N-METHYL-D-ASPARTATE ANTAGONISTS AND TOLERANCE TO PSYCHOACTIVE DRUGS

描述(摘自申请者摘要)：兴奋性氨基酸 (EAA)受体，特别是N-甲基-D-天冬氨酸(NMDA)受体， 已被证明在学习和记忆中起着关键作用 减弱对原型阿片类吗啡的耐受性。 对吗啡的行为影响的耐受性已被证明是 受药理(非联想)和学习的影响 (关联)进程。拟议中的实验调查了 原型竞争性NMDA对药理学和行为学的影响 拮抗剂CGS 19755和典型的非竞争性N-甲基-D-天冬氨酸拮抗剂 地佐西平对发展耐受性行为的影响 吗啡。NMDA慢性给药的药理作用 拮抗剂对发展耐受性的抗伤害性作用 吗啡的含量将在大鼠尾巴戒断程序中确定。这些 实验将确定药理终点，如效力， N-甲基-D-天冬氨酸拮抗剂对吗啡作用的时程和效应 抗伤害和容忍。N-甲基-D-天冬氨酸受体拮抗剂对血管紧张素转换酶活性的影响 与环境有关的发展(即，联想学习) 对吗啡的耐受性也将通过戒断尾巴试验进行研究。 地佐西平对联想的保留或消退的影响 还将检查容忍度。最后，急性和慢性的影响 给予NMDA拮抗剂对小鼠耐受能力的影响 将对工具条件反射过程中的吗啡进行调查。 训练大鼠辨别3.2 mg/kg吗啡和生理盐水 固定比例的送餐时间表。NMDA拮抗剂将是 单独或与吗啡联合使用以确定是否 对吗啡刺激和减速作用的耐受性是 被更改了。

DESCRIPTION (Adapted from the Applicant's Abstract): Excitatory amino acid (EAA) receptors, and particularly the N-methyl-D-aspartate (NMDA) receptor, have been shown to play a critical role in learning and memory and to attenuate the development of tolerance to the prototypic opioid morphine. Tolerance to the behavioral effects of morphine has been shown to be influenced by both pharmacological (non-associative) and learning (associative) processes. The proposed experiments investigate the pharmacological and behavioral influence of the prototypic competitive NMDA antagonist, CGS 19755, and the prototypic noncompetitive NMDA antagonist, dizocilpine, on the development of tolerance to the behavioral effects of morphine. The pharmacological effects of chronic administration of NMDA antagonists on the development of tolerance to the antinociceptive effects of morphine will be determined in a rat tail-withdrawal procedure. These experiments will determine pharmacological endpoints such as potency, time-course, and effectiveness of NMDA antagonists on morphine-induced antinociception and tolerance. The influence of NMDA antagonists on the development of environmentally associated (i.e., associatively learned) tolerance to morphine will also be studied using the tail-withdrawal assay. The effects of dizocilpine on the retention or extinction of associative tolerance will also be examined. Finally, the effect of acute and chronic administration of NMDA antagonists on the development of tolerance to morphine in an instrumental conditioning procedure will be investigated. Rats will be trained to discriminate 3.2 mg/kg morphine from saline under a fixed-ratio schedule of food delivery. NMDA antagonists will be administered either alone or in conjunction with morphine to determine if tolerance to the stimulus and rate-decreasing effects of morphine are altered.