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

1994; Smith and McGinty, 1994). In addition, increased
dynorphin levels were demonstrated in the substantia
nigra, NAC, but not hippocampus (Sivam, 1989; Smiley
et al., 1990; Trujillo et al., 1990).
Studies on animals self-administering cocaine shed
some more light on the potential involvement of -endorphin
in processes underlying cocaine dependence.
Sweep et al. (1988, 1989) found marked decreases in
E-IR levels in the anterior part of the limbic system
(i.e., NAC, septum, hippocampus, and rostral striatum)
in animals self-administering cocaine. Furthermore, using
an in vivo autoradiographic technique, a decrease in
opioid receptor occupancy was found in restricted subcortical
brain regions of animals self-administering cocaine,
including limbic areas (i.e., lateral septum, ventral
pallidum, nucleus stria terminalis, and amygdala)
and some regions of the hypothalamus and thalamus
(Gerrits et al., 1999). The decrease in opioid receptor
occupancy is probably due to a release of endogenous
opioids in these particular brain regions. Interestingly,
both of these changes (i.e., decreased E-IR content and
increased endogenous opioid release) were present just
before a scheduled next cocaine self-administration session
would have taken place; thus, when the desire or
need for the drug is assumed to be high. This might
suggest an involvement of endogenous opioids, and possibly
-endorphin, in the processes underlying the need
for cocaine. When the same methodologies were used in
rats that just had completed their daily cocaine selfadministration
session, it appeared that E-IR levels in
the brain were hardly changed and that a decrease of
opioid receptor occupancy was present in many brain
areas, including the NAC (Sweep et al., 1988; Gerrits et
al., 1999). Daunais et al. (1993), investigating the effect
of cocaine self-administration on the expression of
dynorphin mRNA, found an increased expression in the
patch-like areas of the dorsal, but not in those of the
ventral, striatum. Because repeated high doses of cocaine
given for 6 to 7 days were necessary to induce this
effect, the authors concluded that the increased dynorphin
mRNA expression does not underlie the acute reinforcing
effects of cocaine but is more associated with
long-term adaptation and sensitization.
Besides regulating the level of endogenous opioids and
the expression of opioid mRNA in the brain, studies have
demonstrated that psychostimulant drugs also regulate
the density of opioid receptors in the brain. Chronic
cocaine exposure reduced opioid receptor density, as labeled
by [ 3 H]naloxone, in the hippocampus and striatum
and in the basolateral nucleus of the amygdala, VTA,
substantia nigra, and dorsal raphe nuclei (Ishizuka et
al., 1988; Hammer, 1989). An increase in opioid receptor
density was found in the NAC, ventral pallidum, and
lateral hypothalamus. In light of the selective opioid
receptors in the brain, studies were performed with
more selective radioligands. In short, chronic treatment
of rats with cocaine caused an up-regulation of -opioid
OPIOIDS, REWARD AND ADDICTION 375
receptors in the cingulate cortex, NAC, rostral caudate
putamen, and basolateral amygdala; an up-regulation of
-opioid receptors in the cingulate cortex, rostral caudate
putamen, olfactory tubercle, and VTA; and no
change in -opioid receptors in any of the brain regions
examined (Unterwald et al., 1992, 1994). Itzhak (1993),
studying the effect of chronic cocaine treatment on opioid
receptor densities in guinea pigs, found a significant
down-regulation of -opioid receptors in frontal cortex,
amygdala, thalamus, and hippocampus; an alteration in
the expression of -opioid receptors in the cerebellum;
and no significant changes in -opioid receptor expression.
Furthermore, it was shown that “binge” pattern of
cocaine administration led to significant decreases in
the level of -opioid receptor mRNA in the substantia
nigra but not in the caudate putamen (Spangler et al.,
1997). Finally, to determine the functional consequences
of chronic cocaine on opioid receptors, Unterwald et al.
(1993) measured changes in adenyl cyclase activity.
They found that chronic cocaine administration resulted
in a selective impairment of -opioid receptor-mediated
function in the caudate putamen and NAC.
In conclusion, a role for -opioid receptors and endorphin
in cocaine dependence seems likely. This role
may be at the level of modulating the reinforcing action
of cocaine and the motivational state induced by repeated
cocaine exposure. Concerning the - and -opioid
receptors and the dynorphin and enkephalin systems,
the data so far do not allow definitive conclusions. In
particular, it is not clear how to link effects of passive
administration of cocaine with the addiction, e.g., selfadministration
process.
B. Ethanol
In 1970, a biochemical link was proposed between
ethanol and opioid systems based on the finding that
condensation of the ethanol metabolite acetaldehyde
and biogenic amines produced tetrahydroisoquinolines
(TIQs). These TIQs seemed to have opioid-like effects
(Davish and Walsh, 1970; Cohen and Collins, 1970; Fertel
et al., 1980). Long-term ethanol self-administration
induced the formation of TIQs in the brain of rats (Collins
et al., 1990; Haber et al., 1996). Furthermore, TIQs
induced excessive alcohol drinking, an effect that was
modulated by morphine and naloxone (Critcher et al.,
1983). Evidence for an involvement of the endogenous
opioid systems in ethanol reinforcement and addiction is
provided by studies with opioid antagonists and agonists
(for reviews, see Herz, 1997; Spanagel and Zieglsgängsberger,
1997).
Opioid antagonists, such as naltrexone and naloxone,
decrease ethanol self-administration in rodents and
monkeys under a variety of different experimental conditions.
Although opioid blockade by antagonists blocked
intragastric (Sinden et al., 1983) and i.v. (Altshuler et
al., 1980; Martin et al., 1983) self-administration of ethanol,
the majority of studies on the involvement of en-