Identification and characterization of neuronal circuits mediating the reinforcing effects of opiates have increased understanding of the neurobiological mechanisms of reinforcement. Such information has already benefited the development of therapeutic approaches to disorders involving malfunctions in these systems (drug abuse, depression, mania) as well as helped to define the role of endorphin releasing neurons in these processes. This application proposes experiments to continue the identification and delineation of neurons involved in opiate reinforcement using intravenous and intracranial self-administration procedures in combination with neurochemical, neuropharmacological and neurobiological methodologies. The verification of the involvement of neurons previously identified will be continued using intravenous opiate self-administration, neurotoxin lesions and opiate receptor alkylation procedures. The specificity of such involvement will be evaluated using concurrent schedules of food, water and intravenous opiate presentation. Microdialysis procedures and sensitive high pressure liquid chromatography assays will be used to identify neurohumors specifically released in animals intravenously self-administration heroin compared to littermates receiving yoked-heroin infusions. Intracranial self- administation procedures will continue to be used to identify brain loci and opioid receptor subtypes through which opiates initiate reinforcing activity in these circuits. Specific receptor agonists will be used to engender self-administration at specific brain sites where opiates are thought to initiate reinforcing neuronal activity. Co-infusion of specific antagonists, neurotoxin lesions and opioid receptor alkylation (beta-FNA, beta-CNA) of the self- administration site will be used to identify the post-synaptic receptors responsible for this activity. The more distal neuronal systems and circuits mediating the reinforcing effects of this intracranial self-administration will be characterized using combined 2-deoxyglucose local brain metabolic mapping and neurotransmitter turnover rate assessments. Identified systems will be compared and contrasted with the circuits activated in animals intravenously self-administering morphine. This broad neurobiological approach will continue to define the role of specific neuronal systems in opiate abuse.
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