Identification and characterization of the neuronal circuits responsible for the internal events the underlie reinforcement would be beneficial for development of drugs or therapeutic approaches to the treatment of individuals suffering from malfunctions of these processes (depression, mania, substance abuse). This application proposes experiments to identify brain loci and neuronal receptors that initiate and mediate reinforcement and conditioning processes. Rats will be implanted with intracranial injection guide cannulae into a brain region and allowed to self-administer a neurohumor or neurohumor receptor agonist using an electrolytic microinfusion systems. The use of two-lever discrimination procedures and intermittent schedules of reinforcement will be used to evaluate the reinforcing effects of the neurohumor and pharmacological blockade and neurotoxin lesions of the self-administration site will permit identification and characterization of the receptors responsible for these effects. The potential rate-altering properties of the self- administered neurohumor will be evaluated by presenting intracranial infusions to animals responding under an interresponse time schedule of food reinforcement. A conditioned suppression procedure will be used to determine if intracranial infusions can develop conditioned stimulus properties to more rapidly identify potential neurohumors and self-administration sites. Brain sites and neurohumors that display such activity will then be tested for intracranial self-administration. Once a brain site and neurohumor that initiates reinforcing neuronal activity is identified and characterized then neuroanatomical and neurochemical procedures will be used to investigate the neuronal pathways and circuits that mediate these reinforcing effects. These intracranial self-administration experiments should more specifically identify brain neuronal systems that are responsible for reinforcement.
