Project Summary

Stephanie L. Borgland, Ph.D., (Young Investigator 2005) of Ernest Gallo Clinic and Research Center at the University of California, San Francisco, points out that mesocortical dopaminergic neurons of the ventral tegmental area (VTA) are involved in various brain functions, such as voluntary motor movement, working memory, and reward. Schizophrenia, a pathological condition affecting approximately 2.2 million Americans, results from aberrant activity of dopamine (DA) neurons in the mesocortical system, and antagonism of DA receptors is one of the primary treatments of this disease. Orexin, a neuropeptide produced in the lateral hypothalamus, modulates dopaminergic neurons. Previous studies have indicated that the VTA receives a strong projection from lateral hypothalamic orexin-containing neurons and has high orexin receptor density. Also, application of orexin to midbrain slices increases the firing rate of VTA neurons. However, the exact role of orexin in modulating DA and synaptic plasticity in this brain region is poorly understood. Preliminary results from Dr. Borgland’s laboratory reveal an orexin-mediated potentiation of NMDA currents in VTA neurons. This finding is important as NMDA receptor modulation plays a central role in burst firing, which increases DA release, and produces plasticity at excitatory synapses. In this proposal, Dr. Borgland will use a combination of methods to determine 1) the mechanism of orexin-mediated synaptic enhancement, 2) the role of orexin in modulating dopaminergic output in target regions of the VTA and 3) if orexin actions on dopaminergic neurons mediate locomotor activation or motivated behaviors. These studies will determine how orexin modulates dopaminergic synaptic transmission in the midbrain and may provide a new spectrum of therapeutic targets for the treatment of schizophrenia.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

Search Again