Evidence from clinical and behavioral pharmacology suggest addictive disorders to be the excessive use of reinforcers. The processes that occur when a stimulus is delivered contingent on behavior that results in increases in that behavior is referred to as reinforcement. The neurobiological substrates of these processes have been under investigation for two and one-half decades, resulting in significant progress in some areas. This research project proposes the use of recently developed methodologies to identify and further characterize the neurohumors and brain loci that initiate and mediate reinforcement processes. This will be accomplished by allowing rats to intracranially self-administer neurohumors (neurotransmitters, neuromodulators, neurohormones) directly into discrete brain regions where these endogenous ligands are normally released to determine potential intrinsic reinforcing properties. Intermittent schedules of reinforcement and two-lever discrimination procedures will be used to differentiate the reinforcing effects of self-administered neurohumors from response eliciting properties. Attenuation of self-administration by neurotransmitter receptor antagonists will demonstrate the specificity of the receptors responsible for this effect. Horseradish peroxidase and (3H)-proline-(3H)-leucine retrograde and anterograde transport will identify cell bodies for neurons projecting to or projection areas from neurons at the self-administration site. These neuronal pathways that potentially mediate the reinforcing properties of the neurohumor will be characterized with neurotoxin lesions or intracranial infusion of receptor antagonists into these identified areas and the effects of these treatments assessed on the self-administration. The relevance of the intracranially self-administered neurohumor to drug reinforcement processes will be determined by allowing animals to choose between intravenous cocaine or intracranial neurohumor self-administration. These experiments 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 addictive disorders.
