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

and naltrexone (2 mg/kg) suppressed responding below
the levels seen after saline injections (Stewart and Wise,
1992). Using this reinstatement procedure, the same
research group replicated their findings, in that reexposure
to heroin after abstinence reinstated heroin-seeking
behavior, whereas an injection of naloxone did not
(Shaham and Stewart, 1996; Shaham et al., 1996, 1997).
Moreover, they found that brief exposure to footshock
stress or corticotropin-releasing hormone reinstated
heroin-seeking behavior, thereby mimicking the effect of
a noncontingent priming infusion of heroin, although
differences may be present with regard to the neurobiology
of the various reinstatement stimuli (Shaham and
Stewart, 1994, 1995; Shaham et al., 1996, 1997). By
contrast, the aversive state of opioid withdrawal, induced
by an injection with naltrexone, did not reinstate
drug-seeking behavior. Other abused drugs like amphetamine
and cocaine are also capable to reinstate drugseeking
behavior in animals, previously trained to selfadminister
heroin (De Wit and Stewart, 1983; De Vries
et al., 1998). It has been argued that the reinstatement
model is relevant for assessing opioid-induced relapse.
In general, it seems that both the pure -opioid agonists
(such as morphine, methadone, codeine, and heroin)
and the mixed -opioid agonist-antagonists (such as
butorphanol, nalbuphine, and buprenorphine) serve as
positive reinforcers in the different i.v. self-administration
paradigms in monkeys and rats. On the other hand,
-opioid agonists (such as ethylketazocine, ketazocine,
and benzomorphan ligands) and opioid antagonists
(such as levallorphan, naloxone, and naltrexone) do not
maintain self-administration behavior or even maintain
responses that postpone or terminate their injection
(negative reinforcers). In the rat, however, self-administration
of (ethyl)ketazocine and nalorphine has been
reported.
B. Variables Interfering with Opioid
Self-Administration
Drug-taking behavior in general, and opioid selfadministration
in particular, is controlled by a number
of variables. The most commonly discussed variables
concern those that can readily be manipulated, e.g., the
dose of the drug administered, the route of administration,
the schedules of reinforcement, and the presence or
absence of physical dependence, tolerance, and sensitization.
In addition, a number of predisposing variables
(e.g., preexposure to opioids during gestation, environmental
factors, and genetic factors) can affect drugtaking
behavior. The contribution of these factors will be
discussed briefly. The discussion will focus on studies
with rhesus monkeys and rats since the reinforcing
properties of opioids have been studied most extensively
in these species.
1. Dose of the Drug. The dose of the drug per injection
(“unit dose”) is an important and critical factor in drugtaking
behavior. A linear function between the log dose
OPIOIDS, REWARD AND ADDICTION 351
of drug delivered per injection and the amount of drug
taken (Fig. 1) has been shown to exist for various opioids
in different species of animals (Weeks and Collins, 1964,
1979; Smith et al., 1976; Harrigan and Downs, 1978a;
Van Ree et al., 1978; Dai et al., 1989). Moreover, studying
heroin self-administration, it was demonstrated that
the linear relationship between the log unit dose and
drug intake is present during initial exposure to heroin
and in animals physically dependent on heroin (Van Ree
et al., 1978; Dai et al., 1989).
An intermediate dose range is optimal for maintaining
self-administration of morphine, whereas lower and
higher doses do not favor it. Data from a wide range of
unit doses for drug-naive rats taking i.v. morphine on a
continuous schedule of reinforcement have been reported
(Smith et al., 1976; Weeks and Collins, 1979). On
the fifth or sixth day of self-administration, a medium
dose of around 30 g/kg morphine per infusion maintained
a maximum number of i.v. deliveries. When lower
doses of morphine were tested, a progressive decrease in
the rate of self-administration was found, probably due
FIG. 1. Self-administration of morphine sulfate in rats. Presented are
the mean number of self-infusions (A) and the mean amount of drug
intake (B) by either the i.v. (F) or the intragastric route (E) versus the
unit dose of morphine sulfate per infusion. Data from Smith et al. (1976).