MESOPREFRONTAL DOPAMINE NEURONS: STUDIES ON THEIR REGULATORY CONTRO

The effects of the impulse flow, precursor availability, mild stress, and anxiogenic beta-carbolines on dopamine (DA) synthesis and metabolism were examined in the prefrontal cortex in order to determine the various functional controls modulating this subset of DA-containing neurons.;Similar to the effects observed in mesolimbic and nigrostriatal DA neurons, increased impulse flow in mesocortical DA neurons resulted in an elevation of in vivo tyrosine hydroxylation in the nerve terminal regions such as the prefrontal, cingulate and piriform cortices. However, the DA synthesis in mesoprefrontal DA neurons was most readily enhanced by the administration of a physiologically-relevant dose of precursor tyrosine. This precursor dependency may be attributed to the enhanced state of physiological activity of these DA neurons.;The mesoprefrontal DA neurons were selectively activated by a mild footshock stress paradigm, and such activation of DA metabolism was reversed by pretreatments with various types of anxiolytic drugs such as the benzodiazepine (BZ) receptor agonists, buspirone, gepirone and clonidine. In addition, this dissertation presents several lines of evidence suggesting a BZ receptor modulation of the mesoprefrontal DA system, possibly acting directly at the cell body region of these DA neurons. These BZ receptors mediate the selective activation of prefrontal DA metabolism induced by stress or by anxiogenic beta-carbolines.;These findings provided evidence consistent with the hypothesis that distinct afferent inputs (GABAergic, substance P, noradrenergic, serotonergic, opioid peptide) regulating the activity of the mesoprefrontal DA system may account for some of the unique responses of these DA neurons to stress and pharmacological manipulations. Furthermore, studies on the interaction of stress and beta-carboline suggest that the substance P and GABAergic inputs may exert their regulatory effects through a common pathway.