CHRONIC DRUGS: CNS BIOCHEMISTRY & BEHAVIOR

慢性药物：中枢神经系统生物化学

• 批准号: 3209392
• 负责人: RONALD KUCZENSKI
• 金额: $ 22.26万
• 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/3209392
• 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.

苯丙胺（AMPH）的重复给药导致 在其行为反应曲线中进行性改变， 这些变化背后的机制可能具有重要意义 因为吸毒 在识别这些方面取得的有限成功 机制可能是由于不完全了解 中枢神经系统神经递质功能的刺激作用与 行为反应的特定组成部分。 由于影响 在体内，兴奋剂是多相的、动态的、连续的 自由运动中突触神经递质动力学的测量 在药物反应期间的动物可以提供更准确的 神经递质-行为关系的观点 是不可能的 事实上， 数据表明，这种方法的可行性和实用性， 对刺激物反应的神经递质动力学的研究。 一 作为AMPH功能的行为反应的突出特征 剂量、慢性和个体反应性的变化是 从运动到刻板的转变。 该提案旨在 在测试我们的假设时， (1)纹状体多巴胺（DA）动力学的质的变化， 涉及到神经元从冲动依赖性到冲动依赖性的转变， 独立DA释放;（2）中缝背核5-羟色胺激活 (5HT)纹状体的投射;（3）相对的变化 中纹状体和中脑边缘DA通路的活性。 一个完整 急性AMPH对纹状体DA、5 HT影响的特征 乙酰胆碱将为后续实验提供基础 旨在评估各种系统的假设作用， 行为转变的机制。 各种 操作将被用来检查DA的贡献 神经冲动流，并测试，在体内，的有效性， AMPH诱导DA释放的交换扩散模型。 在体内 受体功能的体外测量将用于评估 5-HT和DA受体激活与脑组织成分的关系 行为反应 同时进行纹状体透析， 原子核的目的是确定是否相对 中纹状体和中脑边缘DA系统的激活有助于 刻板印象的出现。 突触的直接评价 神经递质动力学伴随行为分析，以及 与受体活化的决定因素结合，将 提供刺激性神经递质的基本评价 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。