Role Of Cannabinoid CB1 Receptor Antagonist Rimonabant In Methamphetamine Conditioned Place Preference In Mice

Objectives: Methamphetamine (METH) is a commonly used, addictive drug, and a powerful stimulant that dramatically affects the central nervous system. METH users continually increased in our country in recent years. And its psychological dependence and serious adverse effects have been outstanding day by day. METH abuse not only brings about health problems to drug users, but also results in serious social problems. Drug addiction is a chronic, relapsing brain disorder. Repeated drug use associated with contexts lead to form an abnormally persistent rewarding memory. Similar to normal learning and memory, drug memory achieve a stable and relatively permanent state via an acquisition and consolidation process to form long term memory. However, they become labile when they are reactivated and must be reconsolidated to achieve a stable state again. Thus, some treatments could be used to block acquisition of memory via interfere with memory consolidation and impair original memory through disrupting memory reconsolidation. Cannabinoid CB1 receptor is a new target for drug addiction therapy. Endocannabinoids and CB1 receptor are widely distributed in memory-related brain regions, participated in memory modulation. There have been many studies to investigate the role of CB1 receptor in spatial or fear memory. Conclusions were not consistent since the types of memory were different. Drug-related memory studies using CB1 receptor were concentrated on extinction learning, which indicated that cannabinoid CB1 receptor blocked extinction process and inhibitory extinction behaviors. Conditioned place preference (CPP) paradigm has been widely used to evaluate the rewarding effect. Repeated association of drugs use with contexts predicting drug availability leads to long-lasting behavioral responses that reflect reward-controlled learning. METH-induced conditioned place preference (CPP), the preference for the specific place containing the METH conditioned cues over a natural control place, has been used as a behavioral paradigm for mimicking the METH use-associated memory. In this conditioning paradigm, repeated association of the specific environmental cues (conditioned stimulus) with METH-induced subjective euphoria (unconditioned stimulus) has been suggested to motivate animals'later approaching behavior toward the euphoria-linked environment at a drug-free status. In the present study, we used the conditioned place preference (CPP) paradigm in order to investigate the role of cannabinoid CB1 receptor antagonist in the drug-related memory.Methods: 1, Mice were divided into 6 groups which were saline-20min, saline-60min, 0.5mg/kg-20min, 0.5mg/kg-60min, 2mg/kg-20min and 2mg/kg-60min by different training paradigms. The acquisition of CPP was observed after training. The dose of METH and confining time were then identified and applied to subsequent experiments. 2, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p)and were given intra-peritoneal injections of different doses of rimonabant(0, 1.0mg/kg and 3.0mg/kg) immediately after each conditioning session. After 8 consecutive sessions, mice were tested for CPP. 3, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p). Administrations of different doses of rimonabant (0mg/kg, 1.0mg/kg and 3.0 mg/kg) were given 30min before place preference testing. Retesting of METH CPP was done 24 hours, 7 days or 14 days after rimonabant administration. On the 15th day, mice were injected with a priming dose of METH (0.5mg/kg) and were tested to see whether place preference was reinstated. 4, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p). Administrations of different doses of rimonabant (0mg/kg, 1.0mg/kg and 3.0 mg/kg) were given immediately after place preference testing. Retesting of METH CPP was done 24 hours, 7 days or 14 days after rimonabant administration. On the 15th day, mice were injected with a priming dose of METH (0.5mg/kg) and were tested to see whether place preference was reinstated. 5, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p). After 8 consecutive sessions and tested for METH CPP, mice were not given any treatment and were retest every 3 days. One day after the determination of place preference extinction, mice were injected with a priming dose of METH (0.5mg/kg) and were tested to see whether place preference was reinstated. Different doses of rimonabant (0mg/kg, 1.0mg/kg and 3.0 mg/kg) were administered 30 minutes prior to the priming injection of METH.Results: 1, Compared with saline groups, 4 METH groups with different training paradigms all expressed a METH CPP and no significant difference was found between any two groups. 2, Compared with vehicle group, post-training administration of 1mg/kg and 3mg/kg rimonabant blocked the acquisition of METH CPP, suggesting rimonabant disrupted consolidation of METH rewarding memory. 3, Compared with vehicle group, pre-test administration of 3mg/kg rimonabant inhibited CPP expression while other two groups expressed significant CPP, suggesting rimonabant blocked retrieval of METH rewarding memory. The effect lasted for at least 1 week. 4, Compared with vehicle group, 24h after post-testing administration of different doses of rimonabant, mice in 3mg/kg group which expressed significant CPP in the first place preference testing failed to express CPP the next day and in subsequent tests. However, mice in groups without retrieval expressed CPP persistently, suggesting the effect of rimonabant on memory reconsolidation was retrieval-dependent. 5, Compared with vehicle group, a dose of 0.5mgkg METH failed to induce the reinstatement of CPP in the group of 3mg/kg rimonabant, suggesting rimonabant could inhibit reinstatement of METH CPP.Conclusion: The present study indicated that mice expressed significant CPP produced by METH. Cannabinoid CB1 receptor antagonist disrupted consolidation, retrieval and reconsolidation of METH rewarding memory. A priming dose of METH induced reinstatement of CPP which could be attenuated by rimonabant.