Identification and characterization of the neuronal circuits mediating drug reinforcement are necessary for understanding the neurobiological basis of addictive disorders. This research project proposes a broad neurobiological approach to directly investigate neuronal systems initiating and/or mediating opiate reinforcement. The specific role of neuronal pathways that have been previously identified with neurotransmitter turnover rate and receptor binding studies as involved in these processes will be assessed. This will be accomplished by using neurotoxin or intracranial infusion of neurotransmitter receptor antagonists to modify these pathways in animals on concurrent schedules of food, water and intravenous heroin reinforcement and assessing the effects of these treatments on responding. The neuronal systems that initiate neuronal activity indicative of the occurrence of a reinforcing event in response to endogenous opiate peptides will be determined with intracranial self-administration procedures. Successful demonstration of intracranial self-administration will include the use of intermittent reinforcement schedules, two-lever discrimination procedures and attenuation with specific opiate receptor antagonists. The neuronal systems mediating these reinforcing effects will be further delineated by concurrently measuring the turnover rates of multiple neurotransmitters (acetylcholine, dopamine, norepinephrine, serotonin, aspartate, glutamate, glycine and gamma-aminobutyric acid) in discrete brain regions of animals intracranially self-administering the opiate peptide and in vehicle-infused and naloxone-treated controls. Changes in turnover rates correlated with intracranial self-administration should be more representative of in vivo reinforcement processes than those determined with intravenous self-administration since the general pharmacological actions of the opiate receptor agonist that are reflected centrally would not be present or would be substantially minimized. These data will be integrated with current knowledge of neurotransmitter specific pathways to identify the brain circuits that initiate and/or mediate the reinforcing properties of opiate peptides which could suggest new approaches to the treatment of addictive disorders.
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