DOPAMINE-OPIOID RECEPTOR INTERACTIONS IN BASAL FOREBRAIN

丘脑核中阿片样物质和多巴胺受体的模拟， 至少在一定程度上，负责增加自发活动和 增强全身给予的阿片样物质的性质， 滥用精神兴奋剂 虽然阿片系统不 依赖于多巴胺系统的行动，消耗 中脑核多巴胺增强阿片诱导的运动 活动 这种增强的生物化学基础尚不清楚。 在上一个提案的任期内，μ阿片受体 亚型被确定为在行为增强中最重要的， 但μ-激动剂结合位点的数量没有变化， 在受损的神经元中的亲和力。 此外，这些都没有改变 μ-阿片类药物抑制损伤中腺苷酸环化酶的能力 快来 在这一延续提案中， 实验将描述阿片受体亚型参与 内源性阿片样物质的行为增强和这种增强的时间过程 增强 第二个系列的实验将测试第一个主要 假设在多巴胺耗尽的患者中增加μ阿片类药物 突触后神经元的改变导致突触核， 在μ 1阿片受体结合或转导机制中， 腺苷酸环化酶。 G蛋白或蛋白激酶的作用将是 分析了 初步数据显示佛波醇酯 多巴胺耗尽的丘脑核中的结合支持了 蛋白激酶C的参与。 第二个主要假设是 测试的是阿片类药物影响GABA能投射从 腹侧苍白球，这可能是增加在 多巴胺耗尽的老鼠 为了评估这一假设，两个一般 将进行实验。 首先，细胞核中的神经元 将使用荧光金逆行标记双标记荧光标记物 从腹侧苍白球运输，以及前脑啡肽原或 谷氨酸脱羧酶（GABA的合成酶）。 这些mRNA 在单侧损伤后上调。 这个实验将 确定这些mRNA在双侧病变后是否上调， 因此，腹侧苍白球投射神经元是否在 mRNA。 第二个实验将采用体内微透析来测量 腹侧苍白球细胞外GABA对阿片样物质的反应 刺激延髓核。 这项研究将确定， 阿片类物质在丘脑核中的能力后， 调节腹侧苍白球中的GABA。 这些研究很重要 因为晶核参与了增强性能 阿片类药物和间接多巴胺激动剂。 因此了解 调节阿片类药物作用增强的机制 脑内多巴胺的耗竭可能提供了关于 延髓核反应的神经生物学和可塑性 阿片类药物和间接多巴胺激动剂的滥用。

Simulation of opioid and dopamine receptors in the nucleus accumbens are, at least partly, responsible for increases in locomotor activity and the reinforcing properties of systemically administered opioid and psychostimulant drugs of abuse. Although the opioid system does not depend upon the dopamine system for its actions, the depletion of dopamine in the nucleus accumben augments opioid-induced locomotor activity. The biochemical basis for this augmentation is not known. During the tenure of the previous proposal, the mu opioid receptor subtype was identified as most important in the behavioral augmentation, but there was no change in the number of mu-agonist binding sites or affinity in the lesioned accumbens. Furthermore, these was no alteration in the capacity of mu-opioids to inhibit adenylyl cyclase in lesioned accumbens. In this continuation proposal, the first series of experiments will characterize the opioid receptor subtype involved in behavioral augmentation to endogenous opioids and the time course of this augmentation. The second series of experiments will test the first major hypothesis that the augmentation to mu-opioids in the dopamine-depleted nucleus accumbens results from an alteration in the postsynaptic neuron, either in mu1 opioid receptor binding or transduction mechanisms other than adenylyl cyclase. A role for G proteins or protein kinases will be analyzed. Preliminary data revealing an increase in phorbol ester binding in the dopamine-depleted nucleus accumbens supports the involvement of protein kinase C. The second major hypotheses to be tested is that the opioids affect the GABAergic projection from the nucleus accumbens to the ventral pallidum, which may be augmented in the dopamine-depleted rats. To evaluate this hypothesis, two general experiments will be conducted. In the first, neurons in the nucleus accumbens will be double-labeled with Fluoro-Gold, retrogradely transported from the ventral pallidum, and mRNA for preproenkephalin or glutamic acid decarboxylase (synthetic enzyme for GABA). These mRNA's were upregulated after unilateral lesions. This experiment will determine if these mRNAs are upregulated after bilateral lesions, and if so, whether the ventral pallidal-projecting neurons show upregulation in mRNA. The second experiment will employ in vivo microdialysis to measure extracellular GABA in the ventral pallidum in response to opioid stimulation in the nucleus accumbens. This study will determine if lesions after the capacity of opioids in the nucleus accumbens to modulate GABA in the ventral pallidum. These studies are important because the nucleus accumbens is involved in the reinforcing properties of both opioids and indirect dopamine agonists. Therefore, understanding the mechanisms mediating the augmentation of opioid action following accumbal dopamine depletions may provide mechanistic information on the neurobiology and plasticity in the response of the nucleus accumbens to the abuse of opioid and indirect dopamine agonists.