MARIJUANA AND DOPAMINE/ENKEPHALIN BRAIN REWARD SYSTEMS

拟议研究的总体目标是深入了解 大麻对大脑奖赏回路和多巴胺能和 脑啡肽能机制参与直接的大脑奖赏。这部作品 源于一种假设，即包括大麻在内的滥用药物， 他们的部分滥用责任来自神经药物 大脑奖赏回路的敏感化，是 先前关于药物对大脑奖赏回路的作用的工作是在 申请人的实验室。具体目标是：(1)研究影响 三角洲-9-四氢大麻酚(Delta9-THC)，主要精神活性物质 大麻中的成分，以及精选的类似物对大脑的直接奖励 由脑电自我刺激范式测量的 实验大鼠；(2)研究可能的神经解剖学特异性 直接比较Delta9-THC和SELECTED的效果 纹状体和边缘中脑奖赏机制的类似物；(3)测试 对于纳洛酮-此类影响的可逆性或衰减，类比为 其他具有良好特征的滥用药物；(4)研究 Delta9-THC及其类似物对大鼠中脑纹状体多巴胺释放的影响 与直接脑奖赏相关的中脑边缘前脑多巴胺能基因座， 在体电化学法测定神经递质 (5)研究Delta9-THC及其类似物对血管紧张素转换酶的影响。 脑啡肽能(Delta)受体密度、亲和力和构象 通过受体结合研究和光学显微镜放射自显影测量。 通过增加对大麻对一种 药物滥用倾向的推定神经药理学基础，这些 研究可以很好地洞察潜在的基本大脑机制 大麻的滥用潜力，以及大麻的治疗可能性 虐待。考虑到这些研究与健康的相关性似乎是显而易见的 大麻是美国使用最广泛的非法药物， 考虑到长期滥用大麻对健康造成的后果的证据。

The overall objective of the proposed research is to gain insight into marijuana's actions on brain rewards circuits and on dopaminergic and enkephalinergic mechanisms involved in direct brain reward. This work derives from the hypothesis that drugs of abuse, including marijuana, derive part of their abuse liability from neuropharmacological sensitization of brain reward circuits, and is a direct outgrowth of previous work on drug action on brain reward circuits carried out in the applicants' laboratories. The specific aims are (1) to study the effects of delta-9-tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in marijuana, and selected analogs on direct brain reward as measured by the electrical intracranial self-stimulation paradigm in laboratory rats; (2) to study possible neuroanatomic specificity of such effects by directly comparing the effects of Delta9-THC and selected analogs on mesostriatal and mesolimbic brain reward mechanisms; (3) to test for naloxone-reversibility or attenuation of such effects, by analogy to other well-characterized drugs of abuse; (4) to study the effects of Delta9-THC and its analogs on dopamine release, in mesostriatal and mesolimbic forebrain dopaminergic loci associated with direct brain reward, as measured by in vivo electrochemical determination of neurotransmitter release; and (5) to study the effects of Delta9-THC and its analogs on enkephalinergic (delta) receptor density, affinity, and conformation as measured by receptor binding studies and light microscopy autoradiography. By adding to the understanding of marijuana's effects on one of the presumptive neuropharmacologic substrates of drug abuse liability, these studies may well give insight into fundamental brain mechanisms underlying marijuana's abuse potential, and to treatment possibilities for marijuana abuse. The health relatedness of such studies seems clear, given that marijuana is the most widely used illicit drug in the United States, and given the evidence for health consequences of chronic marijuana abuse.