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

self-administration behavior according to the unit dose
delivered, with a maximum number of self-infusions at a
unit dose of 30 g/kg/inf (Fig. 1) (Smith et al., 1976). In
rats offered morphine via an intragastric route, a unit
dose of 30 g/kg/inf morphine did not maintain responding.
The curve of intragastric morphine reinforcement
was shifted to the right and the maximum number of
self-infusions was lower than with the i.v. route (maximum
number of self-infusions at 300 g/kg/inf). These
data indicate that the i.v. route enables a more potent
(and efficacious) behavioral effect of morphine. Placement
of the drug directly into the blood as compared
with oral delivery enables a higher quantity of the agent
at its site of action with a more rapid onset, which
probably increases the drugs’ reinforcing effects. Administration
of morphine via the intragastric route might
cause loss of potential through incomplete and slow absorption,
biotransformation, and delayed latency of onset
(Iwamoto and Klaassen, 1977).
3. Schedules of Reinforcement. Schedules of reinforcement
or schedules of drug availability can influence
opioid self-administration behavior in animals. The
schedules used include fixed ratio (FR) schedules where
a fixed number of behavioral responses is required to
obtain a drug, and fixed interval schedules where the
drug can be obtained after a fixed amount of time responding
for it. Studies with these schedules of drug
availability generally show that an increase in response
requirement or interinjection interval decreases the
amount of drug self-administered. In general, the influence
of the various schedules of reinforcement on drug
self-administration is comparable to that on food and
water reinforcement.
A typical model of schedule-controlled responding is
the progressive-ratio paradigm. This model, in which
each next drug infusion requires more responses than
the one before (increased FR requirement), allows the
determination of the maximal effort the animal will
perform to receive a drug infusion (“breaking point”).
The breaking point depends on the dose of the selfadministered
drug and is thought to provide a measure
of the reinforcing efficacy of the drug. For example,
Hoffmeister (1979) investigated the reinforcing efficacy
of a number of opioid drugs in rhesus monkeys using a
day-by-day increasing progressive ratio schedule. Before
opioid drug experiments, stable self-administration behavior
was established with 1-mg/kg codeine infusions
contingent on completion of a FR 100. Doses of the opioid
drug studied were substituted for codeine and the FR
schedules were doubled daily (up to FR 64,000) until the
number of self-infusions per day decreased to less then
two infusions (the breaking point). The breaking points
of either opioid drug studied, i.e., heroin, codeine, dextropropoxyphene,
and pentazocine, increased dosedependently.
The highest breaking point with heroin
(FR 12,800) was observed with infusions of 0.5 mg/kg
and for codeine (FR 6,400) with a dose of 16 mg/kg/inf.
OPIOIDS, REWARD AND ADDICTION 353
When dextropropoxyphene and pentazocine maintained
behavior, the highest breaking points (FR 6,400) were
observed with infusions of 5 mg/kg. The progressive
ratio paradigm demonstrates a certain rank ordering in
the breaking points, i.e., the reinforcing efficacy, of different
opioid drugs. It has been argued that the progressive
ratio model provides a measure of drug craving in
the presence of the drug (Markou et al., 1993). The
authors emphasize that the breaking point measure is
composed of two components: the unconditioned incentive
(i.e., reinforcing) and the conditioned incentive
properties of the drug. According to this, the fact that
animals will exhibit more effort to receive one of two unit
doses can be considered to reflect the relative incentive
motivational value of the expected drug dose, and thus a
measure of drug craving.
Another schedule-controlled paradigm, which also is
thought to provide a measure for drug craving, is the
second-order schedule paradigm (Markou et al., 1993). A
second-order schedule is defined as “one in which the
behavior specified by a schedule contingency is treated
as unitary response that is itself reinforced according to
some schedule of primary reinforcement” (Kelleher,
1966; Goldberg and Gardner, 1981). In short, completion
of a specific FR schedule results in the presentation of a
brief stimulus and completion of an overall schedule
produces a brief stimulus and a drug injection. For example,
every 30th key-pressing response during a 60min
interval produced a 2-s light; the first 30-response
component completed after 60 min produced both the
light and an i.v. injection with morphine (Goldberg and
Tang, 1977). Under this second-order schedule of morphine
injections, high rates of responding were maintained
by monkeys and the unit dose-response relationship
tends to be an inverted U-shaped curve. The
second-order schedule can be repeated several times
which will result in multiple drug injections. One of the
advantages of second-order schedules as a model for
drug craving is that animals will perform a high rate of
responding and extended sequences of behavior before
any drug administration.
4. Physical Dependence, Tolerance, and Sensitization.
Repeated self-administration of drugs may alter a variety
of homeostatic mechanisms, changes that alternatively
may contribute more or less to drug-taking behavior.
The development of physical dependence and
tolerance is of particular interest, since these phenomena
have been regarded in the past as being critically
involved in opioid addiction.
Physical dependence refers to an altered physiological
state produced by the repeated administration of a drug,
which necessitates the continued administration of the
drug to prevent the appearance of a withdrawal or abstinence
syndrome (Jaffe, 1990). Tolerance represents a
decrease in effectiveness of a drug after repeated administration
and consequently the need for a higher dose to
produce the same effect. Treatment of animals with