Opioids, Reward and Addiction: An Encounter of Biology ...

indications for release of endogenous opioids in some
limbic brain areas have been found in animals selfinjecting
cocaine or ethanol (Gerrits et al., 1999). These
effects have been linked to the desire and/or the need for
the drug probably present at that moment and may thus
be related to craving and/or dysphoria present in a human
addict before drug-taking. Since at the same time
the basal release of DA in the NAC is decreased (M. A. F.
M. Gerrits, P. Petromilli, H. G. M. Westenberg, G. Di
Chiara, J. M. Van Ree, unpublished data), the endogenous
opioids and mesolimbic DA, separately or interactively,
may be implicated in subjective feelings of addicts
leading to daily drug intake.
The third stage of the addiction course is the withdrawal
phase. Heroin and alcohol addicts frequently
experience withdrawal, either or not with medicinal and
psychological support. The contribution of this experience
and of the conditioning of withdrawal symptoms to
the addictive behavior is not well understood. As in
humans, both somatic and affective symptoms of withdrawal
can be observed in animals (Schulteis and Koob,
1996). Somatic symptoms include among others, weight
loss, diarrhea, wet dog shakes, jumping, penile erection,
ptosis and teeth chattering, and affective symptoms elevation
of ICSS threshold, suppression of operant responding,
reduced exploration, and place aversion. Different
brain sites have been implicated in these sets of
symptoms, i.e., the periaquaductal gray in the somatic
symptoms and the NAC in the affective symptoms. Data
from experimental animals indicate that endogenous
opioids can induce physical dependence and the related
occurrence of typical withdrawal symptoms upon discontinuation.
The significance of endogenous opioids in the
withdrawal phase has yet to be elucidated. Maybe alterations
in the endogenous opioid systems during this
phase have influences on the next stage, relapse. Rhesus
monkeys who had about 1 year of experience with freechoice
alcohol-drinking appear to be more sensitive for
naltrexone, with respect to the naltrexone-induced decrease
of alcohol consumption, after a period of imposed
abstinence as compared to the condition of continuous
access to alcohol, indicating changes in the endogenous
opioid systems during a period of abstinence (Kornet et
al., 1991).
The fourth phase of the addiction course, the relapse
phase, is quite important from a theoretical and a therapeutic
viewpoint of addiction (O’Brien, 1997). The major
problem of treating addicts is not discontinuation of
drug taking, but the relapse in their former addiction
habit sooner or later after discontinuation of drugtaking.
In experimental animals, it has been shown that
after extinction of self-administration behavior, priming
with the drug used or another drug of abuse induces
responding on the lever associated with receiving the
drug (Stewart et al., 1984). Similar responding could be
induced by experimental stress. This indicates that conditioned
drug effects but also other events like stressful
OPIOIDS, REWARD AND ADDICTION 383
experiences are important for reinitiating drug self-administration.
In the period(s) of drug-taking and abstinence,
brain mechanisms are changed, probably leading
to homeostatic dysregulations, in which processes like
sensitization and counteradaptation may be involved
(Koob and Le Moal, 1997). These changes may contribute
to the vulnerability to relapse in individuals with a
history of addiction.
An important issue in relapse is craving. Craving, the
intense desire to use the drug , is already present during
the maintenance phase but also long after discontinuation
of drug-taking. Whether the craving during maintenance
and after discontinuation is mediated by the
same brain mechanisms is not known but likely. Craving
develops during repeated drug use and has been
theoretically explained by the process of incentive sensitization
(Robinson and Berridge, 1993). The addicts
may, by taking the drug, become sensitized to the drug
and the drug-associated stimuli and therefore want the
drug more and more, which could lead to compulsive
drug-seeking and drug-taking. This process is suggested
to result from incremental neuroadaptations. It has
been argued that the ventral tegmental-accumbal dopaminergic
system may play a role in this respect, although
other systems present in the limbic area have
been implicated as well. Indeed, chronic opioid exposure
induces long-lasting molecular and cellular adaptations
among others in the VTA and the NAC, in which transcription
factors, glutamatergic transmission, neurotrophic
factors, and neurofilament proteins may be involved
(Kalivas and Stewart, 1991; Self and Nestler,
1995; Spanagel, 1995). The neuroadaptation remains
long after drug discontinuation and perhaps more or less
during the entire life of the individual. The relationship
between craving present long after discontinuation of
drug-taking and the affective effects conditioned during
drug-taking and abstinence and the (conditioned) expectations
induced during these periods is not clear. Several
animal models have been proposed to investigate drugcraving
(Markou et al., 1993), but have hardly been used
to investigate the significance of endogenous opioids in
drug-craving. Endogenous opioids may play a role in the
expression of conditioned place preference with addictive
drugs, that may measure aspects of drug-craving
(see VI. Endogenous Opioids and Nonopioid Drugs of
Abuse).
The administration of opioids and other drugs of
abuse can be accompanied by the development of tolerance
and sensitization to the effects of the drug.
The actual intake of drugs in human addicts and selfadministering
animals is quite stable for months and
years, suggesting that tolerance nor sensitization to the
drugs’ reinforcing action is hardly present. It may, however,
be that both tolerance to certain nonreinforcing
and aversive effects of the drug and sensitization to
some motivational effects may contribute to the vulnerability
of the individual to become dependent. Moreover,