A considerable research effort as been made to characterize the capacity of neurotransmitters to modulate the mesolimbic dopamine (DA) system, which has neuronal perikarya in the AlO region and axonal terminals in the nucleus accumbens (NA). Recently, it has become clear that efferent projections from the NA to the substantia innominata (SI) and from the SI to the pedunculopontine nucleus (PPN) play a major role in mediating the behavioral stimulant effect of increased mesolimbic DA activity. Because of its anatomical connections, the neuronal circuit from the AlO region - NA - SI - PPN - AlO region, the mesolimbic locomotor circuit (MLC), is thought to play a major role in integrating the limbic system with motor systems, thereby allowing motivation to be translated into adaptive motor behaviors. Four neurotransmitters have been identified as playing a major role in modulating MLC activity, including DA, gaminobutyric acid (GABA), enkephalin and neurotensin. In the present proposal these transmitters, or analogues, will be microinjected into the nuclei of the MLC, and changes measured in 1) spontaneous motor activity, 2) DA neurochemistry, 3) GABA neurochemistry, and 4) neurotensin and Met-enkephalin levels. Alternatively, the nuclei will be lesioned and changes evaluated. The neuroanatomy of transmitters within the MLC will be determined by using anterograde and retrograde tracing combined with immunocytochemistry, and by measuring the receptors of the transmitters using light microscopic receptor autoradiography. Finally, experiments are included to evaluate the role of the MLC in the psychostimulant model of psychosis. These studies are designed to determine the neuroanatomy, neurochemistry and function of the MLC, and to evaluate a role in the psychostimulant model of psychosis. This proposal constitutes a novel series of experiments that will expand our understanding of how the limbic system integrates with motor systems. Considering the proposed role for the MLC in the pathophysiology of psychosis, and the motor side-effects associated with current antipsychotic psychopharmacologic therapy, the information generated by these studies may impact our understanding and treatment of psychosis.
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