Mianserin enhancement of ethanol-induced conditioned place preference

This experiment examined the influence of mianserin, a 5-HT(2) receptor antagonist, on the rewarding effect of ethanol in a place conditioning paradigm. Swiss-Webster mice received four pairings of a tactile stimulus with drug treatment consisting of two i.p. injections separated by a 30min interval. Drug treatment groups were as follows: saline (10mg/kg) followed by ethanol (2mg/kg); mianserin (10mg/kg) followed by ethanol; mianserin followed by saline. A different stimulus was paired with two saline injections. During conditioning, ethanol produced increases in locomotor activity that were reduced by mianserin. Mianserin alone reduced activity levels. As expected, group saline-ethanol showed a nonsignificant trend towards conditioned place preference. However, mianserin enhanced the acquisition of ethanol preference, whereas mianserin alone did not produce either place preference or aversion. The results are consistent with the notion that serotonergic systems are important in the response to ethanol, and further suggest that 5-HT(2) receptor blockade increases the rewarding effects of ethanol.     

Effects of dopamine receptor antagonists on the acquisition of ethanol-induced conditioned place preference in mice

Rationale

Studies support differential roles of dopamine receptor subfamilies in the rewarding and reinforcing properties of drugs of abuse, including ethanol. However, the roles these receptor subfamilies play in ethanol reward are not fully delineated.

Objective

To examine the roles of dopamine receptor subfamilies in the acquisition of ethanol-induced conditioned place preference (CPP), we pretreated animals systemically with antagonist drugs selective for dopamine D1-like (SCH-23390) and D2-like (raclopride) receptors prior to ethanol conditioning trials.

Methods

Effects of raclopride (0–1.2 mg/kg) and SCH-23390 (0–0.3 mg/kg) on the acquisition of ethanol-induced CPP were examined in DBA/2J mice (experiments 1 and 2). Based on significant effects of SCH-23390, we then determined if SCH-23390 (0.3 mg/kg) produced a place preference on its own (experiment 3). To evaluate whether SCH-23390 impaired learning, we used a conditioned place aversion (CPA) paradigm and pretreated animals with SCH-23390 (0–0.3 mg/kg) before conditioning sessions with LiCl (experiment 4).

Results

Whereas raclopride (0–1.2 mg/kg) did not affect acquisition, SCH-23390 (0.1–0.3 mg/kg) impaired the development of ethanol-induced CPP. SCH-23390 (0.3 mg/kg) did not produce place preference when tested alone and SCH-23390 (0.1–0.3 mg/kg) did not perturb the acquisition of LiCl-induced CPA.

Conclusions

Our results support a role for dopamine D1-like but not D2-like receptors in ethanol’s unconditioned rewarding effect as indexed by CPP. Blockade of D1-like receptors did not affect aversive learning in this procedure.     

Extinction of ethanol-induced conditioned place preference and conditioned place aversion: effects of naloxone

 Four experiments examined the effect of naloxone pretreatment on the expression and extinction of ethanol-induced conditioned place preference (experiments 1, 2, 4) or conditioned place aversion (experiments 1, 3). DBA/2 J mice received four pairings of a distinctive tactile (floor) stimulus (CS) with injection of ethanol (2 g/kg) given either immediately before or after 5-min exposure to the CS. A different stimulus was paired with injection of saline. Pre-CS injection of ethanol produced conditioned place preference, whereas post-CS injection of ethanol produced conditioned place aversion. Both behaviors extinguished partially during repeated choice testing after vehicle injection. Naloxone (10 mg/kg) had little effect on the initial expression of conditioned place preference, but facilitated its extinction. Moreover, repeated naloxone testing resulted in the expression of a weak conditioned place aversion to the CS that initially elicited a place preference. In contrast, naloxone (1.5 or 10 mg/kg) enhanced expression of conditioned place aversion, thereby increasing its resistance to extinction. A control experiment (experiment 4) indicated that repeated testing with a different aversive drug, lithium chloride, did not affect rate of extinction or produce an aversion to the CS previously paired with ethanol. These findings do not support the suggestion that naloxone facilitates the general processes that underlie extinction of associative learning. Also, these data are not readily explained by the conditioning of place aversion at the time of testing. Rather, naloxone’s effects appear to reflect a selective influence on maintenance of ethanol’s conditioned rewarding effect, an effect that may be mediated by release of endogenous opioids. Overall, these findings encourage further consideration of the use of opiate antagonists in the treatment of alcoholism. Received: 4 December 1997 / Final version: 16 February 1998     

Lack of effect of dopamine receptor blockade on expression of ethanol-induced conditioned place preference in mice

Abstract Rationale. Self-administration studies have suggested that dopamine (DA) is important for the reinforcing effects of ethanol. However, ethanol place conditioning studies have less consistently demonstrated a role for DA in conditioned place preference. Objectives. The purpose of the present study was to determine whether blockade of D₁, D₂ or D₃ DA receptors would impact the expression of the conditioned place preference induced by ethanol in DBA/2J mice. Methods. Mice underwent an unbiased place conditioning procedure with 2 g/kg ethanol. Prior to the preference test, mice were injected i.p. with SCH23390 (0, 0.015 or 0.03 mg/kg), raclopride (0, 0.3 or 0.6 mg/kg) or U99194A (0, 10 or 20 mg/kg). Results. Ethanol produced a significant conditioned place preference that was not affected by any of the dopamine antagonists tested. Each of the antagonists decreased locomotor activity, though U99194A was minimally effective. Conclusions. These findings suggest that the conditioned reinforcing effects of ethanol in DBA/2J mice as assessed by place conditioning are mediated by non-dopaminergic mechanisms. Electronic Publication     

Effect of Ro 15-4513 on ethanol-induced conditioned place preference.

The benzodiazepine receptor inverse agonist Ro 15-4513 reverses a number of ethanol's effects, including its reinforcing properties as measured through self-administration. The present study examined the effect of this putative ethanol antagonist in a place conditioning design that has been shown to be sensitive to ethanol's rewarding properties in mice. Using an unbiased differential conditioning procedure, DBA/2J mice received, on alternate days, pairings of a distinctive floor stimulus (CS+) with either ethanol (2 g/kg), Ro 15-4513 (3 mg/kg), or a combination of ethanol and Ro 15-4513. On alternate days, a different distinctive floor stimulus (CS-) was paired with vehicle. Under these conditions, ethanol produced a conditioned place preference that was unaffected by Ro 15-4513. Ro 15-4513 alone did not produce either a place preference or aversion. Ro 15-4513 did produce reductions in locomotor activity during conditioning, indicating it was behaviorally active. These results indicate that a dose of Ro 15-4513 that alters general activity does not affect ethanol reward.     

Proximal ethanol pretreatment interferes with acquisition of ethanol-induced conditioned place preference

Neurobiological mechanisms underlying rewarding and aversive effects of drugs are often studied by examining effects of various pretreatments on acquisition of conditioned place preference (CPP) or conditioned place aversion (CPA). However, few studies have looked at effects of pretreatment with the same drug used during conditioning. Such studies might offer insight into agonist actions on conditioning while also mimicking real world contingencies experienced by drug users. Previous work from our laboratory, which showed that same drug pre-exposure interfered with acquisition of ethanol CPA but not CPP, was limited by the use of only one pre-treatment time interval (65 min). Thus, the present studies were designed to study other intervals (-5, -15, -30). Pretreatment of DBA/2J mice with ethanol (2 g/kg) reduced the activity response normally evoked by the conditioning dose (2 g/kg) at all pretreatment times, but acquisition of CPP was disrupted only by pretreatment at -5 min. The overall pattern of findings suggests that ethanol's early pharmacological effects interfered with learning the association between the conditioned stimulus (CS) and ethanol 5 min later. Thus, one would expect ethanol agonists, when administered in close proximity to CS-ethanol pairings, to interfere with control of ethanol seeking by that CS.     

左旋四氢巴马汀对吗啡条件性位置偏爱的影响

目的探讨不同剂量的左旋四氢巴马汀(lTetrahydropalmatine,lTHP)对吗啡诱导的条件性位置偏爱(CPP)的影响以及自身能否产生CPP效应。方法本实验采用倾向性实验程序,①对♂SD大鼠sc吗啡(5.00mg·kg-1)或生理盐水(NS)训练8d,d9测定大鼠对伴药侧的偏爱效应或测试前40minipNS或不同剂量的lTHP(1.25～5.00mg·kg-1),观察这些预处理对该效应的影响;②测量不同剂量的lTHP(1.25～5.00mg·kg-1)慢性用药(每天1次,ip)对CPP效应消退的影响;③测试ipNS或lTHP(1.25～5.00mg·kg-1)能否诱导大鼠对伴药侧产生偏爱(方法同吗啡)。结果5.00mg·kg-1吗啡诱导大鼠对伴药盒产生明显的CPP;测试前ip2.50mg·kg-1或5.00mg·kg-1的lTHP明显降低吗啡诱导的CPP效应的表达(P<0.05),其慢性给药明显加速吗啡CPP效应的消退;3个剂量的lTHP均不能诱导大鼠形成CPP。结论lTHP能抑制吗啡的奖赏效应,可在吗啡成瘾的治疗中发挥一定的作用。     

Haloperidol reduces ethanol-induced motor activity stimulation but not conditioned place preference

This experiment examined the impact of a dopamine receptor blocker on ethanol's rewarding effect in a place conditioning paradigm. DBA/2J mice received four pairings of a tactile stimulus with ethanol (2 g/kg, IP), haloperidol (0.1 mg/kg, IP) + ethanol, or haloperidol alone. A different stimulus was paired with saline. Ethanol produced increases in locomotor activity that were reduced by haloperidol. However, conditioned preference for the ethanol-paired stimulus was not affected by haloperidol. Haloperidol alone decreased locomotor activity during conditioning and produced a place aversion. These results indicate a dissociation of ethanol's activating and rewarding effects. Moreover, they suggest that ethanol's ability to induce conditioned place preference is mediated by nondopaminergic mechanisms.     

GABAA receptors modulate ethanol-induced conditioned place preference and taste aversion in mice

  Rationale: GABA_A receptor antagonists have been shown to reduce ethanol self-administration and ethanol-induced conditioned taste aversion (CTA) in rats, suggesting a role for the GABA_A receptor in modulating ethanol’s motivational effects. Objectives: The present experiments examined the effects of the GABA_A receptor antagonists, bicuculline and picrotoxin, on the acquisition of ethanol-induced conditioned place preference (CPP) and CTA in male DBA/2J mice. Methods: Mice in the CPP experiments received four pairings of ethanol (2 g/kg) with a distinctive floor stimulus for a 5-min conditioning session (CS+ sessions). During CS+ sessions, mice also received bicuculline (0, 1.0, 3.0, or 5.0 mg/kg) or picrotoxin (2.0 mg/kg) before an injection of ethanol. On intervening days (CS– sessions), the pretreatment injection was always vehicle followed by saline injections that were paired with a different floor type. For the preference test, all mice received saline injections and were placed on a half grid and half hole floor for a 60-min session. For the CTA experiments, mice were adapted to a 2-h per day water restriction regimen followed by five conditioning trials every 48 h. During conditioning trials, subjects received an injection of vehicle, bicuculline (0.5 and 2.0 mg/kg), or picrotoxin (0.75 and 2.5 mg/kg) before injection of 2 g/kg ethanol or saline following 1-h access to a saccharin solution. Results: Both picrotoxin and the lowest dose of bicuculline (1.0 mg/kg) significantly increased the magnitude of CPP relative to vehicle-treated controls. Picrotoxin alone did not produce place conditioning. Ethanol-stimulated locomotor activity was significantly reduced during conditioning trials with picrotoxin and the higher doses of bicuculline (3.0 and 5.0 mg/kg). Bicuculline did not alter ethanol-induced CTA; however, picrotoxin dose-dependently increased the magnitude of ethanol-induced CTA. Bicuculline and picrotoxin did not produce CTA when administered alone. Conclusions: Overall, these results suggest that blockade of GABA_A receptors with bicuculline and picrotoxin enhances ethanol’s motivational effects in the CPP paradigm; however, only picrotoxin enhances ethanol’s motivational effects in the CTA paradigm. Received: 12 September 1998 / Final version: 21 December 1998     

CB1 receptor knockout mice display reduced ethanol-induced conditioned place preference and increased striatal dopamine D2 receptors.

Cannabinoids and ethanol activate the same reward pathways, and recent advances in the understanding of the neurobiological basis of alcoholism suggest that the CB1 receptor system may play a key role in the reinforcing effects of ethanol and in modulating ethanol intake. In the present study, male CB1 receptors knockout mice generated on a CD1 background displayed decreased ethanol-induced conditioned place preference (CPP) compared to wild-type (CB1(+/+)) mice. Ethanol (0.5, 1.0, 1.5, and 2.0 g/kg) induced significant CPP in CB1(+/+) mice at all doses tested, whereas it induced significant CPP only at the highest dose of ethanol (2.0 g/kg) in CB1(-/-) mice. However, there was no genotypic difference in cocaine (20 mg/kg)-induced CPP. There was also no genotypic difference, neither in cocaine (10-50 mg/kg) nor in D-amphetamine (1.2-5 mg/kg)-induced locomotor effects. In addition, mutant and wild-type mice did not differ in sensitivity to the anxiolytic effects of ethanol (1.5 g/kg) when tested using the elevated plus maze. Interestingly, this decrease in ethanol efficacy to induce CPP in CB1(-/-) mice was correlated with an increase in D2/D3 receptors, as determined by [3H]raclopride binding, whereas there was no difference in D1-like receptors, as determined by [3H]SCH23390 binding, measured in the striatum from drug-naive mice. This increase in D2/D3 binding sites observed in CB1 knockout mice was associated with an altered locomotor response to the D2/D3 agonist quinpirole (low doses 0.02-0.1 mg/kg) but not to an alteration of quinpirole (0.1-1.0 mg/kg)-induced CPP compared to wild-type mice. Altogether, the present results indicate that lifelong deletion of CB1 receptors reduced ethanol-induced CPP and that these reduced rewarding effects of ethanol are correlated to an overexpression of striatal dopamine D2 receptors.     

Effects of acute withdrawal on ethanol-induced conditioned place preference in DBA/2J mice

Rationale

Reexposure to ethanol during acute withdrawal might facilitate the transition to alcoholism by enhancing the rewarding effect of ethanol.

Objective

The conditioned place preference (CPP) procedure was used to test whether ethanol reward is enhanced during acute withdrawal.

Methods

DBA/2J mice were exposed to an unbiased one-compartment CPP procedure. Ethanol (0.75, 1.0, or 1.5 g/kg IP) was paired with a distinctive floor cue (CS+), whereas saline was paired with a different floor cue (CS?). The withdrawal (W) group received CS+ trials during acute withdrawal produced by a large dose of ethanol (4 g/kg) given 8 h before each trial. The no-withdrawal (NW) group did not experience acute withdrawal during conditioning trials but was matched for acute withdrawal experience. Floor preference was tested in the absence of ethanol or acute withdrawal.

Results

All groups eventually showed a dose-dependent preference for the ethanol-paired cue, but development of CPP was generally more rapid and stable in the W groups than in the NW groups. Acute withdrawal suppressed the normal activating effect of ethanol during CS+ trials, but there were no group differences in test activity.

Conclusions

Acute withdrawal enhanced ethanol’s rewarding effect as indexed by CPP. Since this effect depended on ethanol exposure during acute withdrawal, the enhancement of ethanol reward was likely mediated by the alleviation of acute withdrawal, i.e., negative reinforcement. Enhancement of ethanol reward during acute withdrawal may be a key component in the shift from episodic to chronic ethanol consumption that characterizes alcoholism.     

Acquisition and expression of ethanol-induced conditioned place preference in mice is inhibited by naloxone

The effects of opioid antagonists on conditioned reward produced by ethanol provide variable and sometimes conflicting results, especially in mice. In the present set of experiments, male C57BL/6 mice received 4 vehicle and 4 ethanol conditionings, and the rewarding effects of ethanol were assessed in an unbiased version of the conditioned place preference (CPP) apparatus and an unbiased stimulus assignment procedure. Intraperitoneal (ip) administration of ethanol (2 g/kg, but not 1 g/kg) resulted in the conditioned reward when conditionings lasted for 6 min but not when conditioning lasted for 20 min. Administration of the non-selective opioid receptor antagonist naloxone (1 and 5 mg/kg) before the conditionings attenuated the acquisition of ethanol-induced place preference. Naloxone (1 mg/kg) also inhibited expression of the CPP response, but it did not alter the preference of vehicle-conditioned mice, suggesting the lack of its own motivational effects in this experimental setting. Taken together, the present results suggest that an unbiased version of ethanol-induced CPP in C57BL/6 mice could be a valid model for the study of the motivational effects of ethanol, confirming and expanding previous findings that have demonstrated inhibitory effects of opioid receptor antagonist on alcohol conditioned reward.     

Allopregnanolone does not influence ethanol-induced conditioned place preference in DBA/2J mice

Rationale The neurosteroid allopregnanolone (ALLOP; 3-hydroxy-5-pregnan-20-one) produces behavioral and discriminative characteristics similar to that of ethanol (EtOH) and can modulate some of the behavioral and electrophysiological effects of EtOH.Objective The present experiments investigated ALLOP modulation of the effects of EtOH in a place conditioning procedure in male DBA/2J mice.Methods In a series of experiments examining different EtOH doses (1, 2 g/kg) and ALLOP administration times, ALLOP (0, 3.2, 10, 17 mg/kg, IP) was administered four times with EtOH prior to placement on a distinctive floor (CS+). On alternate days, vehicle was administered prior to a saline injection paired with the other floor stimulus (CS–). In a separate experiment, finasteride (0, 50, 100 mg/kg, IP), a 5-reductase inhibitor that blocks ALLOP synthesis, was administered prior to both CS+ and CS– trials. In a final experiment, animals were place conditioned to EtOH alone, and ALLOP (0, 3.2, 10, 17 mg/kg, IP) was administered prior to the preference test only.Results During conditioning, ALLOP increased and finasteride decreased EtOH-stimulated activity compared with vehicle pretreatment. Acquisition of 2 g/kg EtOH-induced conditioned place preference was observed in all mice, regardless of treatment with either ALLOP or finasteride. Similarly, ALLOP did not modulate the expression of EtOH-induced place preference. EtOH increased brain ALLOP levels compared with saline; however, ALLOP administration produced dose-dependent elevations in brain ALLOP levels that were not further augmented by EtOH (2 g/kg) administration.Conclusions These findings indicate that ALLOP does not modulate EtOH-induced place conditioning in male DBA/2J mice.     

Nicotine place preference in a biased conditioned place preference design

Conditioned place preference (CPP) is often more effectively produced with nicotine using a biased procedure. Interpretation of results can be problematic, however, given that doses that produce CPP in rats have acute anxiolytic and residual anxiogenic effects. We tested three groups of male rats in a biased, 2-chambered apparatus. Over eight conditioning days, one group (paired group) received four alternating injections of nicotine paired with the non-preferred (white) chamber and of saline in the preferred (black) chamber. A second group (counterbalanced group) received two nicotine injections each paired with the black and white chambers, with saline pairings on alternate days. A third group (saline control) received saline injections paired with both chambers. Following conditioning, the paired group spent significantly more time in the initially non-preferred chamber relative to saline-treated controls, suggesting CPP. The counterbalanced group did not show a significant preference shift, providing evidence that the observed preference shift in the paired group was not due to a drug-induced unconditioned reduction in aversion. Although this finding is consistent with the notion that nicotine produced CPP through its rewarding effects, we cannot discount the possibility of a conditioned reduction in aversion to the non-preferred chamber. For the paired group, a negative correlation was found between time spent in the white chamber before conditioning and preference shift following conditioning, suggesting that animals showing greater initial aversion to a non-preferred context are more likely to form CPP.     

Involvement of nucleus accumbens dopamine D1 receptors in ethanol drinking, ethanol-induced conditioned place preference, and ethanol-induced psychomotor sensitization in mice

Rationale

Dopamine D1 receptor (D1R) signaling has been associated to ethanol consumption and reward in laboratory animals.

Objectives

Here, we hypothesize that this receptor, which is located within the nucleus accumbens (NAc) neurons, modulates alcohol reward mechanisms.

Methods

To test this hypothesis, we measured alcohol consumption and ethanol-induced psychomotor sensitization and conditioned place preference (CPP) in mice that received bilateral microinjections of small interference RNA (siRNA)-expressing lentiviral vectors (LV-siD1R) producing D1R knock-down. The other group received control (LV-Mock) viral vectors into the NAc.

Results

There were no differences in the total fluid consumed and also no differences in the amount of ethanol consumed between groups prior to surgery. However, after surgery, the LV-siD1R group consumed less ethanol than the control group. This difference was not associated to taste neophobia. In addition, results have shown that down-regulation of endogenous D1R using viral-mediated siRNA in the NAc significantly decreased ethanol-induced behavioral sensitization as well as acquisition, but not expression, of ethanol-induced place preference.

Conclusions

We conclude that decreased D1R expression into the NAc led to reduced ethanol rewarding properties, thereby leading to lower voluntary ethanol consumption. Together, these findings demonstrate that the D1 receptor pathway within the NAc controls ethanol reward and intake.     

Post-retrieval propranolol treatment does not modulate reconsolidation or extinction of ethanol-induced conditioned place preference

The reconsolidation hypothesis posits that established emotional memories, when reactivated, become labile and susceptible to disruption. Post-retrieval injection of propranolol (PRO), a nonspecific β-adrenergic receptor antagonist, impairs subsequent retention performance of a cocaine- and a morphine-induced conditioned place preference (CPP), implicating the noradrenergic system in the reconsolidation processes of drug-seeking behavior. An important question is whether post-retrieval PRO disrupts memory for the drug-cue associations, or instead interferes with extinction. In the present study, we evaluated the role of the β-adrenergic system on the reconsolidation and extinction of ethanol-induced CPP. Male DBA/2J mice were trained using a weak or a strong conditioning procedure, achieved by varying the ethanol conditioning dose (1 or 2 g/kg) and the number of ethanol trials (2 or 4). After acquisition of ethanol CPP, animals were given a single post-retrieval injection of PRO (0, 10 or 30 mg/kg) and tested for memory reconsolidation 24 h later. Also, after the first reconsolidation test, mice received 18 additional 15-min choice extinction tests in which PRO was injected immediately after every test. Contrary to the prediction of the reconsolidation hypothesis, a single PRO injection after the retrieval test did not modify subsequent memory retention. In addition, repeated post-retrieval administration of PRO did not interfere with extinction of CPP in mice. Overall, our data suggest that the β-adrenergic receptor does not modulate the associative processes underlying ethanol CPP.     

The selective metabotropic glutamate receptor 7 allosteric agonist AMN082 prevents reinstatement of extinguished ethanol-induced conditioned place preference in mice

Alcohol dependence is considered a major public health problem in modern societies. The role for glutamatergic neurotransmission in the reinforcing effects of ethanol is becoming increasingly evident. Our previous findings have shown that in rats, the mGluR7 positive allosteric agonist AMN082, but not its allosteric antagonist MMPIP, prevented ethanol consumption and preference in the two-bottle choice paradigm. This study was conducted to determine the effects of AMN082 and MMPIP on the extinction and reinstatement of ethanol-elicited place preference (CPP) in C57BL/6 mice. AMN082 and MMPIP were administered during extinction of ethanol CPP to determine whether mGluR7 signaling is required. Furthermore, the effects of AMN082 and MMPIP on reinstatement of CPP were also evaluated. Finally, spontaneous locomotor activity and ethanol pharmacokinetics were assessed following systemic administration of AMN082 and MMPIP. Our results indicate that mGluR7 pharmacological modulation had no effect on ethanol-elicited CPP extinction. In contrast, mGluR7 activation using AMN082 reduced ethanol-induced CPP reinstatement, an effect reversed by co-administration of MMPIP. Collectively, these results indicate, for the first time, that activation of the mGluR7 receptor is effective in reducing the reinstatement of conditioned rewarding effects of ethanol. Taken together, the efficacy of AMN082 on the various phases of alcohol-CPP could represent an interesting pharmacological approach and could open a new line of research for the development of therapies to reduce ethanol intake in patients.     

Morphine conditioned place preference in the hamster

Two experiments investigated the ability of morphine to produce a conditioned place preference in the hamster. In Experiment 1, it was found that a 15 mg/kg dose of morphine produced a conditioned place preference after eight conditioning trials. In addition, naloxone (0.4 mg/kg blocked the development of the morphine-conditioned place preference and itself produced a conditioned place aversion after four conditioning trials. In Experiment 2, the effects of four doses of morphine (0, 2.5, 5 and 15 mg/kg) on the acquisition of a conditioned place preference were studied. Only the 15 mg/kg dose produced a significant place preference. Compared to similar findings in the rat, the present results indicate that a relatively high dose of morphine is required to produce a conditioned place preference in the hamster.     

Magnesium-induced conditioned place preference in mice

A conditioned place preference procedure was used in mice to test the hypothesis that magnesium possesses reinforcing properties. Mice were conditioned to the nonpreferred end of a three-compartment straight shuttle box with MgCl2 injections alternating with saline injections on the preferred end. Dose of MgCl2 was varied (0, 15, 30, 125 mg/kg) as well as number of conditioning trials (8 or 16). On the day after the first postconditioning test, animals were given acute injections of 5 mg/kg cocaine, or other test drug, to determine if the conditioned effect on behavior would be potentiated, maintained or blocked by these test drugs. Results demonstrated that 15 mg/kg MgCl2 induced the greatest amount of conditioning and that increasing the number of MgCl2/place pairings did not enhance the amount of conditioning, but rather, it decreased it. Amphetamine potentiated MgCl2-induced place preference; cocaine and pentobarbital maintained it; and haloperidol blocked it. These data indicate that MgCl2 has some primary reinforcing properties in mice and that MgCl2 shares stimulus properties with other stimulants and reinforcing substances.     

Acute blockade of CB1 receptor leads to reinstatement of MDMA-induced conditioned place preference

Cannabis is one of the drugs most commonly consumed in combination with ecstasy (3,4-methylenedioxymethamphetamine, MDMA). Although numerous studies have attempted to further our understanding of the role of the cannabinoid system in drug abuse, few have focused on how it influences the rewarding effects of MDMA. The aim of the present study was to evaluate the role of the CB1 cannabinoid receptor in vulnerability to reinstatement of a MDMA-induced conditioned place preference (CPP). Mice were first conditioned with 5 mg/kg of MDMA. Once the preference had been extinguished, a priming dose of MDMA, alone or plus the CB1 cannabinoid agonist WIN 55,212-2 (0.1 and 0.5 mg/kg) or the CB1 cannabinoid antagonist SR 141716A (0.3 mg/kg), was administered on alternate days. The CB1 receptor antagonist, alone or with any of the priming doses of MDMA, induced reinstatement of the preference. In contrast, WIN 55,212-2 had no effect on reinstatement of the MDMA-induced CPP when administered alone, but potentiated the effects of subthreshold priming doses of MDMA. These results highlight the important role of the CB1 receptor in vulnerability to reinstatement of drug-seeking behavior and point to the importance of the endocannabinoid system in the addictive potential of MDMA.