ofcxtracellal'ar DA 

evoked by cocaine„ratller, dtan an .absolute amount of cxtraccllular 

DA evoked by cocaine, mayy be dne critical factor correlating 

with cocaine self-administration, siince animalsselfadminisreringsensitizauion 

to methampheramine (292) . The enhanced DA effluxseen 

with cocaine sensitization may be inn large part 

accounted for by increased local concentrations ofcocaine .in 

relevant brain sites . (293)I a f indingthat gains special significanee 

.in vieww of reporrsthattheDA .synthesis rate appearss 

to decrease in cocaine sensitization (303'-305 ) 

. Cocaine's en-hancing effects onextracellular DA in reward-relevant forcbrainDAloci are blocked by tetrodotoxin 

; which prevents 

action pooentialb by blocking voltage-dependenv Na' channels 

; indicating that cocaine's effects on forebrain DA reward 

neurons require the functional integrity of those neurons„ 

which is congruent with cocaine's actions as .a specific inhibitor 

of the.reuptake of alre.advrcleased DA frommhe synaptic 

clefr(306 ;307) ., 

In an dt:gatnr series of in vivo microdialysis experiments, . 

Pettit and .Justdcc (2'97) showed that animals intravenously 

self-administering cocaine adopt a paced and .measured pattern 

of self-infusion that, after an initial burst of responding , 

to produce a loading dose of cocaine and quickly elevated 

extracellulhr DA levels inthe nuclcus accumbens, .maintaiius 

extracellulhr DA levels in the nucll:usaccumbensat signifcantilyelevated, 

.stablE levels that oscillate witltin 

. .Thus, an'emals .volitionally self-adtninisr 

.a relativelyconstrained range 

tering.cocaine appear to.regulate nhcir seif-infusion behavimrr 

so as to deliberately citrate aspecific, set, stable.IL•vdbf exoracellular. 

DAin the rcwar&critical DAtcrminal projection 

f cldk .of thc nuclcuss accum hens . 

Amphetamine al?:o produces a robustenharuenrent :ofextracellular. 

DAin reward rdcvanrncostriatal and nucleus ac- ~ 

cumbcns 

.DA terminal projection areas as measuredby iinrvivo Cnnicrodialy,sis (1~I4,120,281,288,307-315), with stronger N 

dlrect in the nucleus accumbcns than in othcr Forebrain DA ~ 

Iqci (288,308)L When du :anrpheramiinc is miicroinjceOCd di- N 

rcctlyinto die DA reward loci, .instcad ofbeiiog administered ~ 

systemically, nhe enhancing efY-ecron exrraccllular DA is ex- r 

tremcly potent(.310 ;315) . Neither abolition ofaction poten- A 

N 


8 ;2PaK'II: 17crnm

7/' BRAIN R[wntm N1IECtuwtsnr5 83 

cumbens (112') . This ef7ectof barbiturates is dose dependenr ; 

low doses enhatxe DAe[flux wlvlc high doses itiltibirt it (112) . 

&'=fetralnydrocannabinol, the psychoactive constivurnt .of 

marihuana and hashish, also c nhanccs .cxtraccllular DA levels 

in the nucleus acmombcns(330)i neostriatunn . (331-332), 

and medial prefrontalkottex .(333 ) , a11IDAterrrunalificldsof 

the reward-relevant mesooclencephalic DA system . At least 

in .the nudeus accumbens; thiseffects is calcium dependent 

and tetrodotoxinsensi[ive .(330) : 

As noted .by Di Chiara and .Iinperato (228), throughout 

all of these studies a common theme iss seen-drugs that are 

abu.sedd by hmrtans~ and self-administered by laboratory animals 

produce enhanced cxtracellularDA levels inthc terminall 

projection loci of thee rewardkelevant mesotelencephalic . DA . 

system„witH the nucleus accvmbens as a focal .and extremely 

sensitive site of this action . 

Given naloxone's abilitytoy block the brain reward enhancing 

effects of a widc range of abusable substances as assessed 

in the: electrical brain stimulation reward paradigm . 

(see above)S it would be interesting to kttowwhetlner naloxone 

siinilarly blocks the .DA-cnhancing .effects of abusable 

substances asasscssed with thee in vivo brainn microdialysis 

paradigm. This has been tested onlyfor opiates(112),and for 

A9-tetrahydrocannabiirol,(330), and'in both cases low dosess 

of haloxoncc effectively block the enhancing efFectson extracellularDAkvels, 

In Vivo .Brain Voltarmrnetric Electrochemistry 

Studies 

Unfortunately, early im .vivo: brain voltanu»ctrie clectrochemicai 

techniques were flawed by an inabiliry to distinguishbetwecn 

catecholamincs and ascorbic acid (334-337), 

and between indoles and .uric acid .(338-340) ; Since ascoobate 

levels far outweigh DA levelss in forebrain DL°c 

.teominalA loci, and siinceatleast some abusable substances (e.g .,, amptietarnines) 

produce a profound elevation of brain ascormate 

levels (336;337,341), .this was a source of confusion in many early studies 

. Additional major sources of difficulty also attended 

early in vivo brain voltammctric electrochemical smd-ies, such as thee fact that with the combination ofsomccarly 

electrodes andltihe slowvoltammetric scanning techniques : 

used in many early studies, DAA mcasurementswere confounded 

by dace electrocatalytic regeneration of DA in the 

presence of ascorbic acid (342,343) . .Also, many early in vivo 

brain voltammetric electrochemical techniques werc unable 

todistinguish . DAA frosm . 3',4-dihydroxyphcnylacetic acid . 

(DOPAC) : (for d'uscussion ; see 344 .) . Forthcser and lothcr 

.rca-sons{ many early reports ofcnhanced DA rclcasc byabusable 

substances„assessed voltamntetrica111/, arc either erroneous or 

very difficult ooo interpree. Htecently; .liowevcr, in vivo voltantimetric 

laboratory techniques have been improved by the developmcnt 

of neurotransmitter-scleaivc recording proca 

dhresinvolving„among odtenhings, (a) alterati©ns ofclocnrodc 

working surfaces too impart high scl

84 Paa2 .I7: Detcrnrinantrof Subrtanu .Abua 

biphasic c(}cct of morphine on reward-relevann mesostrietal 

DA .ncuronsA as asscsscd byaingle .neuron elcctrophysiologic 

recording studies(3S8) and by electrical .brain stumulation 

reward approaches (107) :. Acute morphine also produces a 

robust .enhancement (-100% increase) of dte DA metaboGte 

homovattillic acid .(HNA) . in dne.nudeusaccumbens (369) . 

When administered systemically for 2 days in a row, morphine 

producesincrcased DA release .in the nucleus :accumbens 

after a singlc nepratcd administmtiom (369) ; suggesting that DA 

turnover mechanisms may be altered early in the 

courscof chronic opiate administration. Fentanyl produces 

a robust (=150%) increasee im neostriatal! DOPAC (370) . 

The 8-scll•ctive opioid neucopeptide agonist [D-Ala',D-Pros]- 

enkephabn appears to be withoutellect on DAm the .nucleus 

accumbens .but inhibits DA release inthe neostriamm(371) . 

Provocatively, the K .opiate receptor agonist dynorphin-(1- 

13), which has thcattnivs .propertics common to a agonists 

in animals rather than tha appetitive propcrticsscenwith µor S agonists (322 

;323), produces a profound and long-lasting 

inhibirion rather than stimulation of DA efflux in nhee 

neostriatum .as deteranined with in vivo voltanunetric electrochemistry 

(372) . 

In awake; .freel/ movinganimals, eaffeine andltheophylline 

significantly enhance extracellular DA levels in the neostziaturm 

as assessed by in vivo voltamnnetric eleeerocliemistty (373) . 

These cffectsare : dose dependent ; low dosess enltanceDA . 

eft7ux while high doses inhibit it (373) . It is noteworrthytbat 

the DA-enhancing effccts of caffeine and theop'hylline are 

seen only in awake, unanesthicti¢ed animals-in anesahetizedd 

animalsadl doscsinhibit DA efflux(373), stressing once again 

the importance of doing these types of in vivo experiments . 

in awake, unanesthetized animals, since the highdosesofanestheticsh needed toproduce immobilizing anesthesia aree 

known to inhibit forebrain DA release sigpalS .as measuredd 

by in vivo voltammetric electrochemistty(374) (see alsomention ofthis 

.pointwith .respect to.in vivo brain microdialysis 

above) . Alcohol produces a robust enhancement of cxtracellular 

DA ira .reward-nelevantn forebrain DA loci .as mcasured 

by in vivo:voltammetric .clectrochemistry(375,376) . 

The . effect iss seen in both the nucleus accumbensand' tlxe 

neostriatum (375.,37fi) and is secn in both anestlnetized (375) 

and freee moving, unanesthetized (376) animals . BothDA . 

release and .DAmetabolism .are enhanced (375), and these 

cffecrs are signifucantlyantagonizcd by pretreatment withYhch calcium channel blocker nifedipine (375) 

. Provocatively„the, same dose of nifedlpinc that blocks alhohol-induced enhancemcnt 

of DA .metabolism and releascin forebrain reward 

.locid also blocksanimals prcfrrence for alcohol, as detcrmincd! by' 

relative intake of alcohol versus water in a free-choice situation 

(375); suggesting thatn alcoholis.rewarding proper¢iess 

may involve caleiumelnannel mechanisms modulating DA . 

release in forebrain reward loci . The abusable dissociarivcre 

anesthetic phencyclidine also,enhances cxtracell ular DA levels in ncostriatum afrter 

.local intracranial microinjeetion 

:electrochemistry(377) ; as mca-sured by in vivovoltatnmetric . The 

phencydidinc analog]v1K-801 markedlyenhances DA metabolism 

.in the .nuclcus accumbens at intraperitoncal doses 

as low as 0 .1 mg/kg, as measured by in vivovoltanomccnic 

electrochemistry (378) . .Studies ofbenzodiazepute action on 

DAfunctiom in reward-rclevant brain loci using,in vivo voltammctricelectrochemistryhavc 

been interpreted as indicating.diatbenzodiazepines 

inhibit DAfimction .Iltus ; :10 mg/ 

kg diaupam significantly reduces DOPAC levels .in ohe striaturn 

(379) and 10 : mg/kgflurazepamsignifiicandyreduces 

the normal noctumal .rise in both HVA levclsand the DO- 

PAC/DA ratio in the nucleus accumbens (380,381) . However, 

severallpoints regarding these smdies .must be .made. 

First, the doses of benzodlazepimes administered were massive, 

and .since it .is .well .estaibfished that, for many drugs of 

abuse, low doses enhance DA eflluxx in reward-relevant DA 

brain loci while high doses inhibit it . (see discussion of this 

point above) ; the : benzodiaupincc dosess may simply have been 

out of theDA-enhancing range . Second, each of these studies 

(379-381) measures DA elR3ux inferrartiallp(on the basis of DOPAC and HVA levels) rather than directly, and it is well- - 

established on .the basis of in vivo brain microdialysis studies 

that some drugs of abuse increase extracellular DA while ri- 

»tultaneaurly.decreaaingDOPAC andiHVA . Third, the pattem 

of bermodiazepine-induad changes in DOPAC and HVA 

reported in these studies is strukingli/ ampheramine-Illce : Fourth, 

low-dose benzodiazepines augSnent food' consumption and 

induce spontaneous eating in many species (382-392), : behaviors 

known tocomelare with DA efllux,in reward-rclevant 

forebrain DA loci (114) attd even to be mediated by the same 

neural fibers mediating electrical brain stimulation reward 

(393,394) . In addition, this Io!w-dtpse benzodiaupine-induced 

feeding is blocked bynaloxone :(387,390) and appears 

identt cal to the augmcnoed feeding inducedlbylow-dose barbiturates(383',389) 

. For all these reasons, it does .notappear 

to :tihis reviewer that claims based omin vivovoltammetric 

elecvochemistrythat benzodiaupiness inhibit DA .funetion 

in brain reward loci can at this point be considered definitive . 

A' -Tetrahydrocannabinol enhanccs extraeellular DA levels in 

rcward-eelevant forebrain DA loci as measured by in vivo 

voltammetric electrochemistry (332) . 

Thus, thesamccommon themecan{bc seen inthese in vivo 

voltammetric electrochemistry studies as previouslynoted in _ . 

the in viv~.o brain microdialysis smdies : (above)-substances 

that are abused byhumansandiself administered by .lhboratory 

.anitmals .produce enhanced extracellular DAlevels innlre 

terminal projection loci off the rrnard-relevanr mesotelencephalic 

DA system ; with .thc nucleus accumbcnsas a focal and 

extremely sensitive site of this action . 

In Wivo : EleclrophysiologicStudues 

Clearly, one of the ways in which~abusable substances can 

enliance extracellular DA release in reward-relevant brain loci 

is too increase thee f ring rate of reward-relevant Di^.A neural 

fibers of the mesotelenceplialic DA system . Thus, classical in 

vivo single neuromelectrophysiofogic recording techniques 

can, be, and .have becn„also applied to thcyuestion of activation 

of rcward-nclcvant DA neural systems in the brain by 

2023451148' 


7/ 1br4.V N' REWLRD . MECHANISMS . 85 

abusable substances . Thcrc is, .imfacr, a lange literature on this 

topic, and ihe presentrevicw must therefore .be selective . 

Equally clEarly, cnlnanccmrent of presynapmcDA ncuronall 

firing in rcward-relevant DA eiecuitswoudd not.be an appro-priate 

.mechanism of action fbrabusable .substancu acting 

dircaliy on ipresynaptic DArelease and/or .rcuptakc'.(e.g:, cocaine„ 

amphetamines) . Im fact, due to compensatory neural 

feedback, autoreceptor-mcdiated, and/or enzymatic regulatory 

mechanisms, many such substances would be expected 

too inhibit pocsynaptic DAneural firing while enhancing pvet* 

all synaptic funcmon in reward-relevant DA synapses . Thus, 

single neuron nticroelearode recording studies .show thatcocaine 

inhibits prcsynaptic DA neural firing (395) while enhancing 

extraeel'7tilarDA in ceward-relevant DA forebrain 

synapses (114,288-297,345-349), and enhancing the normal 

posrsynaptic electrical effects of DA synaptic functioning, 

in reward Ibci (396) . Sintilarli/, the acute :inhibitory'effect of 

. amphetamine on the firing ratc of inesotelencephalie DA 

neurons is well-documenred (397-400) :, ., but the .overall' nett 

effect of amphetaminee is one ofenhanced DA synaptic attiom 

in reward-relevant DA synapses (e.g.,,114,120i281,288;307- 

315,350-363) :. Interestingly, dose response analyses of the 

electrophysiolbgic etliccts of amphetattrine on the activity of 

dopaminoceptive cells (i .e., neurons efferent to theascending 

DA reward' neurons) in forebraim reward lbci reveal qualitative 

as well as quantitative changes in response toamphetamine(401,402) 

. At low doses (/css than 2 .5 mg/kg)„ampketatttine 

dose-dependentdy increases synaptic DA levels and 

dbse-dependentily enhances thenotmallpostsynaptic electrucal 

effectson the dbpaminoceptivecells ; while dbse-depen, 

dently inhibiting the firing rate of the preslmapticDAneu• 

rons; . At highdoses (more tlnan . 2.5 mg/kg), however, a . 

quantitative change' 

.occurs such that the dbpantinoceptivecellsbecome profoundly' activated in the absence of further 

changes in synaptic DA levels .(277;401,402) . 

Opiate-induced enhancement of the fi~ring,rate of rewardrelcvant 

nresotelencephalic DA neurons is well,established 

(113,115,118 ;1 .19 ;368,4I03-4'08)L The mesolimbic DA . 

neurons originating in the ventral ¢egmental area and .projectingto:thenucltus 

accumbens are preferentially sensitive 

to thisopiate-induced activation (404) :. Opiate action on thee 

firingrate of reward-relevant mesotclctncephalic DA neurons 

is heterogeneous ; somrDA neurons are activated by opiates 

while :others are inhibited . (368,4@6-407) . .This dual action 

may well constitute the neural substrate'.for.the observation 

that electrical brain stimulation reward is enhanced by opiatess 

in some brain reward loci .butinhibitcdiby opiatcss in others(107) and alsofordne 

.observation that cxcracc8ularIDA .is . 

enhanced by opiatess in somee reward-relcvano fonebrain DAA 

terminal Ibci but inhibited byopiates in others (365-367) . 

Although the action of µ opiate receptorr agonists on the 

firing rate ofirnesorelencephalic DA ncurons .in reward-relevarrt' 

brain locii isprimariilys an activating one, Kopiate rccepror 

agonistsr.(wlnichhave avcrsivc rathcrehan appctitive 

properties inanimals; see 322-323) inlribit thcfrringrates 

of these samee neurons (408)'. Although the neural mcclianismsbywhichopiares 

~activatc.the fi ring ratcs of IDA ncurons 

in reward-relevant loci : arc mot known, sonnc hypodteses are 

possible. A direcrc .excitatory action mediated via citlneraxo-axonie 

.recepoors or axosomatodendFitic receptors eannorbrt ruled out, in vicw of die prescnce 

:of endogcnous opi©id 

.pep-tide receptors on the axon terminals of inesotelEnceplaalic DAA 

neurons(237-239) attd imview of ieccnt demonstrations'of direct excieatoryefffecrs of opiates on netve membranes, as 

assessed by increased durations ofl caluutn components of 

action potentials of dorsal'root ganglion neurons in ctnlhure 

(409,4110) . On the oaherr hand, the widespread iinllibiooryy 

effcces', of µ opiates on nerve membranes (411-413) may 

make a disinhibitory mechanism (414) :somewhat more likcly . 

Thus, abusable opiates may stimulate the firing of DA reward 

neurons'by directly inhibiting other neurons, 

.possibly inthen ventral tegmental area~ (415), that aretonicallyinhibitoryto the,mesolimbic DA reward neurons 

. 

Nicotine also :acutely activatesmesotelencephahc DA neu-roms, as measured by single neuron 

.electrophysiologic recording 

techniques (416) . The activating : effect is'dosedependent 

within the range of 50'to 500 µg/kg administered 

intravenously . The same range of doses was moretlnan three : 

timesas effectii+e on .mesolimbic DiA neurons :as .on mesostriatal 

DAneuronsi, and all nicotine-induced activation of 

DA neurons was prevented or .oeversed by iintravenousmecamylamtine, 

implicating the involvement of nicotibic dnolfn- 

, ergic receptors un,mediating this neural activation (416) : . 

.suggesr.tlnatnicotine shares 

.AstHe authors note, these results 

with other abusable substances theclnaracteristic of being selectively 

effective in .activatingmesolimbic DAneurons thart 

originate intlte vcntral tegmemtal area and project to the nuclcus 

acetimbens .(416) . Alcohol alsoenhatxcs.thef ring ratess 

ofmesotelencephalic . DAneurons in rcward-relevann braim 

loci (4~.17). The effects ofphencyclidine .and phencyclidineanalogs 

.onDA .neuronal firing .rates anc interesting . When 

administered direetlyontomesotelenccphalic . DA ncuronsy 

pheneyelidine inhibits spontaneous DA ncuronal firing 

iinn a manner similar too that of local applications of DA(418-422)~ When administered svstemically, both phenc eyclidiine an& the'e phencyclidine analog 

: N-[1-(2-dnio• 

pheny,l)ryclohexyllpipcridine (TCP) elicit dose-dependent 

biphasic effects on the firing rate of identified mesotelencer 

phalic DAneurons (420,423)- .At low doses, an activation of 

DA neuron firing rate is seen, fb0owed byyinhitbirionat :higher 

doses(42@ ;423) . When administered sysremically„phe sclective 

pliencyclidinc agpnist MK-801 . activates'.DA .ncurons inn 

a manner equipotcnt too that of phencyclidine itself (424) . 

Diaupam„theTprototypie :benzndiaecpinc, markedly excites 

mesolimbic DA neurons in the .vcntralregmental .area when 

administered intravenously (425) . This excitation'is.reverscd 

by the benzodiazcpinc antagonist Ro 15-1788. Thec same 

doscs of diazcpatn potently inhibit non-DA substantia-nigrapars-rcticulata-like 

neurons in thc ventral tegmental area ; 

suggtstingthat .bcnzodiazcpincs act direcdyon~thcsc latter 

non-DA cells to inhibit .neuronal .activity and disiinhibir the 

ventral tcgmental area mesoGmbicDA .ncurons (425) . Curiousliy, 

at nhe doses tested, chlordiaecpoxidc and tluraupam . 

I 


86IRan I7: Dctmnirrants of Si+brtanu Abrae 

did not ntimic diazcpatnls potent . activating effect on DA 

neurons (425) : . . 

SUMMARY AND CONCLUSIONS 

Abusable substances have twofinndamental eonunonalitics 

: (a) that they arc voluntarily self-adlministered by non+ 

hmmanmarnmals, and (b)) that they acrrtely,enhancelnrain 

rewardmechanisms . From this latter property presumably 

derives their euphorigenic poroency„their appeallto nonhur 

man mammals, and the "hit," "rush," or "high" soug[tt by 

the human substance .abusen Sccond, ohe reward circuiu of 

the brain, upon which .atiusable substancesaa to ettlnancee 

brain reward, indude "first stage" and "second stagc'com-ponents 

. The "first stage" component comprises descending, 

myelinated, moderately fasaconducting neurons that run 

caudally within themedial forebrain bundle and that are preferentdally 

activated by direct electrical brain stimulation reward 

. These "f ist stage" fibers synapse into the ventral mcscncephalic 

:nuclei containing the cell bodies .of the 

. axons of which .ascendingmesonelencephalic DA system„ the run rostrally 

through the medial forebrain bundle to limbic and cortical 

projioctionareas . These mesotelencephalic DA neurons 

constiuute.the "second stage" fibersof the reward system andd 

form a crucialldrttg-sensioive component of the reward circuitry, 

wltichi appears preferentially activated ncurochemically 

and/or electrophysiologically by abusable substances to, 

enhance brain reward . The mesolimbic DA fibers terminating 

im the nucleus accumbens appear to be the most cruciall 

reward-reUcvant component of the ascending mesotelencephalic 

DA system. From the nudeus accumbens,, additional' 

ncward-relevantt neurons ; some of them possibly enkephalinergic, 

arepresumed tocarrydtercward signal ILrthcr, possibly 

to or. via, the ventral pallidum (426) . . Third, aliusable 

substances appear to act on or synaptically dose to these DA 

fiberstos producee dteinreward-enlnanciing actions, possibly 

via an enkephalinergic mechanism .,ThisDA component appearss 

crucial for drug selC-adminisnation, and self-administration 

can be attenuated (at .least in laboratoryy animals) by 

manipulating these DA substrates . Fourdt„diffcrent .classcs 

of abusable substances appear to actt on these DA reward 

substratess at different anatomic levelsand via dlfferent sitcs 

of action on .or near theD75 neurons . This (admittedly incomplete) 

picture of tlle .reward systems of the mammalian 

brain„and drvginteraction therewith, is illustrated in Figure 

7 .21 AcomparisonofFigures :7 .1 and 7 .2 illustrates how little 

we yet knowabout .the functinndanatomyof the brain, as 

compared wiahthe static anatomy. Figure 7.2 also obviously 

representss a rcductio ad minima .approach to the anatomy; 

chcmistry~ pharmacology, and function of the .rcward systems 

of titee mamunalian brain . It .will bee rcmarkablc indccdif thc 

anatomyof brain .reward, and the actions of abusable sub . 

stances diereon, tumout ro.be assimple as .sketchedlin this 

present chapter attd as simtple as shown in Figure.7 .2 . For a 

morecomplex .andcomprchensive scheme, though arguably 

a Icss dcfensible one at our prescnt limited state of knowlcdgc, 

the reader is~s referred .to any of dx recent reviews by Smith . 

and his

7 / Bsutrt B;ewAten Macmtitvtsats 87 

css 

Amphetamine 

Cowine 

Opiates 

11XC' 

Phencyclidine 

Nelamine 

Nicotine 

Opiates 

Ethanol? 

Barbiturates? 

Benzodiazepines? 

Barbiturates? 

BenzodiazepinesR 

Figure .7 .2 : Sohematicdiagtamofthebrafn-reward .circuitMofthemammalian 

lla6nratony .ratl .brain, .withsitesat which various'.abusable substances 

appear to aclito enhance brain-reward andd thus Ao : induce drugtaking 

behavior and possibly drug craving. 1C55 indicates the descending, 

myelinated, moderatelyy tasl-conducting .component .of the :braih-reward 

circuitry that is .preferentially activatedbyelectricallintracranial self-stimulation 

. DA indicates9he subcomponent of the ascending mesolimbic dopaminergic.system 

that appears to.be peferentiallyactivated by abusable 

substances : LCihdicates thelocus coeruleus, VTAihdicates the .ventral 

tegmental area, and Acce indicates the nuckusaccumbens . . NE indicates 

the noradrenergic .Bbers, which originate ih the locus cceruleus .and synapse 

into the general vicinity of the ventral mesencephalic DA cell fields . 

GABit ind .icatess the GABAergic inhibilorNy fiber systems synapsing upon 

both the locus cceruleus noradrenergic fibers and the ventral mesencephalic 

DAeell fields .IModiBed from Wise RA . Action oldrugsofatluse 

on brain reward syakms . Phamacol Biochem Behav 1860 ;13(soppl U :29 3- 

223, .with permission .) 

duration ; hence, they build up strength,and decay more slowly- 

Thcy arc'.aLsom hypothesized to resist the developmentt of tolerance 

. Therefore, if self-adtninistration of an abusaNlc substance 

is repeated frequcntliy, two correlated charges in hedonic 

tone arcpostulated to occur . First, tolerance to the 

cuphorigcnic effects of the substance develops, whil6 .at the 

same .time.thewithdrawal onabstinence syndrome becomes 

more intense and of longerrduration (458,460) . Thus, the 

positivereinforcing'propctties ofdhe drug diminish whilc the 

negative reinforcing properties (rcliefof withdrawal-induced 

anhedonia) strengthcn (458), Koob .and his colleagues propose 

that norottlyare.the positive reihforcing,propetrtics of 

abusable :substances'.medated by dnrgeffects inithe nucleus 

accunnbens, but that opponent processes withiin these same 

brain reward .circuirts become sensitized during,the development 

of dependence and thus become responsible for the 

aversive stimudus properties of dnugwithdrawal, .g and, therefbre 

ultitmatelyfor the negative reinforcement processes that 

come, in dtiss view, to dominate tlnee motivation for chronic 

substance abuse (458) . Thus, brain reward mechanisms, and 

the regulatoryneunal mechanis{ns .controlliing them, are conceptualized 

in this theory todominate not only the positively 

reinforcing acute "hit," "rush," or "highr resulting from early 

administration but .abot the ncgativclyy reinforcing propcrtics 

thatt develbp withh chronic adtninistntion and .d that : are important 

ih,thecmaintenance of drug habits . . 

A seeminglycbsely relatedconcepbto this opponent-proccsranhedbniais 

that ofcraviitg,,Cravingis expericnced by 

chronic substanceabtuers when theyhavebeemdepriNCd of 

drug for a period of time : .By definition, then, animalmodels 

of craving must.dilfer from the acute administration and selfadministration 

paradigms detailed .above . Since craving at the 

human level is often eGcited by sensory stimuli previously 

associatedlwitli drug taluiug, various conditioning paradigms 

have toeen .used to .model craving .in laboratory animals. One 

of themost widelyusedlis.conditiwned place preference (4G1- 

463), .Imthis .parad'[gm; animals are tesoed (,whenfree.of the 

drug) i too determinee wheuher they prefer an environment in 

which they previously received the drug as comparedlwith an 

environmcntt in which they previously received .salineor'vchiclc. 

If the animal, .in thc.dntg-free state, consistently chooses 

the environment previouslyassociaredlwith~drug delivery, thc 

inference is drawn not onlythat the drug was appetitive but 

also that :the appetitivchedonie value was coded in the brain 

and!is .accassible during the drug-ftee soate, which, if noo craving 

f,erJC, would appear to be closely related to craving . Two 

questioauobviouslyarise : (a) is craving coded in the same 

neural circuitry as drug-induced reward? and (b) do pharmacologic 

manipulations and/or .lcsions of thcc.reward-rclc> 


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