PSYCHOMOTOR STIMULANTS AND ADRENERGIC NERVE FUNCTION

精神运动兴奋剂和肾上腺素能神经功能

• 批准号: 3211523
• 负责人: CHARLES B SMITH
• 金额: $ 20.27万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3211523
• 关键词: alpha adrenergic receptor; atrium; brain; caffeine; central nervous system stimulants; cocaine; dextroamphetamine; dihydroxyphenylalanine; dopamine beta monooxygenase; drug addiction; electrochemistry; electrostimulus; epididymis; guinea pigs; high performance liquid chromatography; laboratory rat; methylphenidate; neurotransmitter metabolism; norepinephrine; parasympathetic nervous system; radiotracer; sympathetic nervous system; synapses

Presynaptic receptors are thought to be important in the regulation of transmitter release from a variety of neurons. The alpha2 adrenergic receptor is located upon noradrenergic, serotonergic, dopaminergic and cholinergic neurons and, when stimulated, inhibits neurotransmitter release. The proposed project is based upon the following hypotheses: 1) presynaptic alpha2 adrenergic receptors on noradrenergic neurons in the central nervous system are important sites for the pharmacological actions of psychotropic drugs, especially those psychomotor stimulants such as cocaine and the amphetamines which are known to release catecholamines from neurons and block neurotransmitter reuptake; 2) long-term administration of such drugs causes changes in presynaptic receptor number, affinity and/or function which differ from those produced by short-term drug administration, and those changes in alpha2 adrenergic receptor function after long-term psychomotor stimulant drug administration reflect those which occur in drug- dependent individuals; 3) psychomotor stimulants which produce dependence modify alpha2 adrenergic receptor function at specific cellular sites (e.g. alpha adrenergic receptors located upon nerve endings vs those located on cell bodies), upon specific types of neurons (e.g. noradenergic vs cholinergic neurons) and at specific sites in the brain (e.g. hippocampus vs brainstem). Receptor-ligand binding studies will be performed in order to determine whether the number and/or affinities of various adrenergic receptors change after either short- or long-term psychomotor stimulant drug administration. Functional changes in presynaptic alpha2 adrenergic receptors located upon noradrenergic neurons will be determined in three different preparations: 1) superfused, electrically stimulated rat brain slices 2) the isolated rat vas deferens preparation and 3) isolated rat left atrial strips. The release of neurotransmitter during electrical stimulation of neurons in these preparations will be determined by measuring one or more of the following parameters: a) the release of 3H-norepinephrine after incubating the tissues with 3H-norepinephrine or its precursor, 3H- dihydroxyphenylalanine, b) the efflux of endogenous neurotransmitter by a combination of high pressure liquid chromatography and electrochemical detection, c) the release of dopamine beta-hydroxylase, an enzyme which is released with norepinephrine but which is not taken back up into the neuron or d) changes in the responses of the isolated muscle preparations.

突触前受体被认为很重要 调节发射机从多种神经元释放。 这 α2肾上腺素能受体位于甲肾上腺素能， 血清素能，多巴胺能和胆碱能神经元，以及 刺激，抑制神经递质释放。 提议 项目基于以下假设：1）突触前 α2肾上腺素能受体在去甲肾上腺素能神经元中 中枢神经系统是重要场所 精神药物的药理作用，尤其是那些 可卡因和苯丙胺等精神运动兴奋剂 众所周知会从神经元和 阻止神经递质再摄取； 2）长期管理 这些药物会导致突触前受体数的变化， 亲和力和/或功能与由 短期药物管理和α2的变化 长期心理运动后的肾上腺素能受体功能 刺激药给药反映了药物中发生的药物 - 依赖的人； 3）产生的精神运动兴奋剂 依赖性修改α2肾上腺素能受体功能 特定的细胞位点（例如位于α肾上腺素能受体 在神经末端与位于细胞体上的那些），在特定的 神经元的类型（例如，诺雷丁能与胆碱能神经元）和AT 大脑中的特定部位（例如海马与脑干）。 将进行受体 - 配体结合研究，以便 确定各种数量和/或亲和力是否 短期或长期后，肾上腺素能受体发生变化 精神运动刺激药物管理。 功能变化 位于突触前α2肾上腺素能受体 去甲肾上腺素能神经元将在三种不同的 准备工作：1）超液，电刺激的大鼠脑 切片2）孤立的大鼠VAS递延制剂和3） 老鼠离开心房条。 神经递质在 这些制剂中神经元的电刺激将是 通过测量以下一个或多个来确定 参数：a）孵化后释放3H-甲肾上腺素 具有3H-肾上腺素或其前体的组织3h- 二羟基苯丙氨酸，b）内源性的外流 神经递质通过高压液体的组合 色谱和电化学检测，c）释放 多巴胺β-羟化酶，一种释放的酶 去甲肾上腺素，但没有返回神经元或 d）孤立肌肉制剂的反应变化。