NEUROBIOLOGY OF STIMULANT PSYCHOTOMIMETIC DRUGS

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Alterations in catecholaminergic neuron function have been implicated in psychosis and affective disorders. An understanding of catecholamine neuron function may shed light on the neural basis, as well as provide insight for treatment, of these serious diseases. Our goal is to study the mechanisms of action of psychoactive drugs on catecholamine-containing neurons using single cell recording and microiontophoretic techniques in the rat. Based upon research findings in our laboratories, we wish to pursue four major topics. First, we have found that the d- and 1-isomers of amphetamine (AMP) have differential effects in reducing the firing rates of substantia nigra (nucleus A9) and ventral tegmental area (nucleus A10) dopamine (DA) neurons. d-AMP has equipotent effects on A9 and A10 neurons; however, 1-AMP is relatively impotent on A9 neurons, but is quite potent on A10 neurons. We wish to determine why these AMP isomers have differential effects on these two DA nuclei. Second, AMP and non-AMP (e.g. amfonelic acid) CNS stimulants influence DA and norepinephrine (NE) neurons differently. We wish to further study the mechanisms of action of non-AMP CNS stimulants on DA and NE neurons. Third, AMP and non-AMP stimulants release and block DA uptake at DA axon terminal regions. We wish to study whether these drugs also have the same effects at the DA cell body/dendrite region. Finally, biochemical research from our laboratories suggest that centrally acting muscle relaxants (e.g. zoxzxolamine, chlorzoxazone and mephenesin) influence striatal DA mechanisms. We wish to determine whether and by what mechanisms they influence DA and NE impulse flow.