DOPAMINE RECEPTOR SUBTYPES & FUNCTION

至少两种不同的多巴胺（DA）受体亚型（D1和D2）， 存在于大脑中。 与对每种药物有选择性的激动剂联合治疗 亚型elevated增强行为反应（即刻板）相对 各自产生的影响。 本项目的长期目标 目的是阐明纹状体D1和D2系统在 调节胆碱能和GABA能神经元的活动， 方面的影响. 该项目的具体目标是提供药理学 以下假设的证据：1）纹状体D1和D2受体 系统独立调节纹状体黑质传出，因此激活 两个系统都导致功能输出的收敛， 行为反应（刻板）。 为了验证这个假设，我们将 确定D1（SKF 38393，非诺多泮）或 D2（喹吡罗）激动剂通过纹状体内（i.s.）和 黑质内注射GABA拮抗剂印防己毒素和GABA 激动剂蝇蕈醇。 生物化学研究将检查 多巴胺受体激动剂对黑质GABA更新和释放的影响。 尝试选择性阻断D1（SCH 23390）和D2的作用 （舒必利）拮抗剂将测试纹状体黑质GABA活性是否 由这些受体亚型独立调节。 2)胆碱能 纹状体中的拮抗剂（例如东莨菪碱; SCOP）引起DA样 通过局部或反馈调节D2神经传递的行为效应 而不是通过将纹状体DA能信息传递给运动神经元来实现 输出区域。 为了验证这一假设，我们将确定DA合成是否 抑制或消耗减弱了观察到的i.s. SCOP加D1激动剂非诺多泮），如果需要完整的D2受体， 这种效应（使用受体灭活剂EEDQ），如果 联合使用D1和D2激动剂后获得的增强作用被以下物质减弱： 埃. oxotremorine（一种胆碱能激动剂）。 3)不同的启发 刻板行为的组成部分（嗅闻和口腔行为）需要激活 D2受体的不同部分。 为了验证这个假设，我们将 在不同比例的D2失活后测量这些响应 具有EEDQ的受体。 从这些基础研究中获得的见解是 期望进一步了解多巴胺能系统， 因此，神经精神障碍，包括精神错乱 在该发射器的活动中（例如帕金森病和 精神分裂症）。 此外，这些成果可能会带来丰硕的新成果。 治疗这些疾病和相关疾病的策略。

At least two distinct dopamine (DA) receptor subtypes (D1 and D2) are present in the brain. Combined treatment with agonists selective for each subtype elicits potentiated behavioral response (i.e. stereotypy) relative to effects produce by each alone. The long term objective of this project is to elucidate the relative influence of striatal D1 and D2 systems in regulating cholinergic and GABAergic neuronal activities which mediate DNA effects. The specific aims of this project are to provide pharmacological evidence for the following hypotheses: 1) Striatal D1 and D2 receptor systems independently regulate striatonigral efferents, thus activation of both systems leads to convergent functional output and potentiated behavioral response (stereotypy). To test this hypothesis, we will determine whether the behavioral effects of D1 (SKF 38393, fenoldopam) or D2 (quinpirole) agonists are potentiated by intrastriatal (i.s.) and intranigral injection of the GABA antagonist picrotoxin and the GABA agonist muscimol, respectively. Biochemical studies will examine the effects of he DA agonists on GABA turnover and release in substantia nigra. Attempted selective blockade of effects with D1 (SCH 23390) and D2 (sulpiride) antagonists will test whether striatonigral GABA activity is independently regulated by these receptor subtypes. 2) Cholinergic antagonists (e.g. scopolamine; SCOP) in the striatum elicit DA-like behavioral effects by modulating D2 neurotransmission via local or feedback effects rather than by conveying striatal DAergic information to motor output areas. To test this hypothesis, we will determine if DA synthesis inhibition or depletion attenuates the observed potentiating effect of i.s. SCOP plus a D1 agonist fenoldopam), if intact D2 receptors are required for this effect (using the receptor inactivating agent EEDQ) and if the potentiation obtained after combined D1 and D2 agonists is attenuated by i.s. oxotremorine (a cholinergic agonist). 3) Elicitation of different components of stereotypy (sniffing and oral behaviors) require activation of different fractions of D2 receptors. To test this hypothesis, we will measure these responses after inactivation of different proportions of D2 receptors with EEDQ. The insights gained from these basic studies are expected to further our understanding of dopaminergic systems, and therefore of neuropsychiatric disorders putatively involving derangements in activity of this transmitter (e.g. Parkinson's disease and schizophrenia). Furthermore, the results may lead to fruitful new strategies for treatment of these and related disorders.