CHRONIC DRUGS: CNS BIOCHEMISTRY & BEHAVIOR

慢性药物：中枢神经系统生物化学

• 批准号: 3209387
• 负责人: RONALD KUCZENSKI
• 金额: $ 19.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-10-01 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3209387
• 关键词: amphetamines; behavior disorders; behavior test; brain metabolism; chordate locomotion; dopamine receptor; dosage; drug administration rate /duration; drug metabolism; drug tolerance; enzyme mechanism; haloperidol; laboratory rat; nerve endings; neurochemistry; neuropharmacology; neurotransmitter metabolism; psychopharmacology; radiotracer; scintillation spectrometry; self stimulation; tyrosine 3 monooxygenase

The repeated administration of amphetamine (AMPH) results in a progressive alteration in its behavioral response profile, and the mechanisms underlying these changes may have important implications for drug abuse. The limited success in identifying these mechanisms may be attributable to an incomplete understanding of how stimulant effects on CNS neurotransmitter functions relate to specific components of the behavioral response. Since the effects of stimulants are multiphasic and dynamic, continuous in vivo measures of synaptic neurotransmitter dynamics in freely-moving animals during the drug response may provide a more accurate perspective of neurotransmitter-behavior relationships than has been possiblle with post-mortem techniques. In fact, accumulating data indicate the feasibility and utility of this approach for the study of neurotransmitter dynamics in response to stimulants. One prominent feature of the behavioral response as a function of AMPH dose, chronicity, and individual variation in responsivity is the transition from locomotion to stereotypy. This proposal is aimed at testing our hypotheses that this transition is associated with (1) qualitative changes in striatal dopamine (DA) dynamics, which involve a switch from neuronal impulse-dependent to impulse- independent DA release; (2) an activation of dorsal raphe serotonin (5HT) projections to striatum; and (3) changes in the relative activity of mesostriatal and mesolimbic DA pathways. A complete characterization of the effects of acute AMPH on striatal DA, 5HT and acetylcholine will provide the basis for subsequent experiments designed to assess the hypothesized role of various systems and mechanisms in the behavioral transition. A variety of manipulations will be used to examine the contribution of DA neuronal impulse flow, and to test, in vivo, the validity of the exchange-diffusion model of AMPH-induced DA release. Both in vivo and vitro measures of receptor function will be used to assess the relationship of 5HT and DA receptor activation to components of the behavioral response. Concurrent dialysis of the striatum and nucleus accumbens are aimed at determining if the relative activation of mesostriatal and mesolimbic DA systems contribute to the emergence of stereotypy. The direct evaluation of synaptic neurotransmitter dynamics concomitant with behavioral analysis, and in conjunction with determinants of receptor activation, will provide a fundamental evaluation of stimulant-neurotransmitter interactions, and the basis for subsequent determination of the mechanisms underlying chronic stimulant-induced behavioral change.

反复服用安非他明(Amph)会导致 其行为反应特征的渐进性变化，以及 这些变化背后的机制可能会有重要的影响 因为滥用药物。在识别这些方面取得的有限成功 机制可能归因于对 刺激对中枢神经递质功能的影响如何与 行为反应的特定组成部分。因为这些影响 刺激剂是多相的、动态的、体内连续的 自由活动中突触神经递质动态变化的测量 动物在药物反应过程中可能会提供更准确的 神经递质-行为关系的视角 用尸检技术是可能的。事实上，积累 数据表明这种方法的可行性和实用性。 神经递质对刺激剂反应的动力学研究。一 作为AMPH函数的行为反应的显著特征 剂量、慢性化和个体响应性的差异是 从移动到刻板印象的转变。这项提议旨在 在测试我们的假设时，我们认为这种转变与 (1)纹状体多巴胺(DA)动态的质变 涉及到从神经元脉冲依赖到脉冲的转换- DA的独立释放；(2)中缝背侧5-羟色胺的激活 (5)向纹状体的投射；(3)相对的变化。 中纹状体和中脑边缘DA通路的活动。一个完整的 急性AMPH对纹状体DA、5-羟色胺影响的特征 而乙酰胆碱将为后续的实验提供基础 旨在评估各种系统和系统的假设角色 行为转变中的机制。各种各样的 操作将被用来检查DA的贡献 神经元脉冲流，并在体内测试 Amph诱导DA释放的交换-扩散模型。两者都在体内 受体功能的体外测量将被用来评估 5-羟色胺和多巴胺受体激活与脑组织成分的关系 行为反应。同时透析纹状体和 伏隔核的目的是确定相对的 激活中纹状体和中脑边缘DA系统有助于 刻板印象的出现。突触的直接评估 神经递质动力学伴随着行为分析，并且 结合受体激活的决定因素，将 提供刺激性神经递质的基本评估 相互作用，以及随后确定 慢性兴奋剂诱导的行为改变的潜在机制。