This application is for a research scientist award that will maximize efforts that can be expended in studies of the biological basis of drug abuse. Addictive disorders appear to result from the excessive use of reinforcers. Identification and characterization of the neurobiological substrates of reinforcement is necessary for understanding the biological basis of these disorders. Three research projects are in progress that directly address these issues. These include investigations of the mechanisms of (1) cocaine reinforcement; (2) opiate reinforcement; and (3) endogenous reinforcement processes. These three projects involve identification of sites where reinforcing neuronal activity is initiated by allowing rats to intracranially self-administer either cocaine, opiate receptor agonists or neurotransmitter receptor agonists. Receptors responsible for these behavioral effects are identified by co-infusing neurotransmitter receptor antagonists and assessing intake. Neurons projecting to or projection areas of neurons at the self-administration site are identified using horseradish peroxidase and [3H]amino acid transport. The potential involvement of more distal neurons is investigated by concurrently measuring turnover rates of biogenic amine and amino acid neurotransmitters in rats self-administering these substances and in appropriate control groups. The role of these pathways is further characterized with neurotoxin lesions or intracranial infusion of receptor antagonists into these areas and assessing effects on intracranial self-administration. The specificity of the involvement of identified pathways, projection areas or receptors In cocaine or opiate reinforcement is determined using similar procedures in animals concurrently responding on food, water and intravenous cocaine or heroin reinforced schedules. The relevance of the intracranially self-administered neurohumors to drug reinforcement processes is determined by allowing animals to choose between intravenous cocaine or intracranial neurohumor self-administration. These three related projects will increase understanding of brain-behavior interactions and could make the development of agents to more specifically modulate activity in these systems possible and/or suggest new therapeutic approaches to the addictive disorders.
