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.
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