DOPAMINE-OPIOID RECEPTOR INTERACTIONS IN BASAL FOREBRAIN

伏隔核内阿片和多巴胺受体的模拟， 至少部分原因是运动活动的增加和 全身给药阿片类药物的增强作用 滥用精神刺激性药物。尽管阿片系统不会 依赖于多巴胺系统的活动，耗尽 伏核中的多巴胺增强阿片类药物诱导的运动 活动。这种增强的生化基础尚不清楚。 在前一项提案的有效期内，Mu阿片受体 亚型被认为是行为增强中最重要的， 但MU激动剂结合位点的数量没有变化 损毁的伏隔中的亲和力。此外，这些都没有改变。 穆阿片类药物对损伤性脑组织腺苷环化酶的抑制作用 伏伏草。在这份延续提案中，第一系列 实验将表征参与的阿片受体亚型 内源性阿片类药物的行为增强及其时间进程 增强功能。第二系列实验将测试第一个主要的 多巴胺耗竭患者类阿片类药物增加的假说 伏隔核是突触后神经元改变的结果， 在MU1阿片受体结合或其他转导机制中 而不是腺苷环化酶。G蛋白或蛋白激酶的作用将是 分析过了。初步数据显示佛波酯含量增加 多巴胺耗竭的伏隔核中的结合支持 蛋白激酶C的参与。第二个主要假设是 测试表明，阿片类药物会影响GABA能投射 伏隔核至腹侧苍白球，可在 多巴胺耗尽的大鼠。为了评估这一假设，有两个通用的 将进行实验。在第一种情况下，核内的神经元 伏本将用荧光金进行双重标记，逆行 从腹侧苍白球运输，以及前脑啡肽原或 谷氨酸脱羧酶(合成GABA的酶)。这些基因的 在单侧损伤后表达上调。这项实验将 确定这些mRNAs在双侧损伤后是否上调，以及 因此，腹侧苍白球投射神经元是否在 MRNA.第二个实验将使用体内微渗析来测量 腹侧苍白球细胞外GABA对阿片类药物的反应 伏隔核的刺激。这项研究将确定 阿片类药物损毁后伏隔核内的能力 调节腹侧苍白球内的GABA。这些研究很重要 因为伏隔核参与了增强的特性 阿片类药物和间接多巴胺激动剂。因此，理解 阿片类药物作用增强的机制 伏隔区多巴胺的耗竭可能提供有关 伏隔核反应的神经生物学和可塑性 滥用阿片类药物和间接多巴胺激动剂。

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.