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

the effects of morphine to induce conditioned place preference
(Carlezon et al., 1997). The proposed functional
NMDA antagonist acamprosate was found to prevent
the acquisition of naloxone-precipitated morphine withdrawal-induced
place aversion (Kratzer and Schmidt,
1998).
Administration of an antagonist of the CB1 cannabinoid
receptor, SR 141716 (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide)
blocked the development of morphine place
preference (Chaperon et al., 1998). In addition, prenatal
exposure to 9 -tetrahydrocannabinol appeared to cause
increased sensitivity to the ability of morphine to induce
conditioned place preference (Rubio et al., 1998).
Opposite roles for different types of cholecystokinin
(CCK) receptors in the induction of morphine-induced
place preference have been suggested. Antagonists of
CCK-A receptors, as well as mixed CCK receptor antagonists,
appeared to block the development of morphineinduced
conditioned place preference (Higgins et al.,
1992b; Singh et al., 1996a,b). In contrast, blockade of
CCK-B receptors was reported to actually enhance opioid-induced
place preference, although in another study
a CCK-B antagonist appeared to have no such effect
(Higgins et al., 1992b; Singh et al., 1996b; Valverde et
al., 1996). When administered during the development
of morphine physical dependence, CCK-B antagonists,
but not CCK-A antagonists appeared to inhibit the place
aversion induced by subsequent treatment with naloxone
(Valverde and Roques, 1998).
An inhibitory influence of histamine receptor stimulation
on morphine-induced place-conditioning was suggested
in a study which showed that administration of a
histamine H2 antagonist, which by itself also induced
place preference, potentiated the effects of morphine on
place-conditioning. In addition, a histamine synthesis
inhibitor was also shown to potentiate, whereas administration
of a histamine precursor inhibited morphineinduced
place preference (Suzuki et al., 1995b).
The induction of place aversion induced by lithium chloride
was found to be blocked by coadministration of naloxone
as well as previous lesions of the mediobasal hypothalamus,
which markedly reduced brain -endorphin levels
(Shippenberg et al., 1988b). Chronic administration of
a lithium-containing diet, which did not modify central
-endorphin levels or release, was shown to inhibit place
preference and aversion induced by morphine or naloxone,
respectively. The effects of amphetamine and U69,593 on
place-conditioning were not modified by lithium, suggesting
that lithium might counteract the effects of receptor
ligands (Shippenberg and Herz, 1991).
Calcium channel blockers have been shown to inhibit
acquisition of morphine-place preference (Kuzmin et al.,
1992a; Biala and Langwinski, 1996), as was also shown
for nitric oxide synthase inhibitors (Kivastik et al.,
1996). Calcium-dependent endopeptidase inhibitors
were found to have a similar effect (Lyupina et al., 1996).
OPIOIDS, REWARD AND ADDICTION 369
Inhibition of morphine-induced place preference was
also found with cyclosporine A; this effect was absent in
a -opioid receptor-deficient mouse strain (Suzuki et al.,
1993). In addition, inflammation blocked the development
of morphine place preference, whereas adrenalectomy
was found to potentiate it (Suzuki et al., 1995a,
1996a). In diabetic mice, the capacity of morphine to
induce place preference was enhanced, possibly through
increased -opioid receptor function (Kamei et al., 1997).
Naloxone blocked the place preference induced by Substance
P or a Substance P analog (Hasenohrl et al.,
1991).
The involvement of nondopaminergic neurotransmitter
and neuromodulator systems in opioid place-conditioning
has only been sparsely investigated. Of these systems, a
role for 5-HT and CCK systems in opioid place-conditioning
can be proposed, as well as for NMDA receptors. With
respect to the latter system, the effects of NMDA antagonists
on morphine-induced place-conditioning are not due
to the induction of state-dependent learning (Tzschentke
and Schmidt, 1997), and it has been shown that in selfadministration
and ICSS models, NMDA receptor antagonists
potentiate the reinforcing properties of morphine
and cocaine (Carlezon and Wise, 1993a; Ranaldi et al.,
1996, 1997). Thus, it is likely that the effects of NMDA
antagonists on morphine-induced place-conditioning reflect
the disruptive effects of NMDA antagonists on learning
(Morris et al., 1986; Bliss and Collingridge, 1993).
B. Variables Interfering with Opioid Place Preference
A meta-analysis has been conducted on conditioned
place preference studies with morphine and heroin (as
well as cocaine and amphetamine) in rats, published
between 1979 and 1992 (Bardo et al., 1995). The influence
of a variety of experimental factors was analyzed.
These included drug dose, route of administration, number
of conditioning trials, trial duration, test duration,
drug compartment, number of apparatus compartments,
and use of intervening saline trials or a preconditioning
test, as well as sex, strain, and housing conditions of the
animals. The data revealed no consistent influence of
the sex of the animals used. When the data were analyzed
for strain effects, Sprague-Dawley and Wistar rats
were found to be more sensitive to the place-conditioning
effects of morphine and heroin than other strains. With
regard to social circumstances, individual housing at the
time of the experiment appeared to enhance the sensitivity
for heroin-induced place-conditioning. It has, however,
also been described that isolation rearing made
rats less sensitive to the ability of morphine and heroin
to establish conditioned place preference (Schenk et al.,
1983, 1985; Wongwitdecha and Marsden, 1996). Indeed,
it was recently shown that rats reared in enriched environments
were more sensitive to morphine-induced
place-conditioning than animals reared under impoverished
circumstances, which included social isolation
(Bardo et al., 1997). With respect to social status, dom-