Allen Richard M, Carelli Regina M, Dykstra Linda A, Suchey Therese L, Everett Carson V
Department of Psychology, University of Colorado at Denver and Health Sciences Center, CB No. 173, P.O. Box 173364, Denver, CO 80217, USA.
J Pharmacol Exp Ther. 2005 Oct;315(1):449-57. doi: 10.1124/jpet.105.086355. Epub 2005 Jul 15.
It is difficult to determine the precise role of the N-methyl-D-aspartate (NMDA) receptor system in the reinforcing effects of cocaine since uncompetitive NMDA receptor antagonists alter cocaine self-administration in different ways, depending on the antagonist examined and the behavior being measured. To increase understanding of the role of the NMDA system in cocaine's reinforcing effects, this study measured the effects of the competitive NMDA receptor antagonist, LY235959 [(-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid], in rats that self-administered cocaine under both fixed ratio (FR) 1 and progressive ratio (PR) schedules of reinforcement. Rats were trained to self-administer cocaine (0.33 mg/infusion) under an FR1 schedule of reinforcement. Thereafter, the effects of pretreatment with LY235959, or the uncompetitive antagonists dextromethorphan and dizocilpine, were examined. The number of infusions earned during the first 10 min of responding under the FR1 schedule was analyzed separately. When rats responded for 0.33 mg/infusion cocaine under an FR1 schedule of reinforcement, 3 mg/kg LY235959 decreased cocaine self-administration only during the first 10 min of the responding. This effect was dose and time dependent and blocked by the competitive NMDA receptor agonist, NMDA. LY235959 (3 mg/kg) decreased total responding for cocaine only when the self-administered dose of cocaine was small (0.02-0.04 mg/infusion) or when responding was reinforced under the PR schedule. In contrast, dizocilpine decreased responding under the FR1 schedule but increased responding under the PR schedule. These data suggest that LY235959 decreased the reinforcing effectiveness of cocaine, a finding reported with systemically administered NMDA receptor antagonists other than dizocilpine.
由于非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂会以不同方式改变可卡因的自我给药行为，具体取决于所检测的拮抗剂以及所测量的行为，因此很难确定NMDA受体系统在可卡因强化作用中的确切作用。为了增进对NMDA系统在可卡因强化作用中作用的理解，本研究测量了竞争性NMDA受体拮抗剂LY235959 [(-)-6-膦酰甲基-十氢异喹啉-3-羧酸] 对在固定比率（FR）1和累进比率（PR）强化程序下自我给药可卡因的大鼠的影响。大鼠在FR1强化程序下接受训练以自我给药可卡因（0.33毫克/输注）。此后，研究了LY235959或非竞争性拮抗剂右美沙芬和地佐环平预处理的效果。分别分析了在FR1程序下最初10分钟反应期间获得的输注次数。当大鼠在FR1强化程序下对0.33毫克/输注可卡因作出反应时，3毫克/千克LY235959仅在反应的最初10分钟内减少了可卡因的自我给药。这种作用具有剂量和时间依赖性，并被竞争性NMDA受体激动剂NMDA阻断。仅当自我给药的可卡因剂量较小（0.02 - 0.04毫克/输注）或在PR程序下强化反应时，LY235959（3毫克/千克）才会减少对可卡因的总反应。相比之下，地佐环平减少了FR1程序下的反应，但增加了PR程序下的反应。这些数据表明，LY235959降低了可卡因的强化效力，这一发现与除地佐环平之外的全身给药NMDA受体拮抗剂的报道一致。
