BASAL GANGLIA ANATOMY AND PHYSIOLOGY--MECHANISMS OF ACTION OF DRUGS OF ABUSE

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MBRS undergraduate students will participate in an on-going research program under the guidance of scientist-mentors. These studies on rodents will use electrophysiological, neuropharmacological, and anatomical approaches to reveal the actions of stimulant drugs in the caudate nucleus. This nucleus and its dopaminergic input from the substantia nigra are prominent sites for the action of stimulant drugs, including amphetamine and cocaine. In addition, this major integrative area of the basal ganglia is a significant locus for the pathology of Huntington's and Parkinson's disease. As well as elucidating the action of drugs of abuse, this research will reveal fundamental aspects of neuronal processing in the caudate nucleus and its associated afferent systems. Recent evidence suggests that presynaptic interactions occur in the caudate between dopaminergic nigrostriatal and glutamatergic corticostriatal afferents. These interactions appear to result from the activation of auto- and heteroreceptors located in afferent terminal regions by neurotransmitter released from nearby synapses. These presynaptic interactions may be an important locus for the action of stimulant drugs. Students will have the opportunity to participate in electrophysiological studies employing the measurement of terminal axon electrical excitability to investigate these interactions. Extracellular recording and the terminal excitability technique will also be used to examine possible alterations in both the firing properties of the dopaminergic neurons of the substantia nigra and changes in autoreceptor feedback regulation of the terminals of these neurons within the caudate nucleus related to the behavioral sensitization of the rats to amphetamine. We have previously observed that prenatal cocaine administration produces significant alterations in the rat caudate nucleus. Students will participate in structural studies employing correlated light and electron microscopic examination of basal ganglia and related regions. These experiments will use immunocytochemical techniques, image analysis, and computer assisted three-dimensional reconstruction to further elucidate the changes induced in the brains of these cocaine exposed animals. Anatomical studies are also proposed to accurately characterize the density of dopaminergic synapses, their postsynaptic sites, and the relation between these post-synaptic sites and those of other afferents to caudate neurons.