Effects Of The NMDA Receptor Glycine-site Antagonist 7-chlorothiokynurenic Acid On The Cocaine Rewarding Memory In Rats

Objectives: Drug addiction is a chronic recurrent cerebrosis. Although the research on drug addiction has been conducted extensively and intensively, the effective therapy has not been found so far. Drug addiction is closely related to learning memory. As the important base of memory formation, long-term potentiation (LTP) and long-term depression (LTD) of the glutamate postsynaptic membrane take part in the drug addiction related modifiability of behavior such as relapse and behavioral sensitization by alter the excitability of postsynaptic membrane. Thus the glutamate system, especially the NMDA receptor has get more and more focus in the research of drug addiction. Former studies have found that competitive and noncompetitive NMDA receptor antagonists can inhibit the conditioned place preference induced by addictive drugs. However, both of these two kinds of NMDA receptor antagonists are likely to result in severe side effects and imply the abuse potential. On the contrary, glycine modulatory site of NMDA receptor antagonist induce neither severe side effects nor rewarding effect. The purpose of this study was to examine whether 7-Chlorothiokynurenic acid (7-CTKA), a glycine modulatory site of NMDA receptor antagonist, would disrupt the acquisition and reconsolidation of cocaine-related reward memory, using conditioned place preference paradigm (CPP).Methods: 1, Rats were divided into 4 groups (n = 8 per group) to be trained for cocaine CPP(10mg/kg i.p., 45min)and received 7-CTKA (0 and 5μg/side) micro-infusions bilaterally into the VTA or NAc 10 min before daily administration of cocaine every other day, respectively. After 8 consecutive sessions, rats were tested for CPP. 2, Four groups of rats (n = 8 per group) were pretreated with 7-CTKA (0 and 5μg/side) micro-infusion bilaterally into the VTA or NAc 10 min before administering systemic cocaine. Locomotor activity was determined for 1 hours using the Animal Locomotor Video Analysis System. 3, After the 8-day conditioning sessions, Four groups of rats (n = 8 per group) received one of the following treatments 10 min before cocaine memory retrieval: vehicle, 7-CTKA (5μg/μl). Twenty-four hours later, cocaine CPP was retested. 4, Rats were divided into 4 groups (n = 8 per group) to be trained for cocaine CPP (10mg/kg i.p., 45min). After 8 consecutive sessions, rats were tested for CPP and received 7-CTKA (0 and 5μg/side) micro-infusions bilaterally into the VTA or NAc immediately after the retrieval trial, respectively.Results: 1, After cocaine CPP training, the CPP score was significantly increased in the groups of rats that received vehicle and 7-CTKA micro-infusions bilaterally into NAc, but not 7-CTKA micro-infusions bilaterally into the VTA compared with baseline, suggesting 7-CTKA (5μg/side) micro-injected in VTA, but not NAc disrupted acquisition of cocaine rewarding memory. 2, Compared with vehicle group, the groups of rats that received 7-CTKA in the VTA or NAc revealed no significant difference. The results suggest that intra-VTA or NAc administration of the glycine antagonist 7-CTKA did not affect cocaine-induced locomotion. 3, A significant differences for CPP score were only observed in the rats micro-injected with vehicle in the VTA, but not NAc, compared with baseline, suggesting 7-CTKA (5μg/side) micro-injected in VTA, but not NAc blocked retrieval of cocaine rewarding memory. 4, Compared with vehicle group, the rats received 7-CTKA micro-infusions into VTA, but not NAc, expressed significant CPP in the first place preference testing failed to express CPP the next day tests. In the priming test, there was no significant difference for the CPP score in the 7-CTKA-VTA group, but not 7-CTKA-NAc group between the priming_post and priming_pre test, indicating that 7-CTKA micro-injected in VTA, but not NAc can disrupt the reconsolidation and reinstatement of cocaine rewarding memory and the inhibitory effect of 7-CTKA lasted at least 2 weeks.Conclusions: The present study demonstrated that 7-CTKA micro-injected into VTA, but not NAc, impaired the acquisition, retrieval, reconsolidation and reinstatement of cocaine CCP. A priming dose of cocaine induced reinstatement of CPP which could be attenuated by 7-CTKA micro-injected into VTA, but not NAc. Our findings suggest that glycine modulatory site of NMDA receptors in the VTA play a major role in cocaine reward memory, and glycine modulatory site of NMDA receptor antagonists may be a potential pharmacotherapy to manage relapse associated with drug-reward-related memory.