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

in the nucleus caudatus and periventricular gray, could
reinstate lever-pressing, previously resulting in i.v. heroin
or cocaine injections. This priming effect of morphine
was attenuated by prior administration o f naltrexone
(Stewart, 1984; Stewart et al., 1984).
Intracranial self-administration studies also suggest
that opioid systems in the NAC may be part of the
structures mediating the reinforcing effects of opioids.
Olds (1982) demonstrated that self-administration was
induced and maintained by morphine infusions (0.2 g/
inf) into the NAC and blocked by coadministration of
naloxone. Bozarth (1983), however, was not able to establish
a self-administration behavior of a similar dose
of morphine in this area. Based on the divergent findings
with respect to the involvement of the NAC in
opioid reinforcement, studies examining the effects of
intra-NAC administration of different quaternary opioid
antagonists on heroin self-administration were performed.
However, the results from these studies also
seem controversial. Britt and Wise (1983) did not find an
effect of intra-NAC infusions with the antagonist diallylnormorphinium
on the rate of i.v. heroin self-administration,
whereas others demonstrated that infusions
with a low dose of methylnaloxonium into the NAC
significantly attenuated i.v. heroin self-administration
(Vaccarino et al., 1985a; Corrigall and Vaccarino, 1988).
The discrepancy between the results of these studies
might be explained by the fact that diallyl-normorphinium,
unlike methylnaloxonium, has been shown to be ineffective
as an opioid antagonist in commonly used bioassays
for opioids and seems to have opioid agonistic properties
as well (Valentino et al., 1983). That the NAC may be
involved in opioid self-administration was also suggested
from data showing that kainic acid-induced lesion
of the cell bodies of the NAC disrupted i.v. heroin
and morphine self-administration (Zito et al., 1985).
Moreover, inactivation of G i and G 0 by injecting pertussis
toxin in the NAC resulted in a long-lasting increase
in i.v. heroin self-administration (Self et al., 1994; Self
and Nestler, 1995).
Some studies were aimed at a possible role of the
periaquaductal gray (PAG) in mediation of opioid reinforcement.
Intracranial self-administration studies
showed that morphine self-administration into the PAG
could not be established in opioid-naive rats (Bozarth,
1983). However, rats made physically dependent on
morphine by continuous intra-PAG infusion of morphine
for 72 h readily learned to self-administer 0.1-g infusions
of morphine into the PAG (Bozarth and Wise,
1984). In a study using mice it was, however, shown that
a low dose of morphine (5 ng/inf) was readily selfadministered
into the PAG by opioid-naive animals
(Cazala, 1990). Self-administration was more difficult to
detect in the opioid-naive mice when a 10 times higher
dose of morphine was applied, since the animals rapidly
adopted a strategy of delaying the infusions. Based on
his findings in mice, Cazala (1990) suggested that the
OPIOIDS, REWARD AND ADDICTION 359
absence of intra-PAG morphine self-administration in
opioid-naive rats (Bozarth, 1983) might originate from
the above-mentioned response-inhibiting effects which
could be present since a relatively high dose of morphine
(100 ng/inf) was offered. Opioid antagonist treatment
with methylnaltrexone (1 g) in the PAG significantly
increased heroin intake, suggesting a role of opioid receptors
in the PAG in opioid reinforcement (Corrigall
and Vaccarino, 1988).
In a study the role of the ventral pallidum, a major
projection area of the NAC, in mediation of opioid selfadministration
has been investigated. That is, lesions of
the ventral pallidum reduced heroin self-administration
in rats (Hubner and Koob, 1990). Another study suggests
an involvement of the pedunculopontine tegmental
nucleus in opioid reinforcement, in that lesions of the
pedunculopontine tegmental nucleus decreased the responding
for heroin infusions during acquisition of this
behavior (Olmstead et al., 1998).
Thus, opioid systems in specific areas in the brain are
involved in mediation of opioid reinforcement. Moreover,
it seems that opioid systems in different brain areas are
involved in distinct aspects of opioid actions. For instance,
it has been demonstrated that repeated morphine
infusions into the VTA did not produce signs of
withdrawal in the animal. Morphine self-administration
into the PAG and LH produced overt signs of physical
dependence (e.g., teeth chattering and wet dog shakes)
in animals challenged with naloxone (Bozarth and Wise,
1984; Cazala, 1990). This suggests that opioid systems
in the PAG and LH are involved in the physical dependence-creating
properties of opioids, whereas opioid systems
in the VTA, and possibly the NAC, might be more
concerned with the reinforcing effects of opioids.
With regard to the opioid systems in the VTA and
NAC, Vaccarino et al. (1985a) performed a study in
which they compared the effect of local treatment with
the quaternary opioid antagonist methylnaloxonium on
i.v. heroin self-administration. They found that the lowest
intra-NAC dose of methylnaloxonium needed to increase
heroin self-administration was 8 times lower
than the dose of the opioid antagonist that attenuated
i.v. heroin self-administration when injected into the
VTA. The authors suggested that opioid receptors in the
NAC play a crucial role in opioid reinforcement, while
those in the VTA might be of secondary importance in
mediating opioid self-administration. However, i.c. selfadministration
studies suggest the opposite. Intra-VTA
morphine self-administration is maintained by doses of
morphine (0.1 g/inf) (Phillips and LePiane, 1980;
Bozarth and Wise, 1981b; Devine and Wise, 1994)
that were not able to establish and maintain selfadministration
behavior in the NAC (Olds, 1982). Moreover,
in rats trained to i.v. self-administer heroin, application
of morphine centrally in the VTA, but not in the
PAG and the nucleus caudatus readily reinstated heroin
self-administration (Stewart, 1984). This priming effect