ACCUMBENS Area DA Receptors And NMDA Receptors Influence Of Cocaine Self-administration Maintained

Cocaine is a powerful nervous system stimulant. The regular use of cocaine may cause cocaine addiction. Cocaine abuse does typically lead to severe physical and social problems. It has been classed as one of the five categories of common abused drugs by International Anti-drug Organization. The most extensively studied effect of cocaine on the central nervous system is the blockade of the dopamine transporter. Cocaine binds tightly at the dopamine transporter forming a complex that blocks the transporter’s function. The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates in the synaptic cleft. Dopamine-rich brain regions such as nucleus accumbens are frequent targets of cocaine addiction research. Large trials of single injection of dopamine receptor antagonist in NAc can be adjusting in cocaine addiction behavior, but, due to the variety way of drug delivery, experimental procedures, the effects of it were different. Moreover, lots of researches have shown that the glutamatergic system as an important contributor to the process of cocaine addiction. System or NAc local application of the nonselective NMDA receptor antagonists can cause the inhibition of cocaine intake. However, because of the serious side effects, it cannot be used in clinical trials. NMDA receptors mainly divided into two subtypes, NR2A-containing NMDA receptors and NR2B-containing NMDA receptors. Each subtype has its unique biophysics and pharmacological properties that might play a different role in cocaine addiction. Some studies have shown that the selective antagonists of NR2B-containing NMDA receptor had efficient neuronal protective effect with less adverse effect. Thus, functional modulation on NMDA receptor subtypes might be the key to cocaine addiction treatment. However, the role of the two kinds of subtypes of NMDA receptors in cocaine addiction is unclear.Here we used cocaine intravenous self-administration model to study the influence of repeated (5days) injection of D1or D2dopamine receptor antagonist into the NAc shell on cocaine addictive maintenance, extinction and relapse. We also observed the influence of repeated injection of NR2A-or NR2B-containing NMDA receptor antagonist on cocaine addictive maintenance.The purpose is to get the role of D1/D2receptors, NR2A/NR2B-containing NMDA receptors in cocaine addiction, and provides a new possible way for the treatment of cocaine addiction. The main results are as follows:(1) During the platform intra-accumbal shell microinjection of the saline failed to alter cocaine self-administration and rat’s weight, either initial or repeated pretreatment.(2) During the platform intra-accumbal shell microinjection of the D1receptor antagonist SCH-23390have different performance with the time course. Initial pretreatment failed to alter the intake of cocaine, but the patten of cocaine self-administration was be changed. During the first half of the test session, rats have no response for cocaine. But during the second half of the test session, rats intake cocaine at a higher rate. After repeated pretreatment, the behavior of cocaine self-administration completely suppressed. Pretreatment with D1receptor antagonist failed to alter rat’s weight.(3) During the platform intra-accumbal shell microinjection of the D2receptor antagonist sulpiride have different performance with the time course. Initial pretreatment failed to alter cocaine self-administration, but repeated pretreatment inhibited cocaine intake. Pretreatment with D2receptor antagonist failed to alter rat’s weight.(4) During the platform intra-accumbal shell microinjection of the NR2A-containing NMDA receptor antagonist NVP-AAM077have different performance with the time course. Initial pretreatment significantly reduced the effective response for cocaine and the weight of rats. The suppression effect was gradually reduced with repeated pretreatment.(5) During the platform intra-accumbal shell microinjection of the NR2B-containing NMDA receptor antagonist Ro25-6981failed to alter cocaine self-administration and rat’s weight, either initial or repeated pretreatment.(6) Intra-accumbal shell repeated microinjection of the D1or D2receptor antagonist during the platform and then training for extinction program. The rats response for cocaine were kept at the low level of pretreatment during the whole process of extinction.(7) Intra-accumbal shell repeated microinjection of the D1or D2receptor antagonist during the platform have no effect on cocaine relapse. These results suggest that:both D1and D2receptors in the NAc shell are involved in the maintenance of cocaine self-administration, selectively blocking one of that will significantly inhibit the cocaine self-administration and promote the withdrawal from cocaine addiction, but have no effect on cocaine priming-induced reinstatement. Rats are more sensitive to the D1receptor antagonist. Moreover, maintenance of cocaine self-administration is also dependent on the activation of NR2A-containing NMDA receptor, nor NR2B-containing NMDA receptor.