The neural substrates of amphetamine conditioned place preference: implications for the formation of conditioned stimulus-reward associations

Associations formed between conditioned stimuli and drug reward are major contributors in human drug addiction. To better understand the brain changes that accompany this process, we used immunohistochemistry for c-Fos (a neuronal activity marker), synaptophysin (a marker for synaptogenesis) and tyrosine kinase B receptor (a neurotrophic factor receptor that mediates synaptic plasticity) to investigate the neural substrates of amphetamine-induced conditioned place preference in rats. Conditioned place preference was induced by both 1.0 mg/kg and 0.3 mg/kg doses of amphetamine. Furthermore, amphetamine conditioning increased the density of c-Fos-immunoreactive cells and these cells were fully colocalized with the tyrosine kinase B receptor in the dentate gyrus, CA1 field and basolateral amygdala. Amphetamine conditioning increased the density of synaptophysin-immunoreactive varicosities in all brain regions studied, except the nucleus accumbens shell and dorsolateral striatum. The degree of conditioned place preference was highly correlated with c-Fos-immunoreactive cell density in the basolateral amygdala and with the density of synaptophysin-immunoreactive varicosities in all mesolimbic regions studied. The latter correlation was particularly impressive for the ventral pallidum and basolateral amygdala. The formation of conditioned stimulus-amphetamine reward associations is accompanied by tyrosine kinase B receptor expression in the basolateral amygdala and dentate gyrus, CA1 and CA3 fields of the hippocampus. These data therefore suggest that the formation of conditioned stimulus-reward associations requires, at least in part, activation of amygdalar-hippocampal circuits.     

Lack of evidence of a role for the neurosteroid allopregnanolone in ethanol-induced reward and c-fos expression in DBA/2 mice

Previous studies using the 5alpha-reductase inhibitor finasteride suggest that progesterone metabolites, particularly the endogenous neurosteroid allopregnanolone, mediate some of the effects of ethanol. Consequently, we studied the effect of finasteride (2 x 25 mg/kg s.c., 12 h apart) pretreatment on the acquisition and expression of ethanol (2 g/kg i.p.) induced conditioned place preference and c-fos expression in DBA/2 mice; a strain known to be particularly sensitive to ethanol. Ethanol administration induced a clear conditioned place preference and widespread c-fos expression, with elements of the extended amygdala, Edinger-Westphal nucleus and paraventricular nucleus being especially sensitive. However, despite an approximately 99% decrease in whole brain allopregnanolone content, finasteride pretreatment had remarkably little effect on either ethanol-induced conditioned place preference or ethanol-induced c-fos expression. Thus, aside from a general stimulatory effect on c-fos expression in the ventral tegmental area, and generally mild depression of locomotor activity, no other effects of finasteride or interaction with ethanol effects were identifiable. Together, these studies suggest that endogenous allopregnanolone plays little part in mediating acute ethanol-induced reward or neural activation in DBA/2 mice.     

Functional heterogeneity of the rat medial prefrontal cortex: effects of discrete subarea-specific lesions on drug-induced conditioned place preference and behavioural sensitization

While the principal components of the brain reward system, the nucleus accumbens septi and the ventral tegmental area have received much attention, their efferent and afferent structures have not been investigated to the same degree. One major input to this system originates from the medial prefrontal cortex (mPFC) which is not a homogenous structure but can be divided into different subareas that can be distinguished on anatomical and possibly functional grounds. We examined the effects of discrete bilateral quinolinic acid lesions (45 nmol/0.5 micro(L)) of each of the mPFC subareas, the infralimbic (il), prelimbic (pl) and the anterior cingulate (cg) mPFC, on the conditioned place preference (CPP) and psychomotor activation induced by several drugs. Lesions of the il mPFC blocked CPP induced by morphine (10 mg/kg) and CGP37849 [DL-(E)-2-amino-4-methyl-5-phosphono-3-pentic acid, a competitive N-methyl-D-aspartate receptor antagonist; 10 mg/kg]. Lesions of the pl mPFC blocked CPP induced by cocaine (15 mg/kg) and CGP37849, and lesions of the cg mPFC only blocked CGP37849-induced CPP. Lesions of the whole mPFC blocked morphine-, cocaine- and CGP37849-induced CPP. None of the lesions affected DL-amphetamine (4 mg/kg)-induced CPP. During the conditioning period, none of the lesions affected amphetamine-induced psychomotor activation and sensitization, whereas both phenomena were attenuated by pl and whole mPFC lesions in the case of cocaine, and by il and whole mPFC lesions in the case of morphine. These results show that the different mPFC subregions have distinct functional roles in the generation of behavioural effects produced by different classes of drugs. This heterogeneity should be taken into account in future studies addressing the role of the mPFC in drug reward and sensitization.     

Effects of withdrawal from an escalating dose of amphetamine on conditioned fear and dopamine response in the medial prefrontal cortex

Neurochemical studies have shown that mesocortical dopamine projections are particularly responsive in aversive situations such as fear conditioning. The present study assessed behavioural and medial prefrontal cortex (mPFC) dopamine responses utilizing in vivo microdialysis during acquisition and expression of a conditioned fear response. In two independent experiments, rats were presented with either two or nine tone-shock pairings during formation of a conditioned fear response. In the second experiment, rats were pre-treated with repeated injections of either amphetamine or saline over a 6-day period and tested during withdrawal. Amphetamine pre-treatment as well as the conditioning procedure itself potentiated an increase in dopamine levels during formation, but not expression of a conditioned fear response. Locomotor activity induced by an amphetamine challenge (1mg/kg) was also enhanced in pre-treated amphetamine compared to saline pre-treated animals (experiment two). However, mPFC dopamine response to amphetamine challenge did not differ between treatment groups. We conclude that while the exact role of mPFC dopamine in behavioural sensitization is yet to be determined, mPFC dopamine release may underlie the increased fear response during acquisition but not expression of fear response.     

Consequences of amygdala kindling and repeated withdrawal from ethanol on amphetamine-induced behaviours

It has been shown previously that chronic ethanol treatment in mice leads to accelerated behavioural sensitization to psychomotor stimulants [Manley & Little (1997) J. Pharmacol. Exp. Ther., 281, 1330-1339], whilst repeated experience of ethanol withdrawal sensitizes pathways underlying seizure activity (Becker & Hale (1993) Alcohol Clin. Exp. Res., 17, 94-98]. The aim of the current experiment was to investigate the consequences of repeated withdrawal from ethanol on amphetamine-induced behaviours in the rat and compare this with animals with electrical kindling of the amygdala, a procedure that has been shown to enhance alcohol withdrawal seizures [Pinel et al. (1975) Can. J. Neurol. Sci., 2, 467-475]. For the kindling experiments, electrodes were surgically implanted in the left basolateral amygdala and were stimulated daily at the afterdischarge threshold until a criterion of three consecutive stage 5 seizures was reached. Fully kindled rats showed a marginally significant reduction in sensitivity to the locomotor stimulant effects of acute amphetamine compared with sham and partially kindled rats which had experienced subthreshold stimulation of the amygdala. Sham and partially kindled rats sensitized readily to the locomotor activating effects of amphetamine (0.125 mg/kg) following repeated treatments, but the fully kindled rats did not. Fully kindled rats also failed to show place preference conditioning to amphetamine (0.5 mg/kg). Rats, withdrawn three times from chronic ethanol (liquid-diet), kindled more quickly to PTZ (30 mg/kg, i.p.) than rats with the same overall exposure to ethanol (24 days) followed by a single withdrawal or control animals. However, there was no difference in the locomotor stimulating effects of acute amphetamine (0.25-1 mg/kg, i.p.), the rate of sensitization to amphetamine (0.125 mg/kg, i.p.) or amphetamine induced conditioned place preference (1 mg/kg, i.p.). These observations suggest that, in rats, repeated withdrawal from a relatively mild chronic ethanol treatment modulates neuronal systems that may also be involved in PTZ-induced kindling but not those involved in either the acute stimulant effects of amphetamine or behavioural sensitization or appetitive conditioning following repeated amphetamine administration. Behavioural changes following amygdala kindling differed from those following repeated ethanol withdrawal, suggesting that withdrawal kindling from a mild ethanol treatment differs in its effects from amygdala kindling.     

A cannabinoid receptor antagonist attenuates conditioned place preference but not behavioural sensitization to morphine

The present study compared the effects of the cannabinoid receptor antagonist SR 141716 on morphine-induced locomotor sensitization (Experiment 1) and conditioned place preference (CPP, Experiment 2) in male albino Wistar rats. In Experiment 1, rats received seven consecutive daily treatments with morphine (10 mg/kg, SC) in combination with either SR 141716 (0, 0.1, 0.5 or 3.0 mg/kg, IP), or naloxone (10 mg/kg, IP). Three days later, all rats were challenged with a lower dose of morphine (5 mg/kg, SC). Rats pre-treated with morphine showed significantly elevated locomotor activity during the challenge session compared to vehicle-pre-treated animals indicating behavioural sensitization. Prior naloxone, but not SR 141716, co-administration with morphine, significantly attenuated the locomotor sensitization observed. In Experiment 2A, SR 141716 (0.1 mg/kg, IP), co-administered during conditioning, significantly attenuated the place preference produced by morphine (4 mg/kg, SC) in a standard unbiased two compartment place conditioning task. In Experiment 2B, the timing of drug administration and drug doses used were altered to be similar to Experiment 1, such that a comparison between the sensitization and CPP paradigms could be made. Thus, rats were conditioned with morphine (10 mg/kg, SC) combined with SR 141716 (0, 0.1, 0.5 or 3.0 mg/kg, IP) and tested for place preference under the influence of morphine (5 mg/kg, SC). SR 141716 attenuated morphine place preference at a dose (3.0 mg/kg) that did not itself affect place conditioning. Morphine also induced locomotor sensitization in the drug-paired compartment in Experiment 2B which was not blocked by any dose of SR 141716. We conclude that CB1 receptor antagonism modulates the rewarding value of opioids, but not the behavioural sensitization induced by chronic opioid administration.     

Potentiation of morphine-induced conditioned place preference with concurrent use of amantadine and fluvoxamine by the intraperitoneal and intracerebroventricular injection in rat

In this study, the effect of concurrent use of fluvoxamine and amantadine on morphine-induced conditioned place preference (CPP) was investigated by the intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) injection in rat. The CPP paradigms took place on 6 consecutive days by using an unbiased procedure. Our results showed that i.p. injection of morphine sulfate (2.5–10 mg/kg) induced CPP in rat. On day 6, fluvoxamine (5 and 10 mg/kg, i.p.), and amantadine (5 and 10 mg/kg, i.p.) both increased morphine-induced conditioned place preference. Intracerebroventricular injection of fluvoxamine (10 μg/rat) and amantadine (10 μg/rat) were also increased morphine-induced conditioned preference significantly. Concurrent use of fluvoxamine (5 mg/kg, i.p.; 10 μg/rat i.c.v.) and amantadine (10 mg/kg, i.p.; 10 μg/rat, i.c.v.) potentiated morphine-induced conditioned preference significantly. Release of dopamine from neurons cause reinforcing behavior. Morphine produces reinforcement (reward) effect by activation of μ receptors which facilitated dopaminergic transmission through dopamine release. Fluvoxamine, a serotonin reuptake inhibitor, increase serotonin concentration in synaptic clefts, which is a potent stimulator of dopamine release. Amantadine also appears to work by increasing dopamine release from neuron. In conclusion, our results show that concurrent use of fluvoxamine and amantadine potentiate morphine-like effect on CPP through increasing dopaminergic transmission and this combination may simulate the rewarding effect of morphine and can be candidate for controlling the drug compulsive seeking in morphine dependent subjects.     

Compartment-specific changes in striatal neuronal activity during expression of amphetamine sensitization are the result of drug hypersensitivity

Repeated exposure to drugs of abuse induces behavioural sensitization, i.e. a persistent hypersensitivity to the psychomotor stimulant effects of these drugs. This may be the result of increased responsiveness, to drugs, of mesostriatal dopamine systems and their projections, but it has also been suggested that acute and sensitized behavioural responses to psychostimulant drugs involve activation of distinct neuronal circuits. In order to distinguish between these possibilities, we studied amphetamine-induced c-fos immunoreactivity in subregions of rat striatum (patch and matrix compartments of caudate-putamen and nucleus accumbens core and shell) in drug-naive rats, as well as during long-term expression of amphetamine sensitization. We found that, in sensitized animals, amphetamine (1.0 mg/kg) evoked an increase in the ratio of c-fos-immunopositive cells in striatal patch and matrix compartments, suggesting a preferential involvement of striatal patches in the sensitized response to amphetamine. In drug-naive rats, amphetamine (0.5-5.0 mg/kg) dose-dependently increased c-fos expression in all striatal subregions. Remarkably, the highest dose of amphetamine also evoked an increase in patch : matrix ratio of c-fos immunoreactivity. In nucleus accumbens core and shell of amphetamine- and saline-pretreated animals, amphetamine (1.0 mg/kg) evoked comparable increases in c-fos expression. These data indicate that distinct striatal compartments display a differential sensitivity to amphetamine in both drug-naive and amphetamine-sensitized animals. In addition, they suggest that the shift in amphetamine-induced c-fos expression from striatal matrix to patches in sensitized animals is the consequence of a change in the sensitivity to amphetamine, rather than a long-term circuitry reorganization that is exclusive to the sensitized state.     

The Type IV phosphodiesterase inhibitor rolipram interferes with drug-induced conditioned place preference but not immediate early gene induction in mice

Behavioural effects of psychostimulant and opiate drugs are mediated in part by cAMP pathways operating in the nucleus accumbens. Degradation of cAMP occurs through the action of phosphodiesterases, such as the Type IV phosphodiesterases (PDE4s) that are found throughout the brain. To examine the potential role of PDE4 in reward-mediated behaviour, we measured the effects of rolipram, a PDE4 selective inhibitor, on cocaine (18 mg/kg i.p.) and morphine (5 mg/kg s.c.) conditioned place preference in Swiss Webster mice. Rolipram (0, 0.2 or 1.0 mg/kg i.p.) given 30 min prior to drug administration dose-dependently reduced conditioning due to both cocaine and morphine. However, rolipram did not affect place preference induced by food, nor did it prevent the expression of a previously established place preference conditioned by cocaine or morphine. In a second experiment, rolipram administered 30 min prior to a single cocaine injection (50 mg/kg i.p.), did not alter cocaine-induced c-Fos expression in the caudate putamen or nucleus accumbens core. However, rolipram, but not cocaine, induced c-Fos in the nucleus accumbens shell. These results indicate that elevation of cAMP in neurons that express PDE4s may attenuate the rewarding properties of cocaine and morphine, but does not alter the cocaine signalling cascade that induces c-Fos expression. Thus, PDE4-mediated regulation of cAMP levels could underlie the establishment of reward valence to abused drugs.     

The H3 antagonist thioperamide reveals conditioned preference for a context associated with an inactive small dose of cocaine in C57BL/6J mice

The histaminergic system has been speculated to be involved in the inhibitory control of drug reward, H1 and H2 antagonists having been found to potentiate conditioned place preference induced by morphine or cocaine. In contrast, the role of H3 receptors in cocaine-induced place preference is still unknown. The present study tested the effects of thioperamide (0, 10 and 20 mg/kg, i.p.), an H3 autoreceptor antagonist, on the development of a conditioned place preference induced by cocaine (0, 2 and 8 mg/kg, i.p.) in C57BL/6J mice. Thioperamide was injected 10 min before each cocaine-pairing session. The activity scores recorded on the first cocaine-pairing session were also used to test the effects of thioperamide on cocaine-induced locomotor activity. Thioperamide alone had no reinforcing effects and did not affect the conditioned place preference induced by 8 mg/kg cocaine. However, thioperamide dose-dependently revealed a conditioned place preference induced by 2 mg/kg cocaine, a dose that was inactive per se. Finally, thioperamide dose-dependently potentiated the stimulant effects of cocaine, in spite of its slight hypolocomotor effect when given alone. Our results strongly suggest that H3 antagonists potentiate the stimulant and reinforcing effects of cocaine in mice.     

The amygdala mediates memory consolidation for an amphetamine conditioned place preference.

Drug-induced conditioned place preference (CPP) behavior requires memory for an association between environmental cues and the affective state produced by the drug treatment. The present study investigated whether memory consolidation underlying an amphetamine CPP could be modulated by post-training intra-amygdala infusion of the local anesthetic drug bupivacaine. On 4 alternating days adult male Long-Evans rats received peripheral injections of amphetamine (2.0 mg/kg) or saline vehicle prior to confinement for 30 min to one of two compartments of a place preference apparatus, followed by post-training intra-amygdala infusions of bupivacaine (0.75% solution/1.0 microl) or saline. On day 5 the rats were given a drug-free 20-min test session, and the amount of time spent in each of the pairing compartments of the apparatus was recorded. On the test day, rats receiving post-training intra-amygdala saline injections displayed an amphetamine conditioned place preference. Post-training intra-amygdala infusions of bupivacaine blocked amphetamine CPP. Intra-amygdala infusions of bupivacaine that were delayed 1 h post-training did not block amphetamine CPP, indicating a time-dependent effect of the treatment on memory storage processes. Pre-training or pre-retention test intra-amygdala infusions of bupivacaine also blocked acquisition and expression of an amphetamine CPP, respectively. The findings indicate that the mechanism(s) by which amphetamine elicits conditioned approach responses to environmental cues can be manipulated post-training, and suggest a role for the amygdala in acquisition, consolidation, and expression of amphetamine CPP behavior.     

Systemic or intra-amygdala injections of glucose facilitate memory consolidation for extinction of drug-induced conditioned reward

The conditioned place preference (CPP) task has been used extensively to investigate the neurobiological bases of drug-induced reward. The initial expression of a CPP involves memory for an association between environmental stimuli and the affective state produced by a rewarding treatment. The present experiments examined the hypothesis that post-trial administration of glucose can facilitate memory consolidation processes underlying the extinction of drug-induced CPP behaviour. Adult male Long-Evans rats acquired an amphetamine CPP, and subsequently received extinction training. Immediately following extinction training, separate groups of rats received peripheral (100 mg/kg, 500 mg/kg, or 2 g/kg) or intra-amygdala (basolateral nucleus; 1.5 micro g/0.5 micro L or 10 micro g/0.5 micro L) injections of glucose or vehicle. Peripheral (100 mg/kg and 2 g/kg) and intra-amygdala (1.5 and 10 micro g) glucose injections facilitated the extinction of amphetamine CPP behaviour relative to vehicle-injected controls. Postextinction trial peripheral or intra amygdala glucose injections that were delayed 2 h had no effect. The findings indicate that: (i) extinction of approach behaviour to drug-associated cues involves the formation of new memories that undergo a time-dependent consolidation process; and (ii), systemic or intra-amygdala administration of a known memory-enhancing agent facilitates extinction of drug-induced CPP behaviour.     

Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice

The involvement of cannabinoid CB1 receptors in morphine and cocaine motivational effects was investigated using CB1 knockout mice. For this purpose, we evaluated the rewarding effects in the place conditioning paradigm and the sensitization to the locomotor responses induced by these drugs. The hyperlocomotion induced by acute morphine administration (15 mg/kg, s.c.) was preserved, but the sensitization to this locomotor response induced by chronic morphine treatment was abolished in CB1 mutant mice. Morphine (5 mg/kg, s.c.) induced conditioned place preference in wild-type mice but failed to produce any response in knockout mice, indicating the inability of morphine to induce rewarding effects in the absence of CB1 cannabinoid receptors. When the aversive effects of morphine withdrawal were investigated using the place aversion paradigm, no differences between genotypes were observed. Acute cocaine (10 mg/kg, i.p.) induced hyperlocomotor responses in wild-type and knockout mice and a chronic cocaine treatment produced a similar sensitization to this response in both genotypes. In the conditioning place preference paradigm, cocaine (20 mg/kg, i.p.) produced rewarding responses in both wild-type and knockout mice. These results demonstrate that CB1 receptors are essential for adaptive responses produced by chronic morphine but not by chronic cocaine treatment.     

Functional interaction between morphine and central amygdala cannabinoid CB1 receptors in the acquisition and expression of conditioned place preference

The present study was done to determine whether cannabinoid CB1 receptors of the central amygdala (CeA) are implicated in morphine-induced place preference. Using a 3-day schedule of conditioning, it was found that subcutaneous (s.c.) administration of morphine (2, 4 and 6 mg/kg) caused a significant dose-dependent conditioned place preference (CPP) in male Wistar rats. Intra-CeA microinjection of the cannabinoid CB1 receptor agonist arachidonylcyclopropylamide (ACPA; 0.5, 2.5 and 5 ng/rat) dose-dependently potentiated the morphine (2mg/kg)-induced CPP. Furthermore, the administration of ACPA (5 ng/rat, intra-CeA) alone induced a significant CPP. It should be considered that the higher dose of ACPA (5 ng/rat, intra-CeA) in combination with morphine decreased locomotor activity on the testing phase. On the other hand, intra-CeA microinjection of the cannabinoid CB1 receptor antagonist AM251 (120 ng/rat) alone induced a significant conditioned place aversion (CPA). Moreover, intra-CeA microinjection of AM251 (90 and 120 ng/rat) inhibited the morphine-induced place preference with a significant interaction. Intra-CeA microinjection of AM251 reversed the effect of ACPA on morphine response. Interestingly, microinjection of ACPA (2.5 and 5 ng/rat) or AM251 (60-120 ng/rat) into the CeA increased or decreased the expression of morphine (6 mg/kg)-induced place preference respectively. These observations provide evidence that cannabinoid CB1 receptors of the CeA are involved in mediating reward and these receptors are also implicated in the acquisition and expression of morphine-induced CPP.     

Interactions between modafinil and cocaine during the induction of conditioned place preference and locomotor sensitization in mice: Implications for addiction

Modafinil is a wake-promoting drug effective at enhancing alertness and attention with a variety of approved and off-label applications. The mechanism of modafinil is not well understood but initial studies indicated a limited abuse potential. A number of recent publications, however, have shown that modafinil can be rewarding under certain conditions. The present study assessed the reinforcing properties of modafinil using conditioned place preference and locomotor sensitization in mice. Experiment 1 examined a high dose of modafinil (75mg/kg) as well as its interactions with cocaine (15mg/kg). Cocaine alone and modafinil co-administered with cocaine induced sensitization of locomotor activity; modafinil alone showed little or no locomotor sensitization. Animals given modafinil alone, cocaine alone, and modafinil plus cocaine exhibited a strong and roughly equivalent place preference. When tested for sensitization using a low challenge dose of modafinil, cross-sensitization was observed in all cocaine-pretreated mice. Experiment 2 examined a low dose of modafinil that is similar to the dose administered to humans and has been shown to produce cognitive enhancements in mice. Low dose modafinil (0.75mg/kg) did not produce conditioned place preference or locomotor sensitization. Together, these results suggest that modafinil has the potential to produce reward, particularly in cocaine addicts, and should be used with caution. However, the typical low dose administered likely moderates these effects and may account for lack of addiction seen in humans.     

Effects of ethanol on nicotine-induced conditioned place preference in C57BL/6J mice

It has been shown that small doses of ethanol (相似文献   

Involvement of dopamine D(1) and D(2) receptors in the ethanol-associated place preference in rats exposed to conditioned fear stress.

The present study was designed to investigate: (1) the involvement of dopamine D(1) and D(2) receptors, and (2) the roles of these receptors and endogenous opioid systems (endorphinergic and enkephalinergic systems) in the ethanol-induced place preference in rats exposed to conditioned fear stress using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) induced a significant place preference. The selective D(1) receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H3-benzazepine)hydrochloride (SCH23390; 0.01 and 0.03 mg/kg, s.c.) and the selective D(2) receptor antagonist S(-)-5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2- methoxybenzamide (sulpiride; 20 and 40 mg/kg, s.c.) significantly attenuated the ethanol-induced place preference. The administration of ethanol (75 mg/kg, i.p.) tended to produce a place preference, but this effect was not significant. SCH23390 (0.03 mg/kg, s.c.) and sulpiride (40 mg/kg, s.c.) significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.). In addition, SCH23390 (0.03 mg/kg, s.c.) also significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12aalpha-octahydroquinolino[2,3,3,-g]isoquinoline (TAN-67; 20 mg/kg, s.c.). On the other hand, sulpiride (40 mg/kg) had no significant effect on the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by TAN-67. These results suggest that D(1) and D(2) receptors may be involved in the rewarding mechanism of ethanol under psychological stress. In addition, D(1) receptors may participate in the rewarding effect of ethanol modulated by the activation of mu- and delta-opioid receptors, whereas D(2) receptors may participate in the rewarding effect of ethanol modulated by the activation of mu-opioid receptors, but not in that modulated by the activation of delta-opioid receptors.     

Systemic administration of 1R,4S-4-amino-cyclopent-2-ene-carboxylic acid, a reversible inhibitor of GABA transaminase, blocks expression of conditioned place preference to cocaine and nicotine in rats

We examined the effect of 1R,4S-4-amino-cyclopent-2-ene-carboxylic acid (ACC), a reversible inhibitor of GABA transaminase, on the expression of conditioned place preference response to cocaine and nicotine in rats. Cocaine (20 mg/kg i.p.) and nicotine (0.4 mg/kg s.c.), but not vehicle or 300 mg/kg i.p. of ACC, produced a significant conditioned place preference response. Pretreatment of animals with 300 and 75 mg/kg i.p. of ACC significantly attenuated the expression of the cocaine- and nicotine-induced conditioned place preference responses, respectively. These results are the first to suggest that reversible inhibition of GABA transaminase may be useful in blocking cue-induced relapse to nicotine and cocaine.     

Haloperidol does not alter expression of ethanol-induced conditioned place preference

A recent experiment (Risinger et al., Psychopharmacology, 107 (1992) 453-456) has shown that haloperidol does not prevent acquisition of ethanol-induced conditioned place preference, suggesting that dopaminergic mechanisms do not mediate the primary rewarding properties of ethanol. The present experiment examined whether haloperidol would prevent the expression of conditioned reward to ethanol-paired stimuli using the place conditioning paradigm. DBA/2J mice received four pairings of a tactile stimulus with ethanol (2 g/kg, IP). A different stimulus was paired with saline. Before preference testing, different groups received one of three doses of haloperidol (0, 0.05 or 0.1 mg/kg); ethanol was not given. Haloperidol produced a dose-dependent decrease in locomotor activity, but did not affect conditioned place preference. These results suggest that expression of ethanol-induced conditioned place preference is mediated by non-dopaminergic mechanisms.     

Involvement of the sigma1 receptor in the cocaine-induced conditioned place preference

The sigma1 (sigma1) receptor constitutes a particular target of cocaine believed to be involved in some of its behavioral effects. In the present study, its involvement in the rewarding effect of cocaine was examined using the conditioned place preference (CPP) procedure. CPP was induced in C57Bl/6 mice injected repeatedly with cocaine (20 mg/kg, i.p.). The selective sigma1 receptor antagonists NE-100 and BD1047 (1-10 mg/kg, i.p.) significantly attenuated or blocked the cocaine-induced CPP. Animals treated centrally with a sigma1 receptor antisense oligodeoxynucleotide failed to develop cocaine-induced CPP, unlike mismatch controls. The sigma1 receptor thus appears to be critically involved in the development of the cocaine-induced CPP and, in consequence, may constitute a promising approach to blocking cocaine reward.