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的作用， 脑啡肽能机制参与大脑的直接奖赏。 这项工作 源于一种假设，即滥用药物，包括大麻， 从神经药理学中获得部分滥用倾向 大脑奖励回路的敏感化，是一个直接的产物， 以前关于药物对大脑奖赏回路作用的研究是在 申请人的实验室。 具体目的是：（1）研究 δ-9-四氢大麻酚（Delta 9-THC），主要的精神活性物质 大麻的成分，以及直接大脑奖励的选择类似物， 通过颅内电自我刺激范例测量， 实验大鼠;（2）研究可能的神经解剖学特异性， 通过直接比较Delta 9-THC和选择的 类似物对中纹状体和中脑边缘脑奖励机制;（3）测试 对于纳洛酮-这种作用的可逆性或衰减，通过类比 其他滥用的药物;（4）研究 Delta 9-THC及其类似物对中纹状体和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位点， 如通过神经递质的体内电化学测定所测量的 （5）研究Delta 9-THC及其类似物对大鼠肝脏的影响。 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定。 通过增加对大麻对其中一种生物的影响的理解， 药物滥用倾向的假定神经药理学底物，这些 这些研究很可能让我们深入了解 大麻的滥用潜力，以及大麻的治疗可能性 虐待 这些研究的健康相关性似乎很清楚，因为 大麻是美国使用最广泛的非法药物， 鉴于长期滥用大麻对健康的影响的证据。

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.