MARIJUANA & DOPAMINE/ENKEPHALIN BRAIN REWARD SYSTEMS

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The objective of the proposed research is to gain further insights into marijuana's action on brain reward circuits and on dopamine (DA) and enkephalinergic mechanisms involved in marijuana, derive part of their abuse liability from neuropharmacological facilitation of brain reward circuits. During the period of previous NIDA grant support for this work, we demonstrated that delta-9-tetrahydrocannabinol (delta9-THC), the major psychoactive ingredient in marijuana, does the following: (1) lowers direct brain reward thresholds in the medial forebrain bundle, in a rat strain-specific fashion, (2) enhances presynaptic release of known to support brain reward, and (3) interacts noncompetitively with endogenous brain delta and Mu opioid receptors but not Kappa receptors, and the opioid receptor interaction of a series of cannabinoid analogs correlates crudely but not precisely with psychoactive potency. The general aim of the presently proposed work is to carry forward and extend all these findings. The specific aims are to (1) extend ours studies of delta9-THC and analogs on direct brain reward as measured by electrical intracranial self- stimulation in laboratory rats; (2) extend our studies of the effects of delta9-THC and analogs on DA release, in forebrain DA loci supporting direct brain reward, as measured by both in vivo voltammetric electrochemistry and in vivo intracranial microdialysis; and (3) extend our studies of the interaction of delta9-THC and selected analogs with endogenous brain opioid receptors, as measured by receptor binding and quantitative autoradiography. A major aim running throughout is to learn the specific locus in the brain of the already-demonstrated delta9-TCH effects. This proposal addresses specific research needs stipulated in the NIDA Marijuana Research Announcement and in NIDA Grant Announcement DA-87- 24 ("...studies are needed concerning the neurophysiological effects of marijuana, including potential sites and mechanisms of action.." "...research areas of particular importance include...brain reward mechanisms"). By adding to our understanding of marijuana's effects on one of the presumptive principal neurophysiological substrates of drug abuse liability, these studies should yield additional insight into fundamental brain mechanisms underlying marijuana's abuse potential, and to treatment possibilities for marijuana abuse. The health relatedness is 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.