The dopamine transporter, the principle binding site for such drugs of abuse as cocaine and amphetamines, has a critical role in limiting dopamine availability. Several lines of evidence, including variation of DAT density in human alcoholics and in vervet monkeys with a preference for alcohol, have implicated this locus as a candidate gene, which might increase vulnerability to alcoholism. The objective of this study was to identify polymorphisms in the regulatory region of the dopamine transporter and determine whether there was an association between any of the alleles and alcoholism. Five polymorphisms were identified: three in humans and two in vervet monkey subjects. Mutation analysis of this locus may be a critical step in identifying alleles which increase susceptibility to alcohol abuse in humans and vervet monkeys.

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The primary focus of the present thesis is the exploration of factors that influence the dopamine (DA) neuron by examining the expression of the dopamine transporter (DAT), a marker of the DA neuron. The secondary focus of this thesis is on the serotonin neuron and in particular the serotonin transporter (SERT), a marker of the serotonin neuron. To this end three distinct and separate models have been employed. The goals of this thesis were: (1) to test the hypothesis that monoamine oxidase inhibition during development alters serotonergic innervation in the cortex and raphe, while not affecting relative DA innervation of nigrostriatal pathway, (2) to test the hypothesis that elevated brain levels of hypoxanthine (Hx) deleteriously affect the DA neuron, and (3) to test the hypothesis that densities of DAT and SERT in brainstem cell body regions distinguish alcohol-preferring vervet monkeys with different behavioral patterns of ethanol consumption. / Alterations in the activity of monoamine oxidase (MAO), a degradative enzyme that plays an important role in regulating levels of monoamine transmitters, may have a profound effect on brain development. The present study investigates relative DA and serotonin innervation of cortical and subcortical areas, measured by DAT and SERT densities, following MAO inhibition (A or B or A+B) in mice throughout gestation and early post-natal development. DAT binding was unaltered within the nigrostriatal pathway. The most significant finding reported here is that the combined MAO-A+B inhibition significantly reduced SERT binding by 25% in both the cortex and raphe nucleus. Lower levels of SERT binding were apparent during the early post-natal period (PND 14), a period during which pups were still exposed to MAO inhibitors in the dam's milk, but also persisted into later life (PND's 35 and 90) after inhibitors were no longer being administered. Persistent effects were restricted to cortex and raphe, suggesting a relative vulnerability of these regions to alterations in monoamine transmitter levels during development. / The second study presents data demonstrating that Hx delivered intracerebroventricularly significantly reduces the number of tyrosine hydroxylase immunoreactive cells (TH-ir) in the substantia nigra by 22% and 30%, at 7 and 21 days, respectively. After 3 days of Hx administration, striatal DA and serotonin were elevated over control levels by 22% and 25%, respectively, but returned to control levels by 7 days. The serotonin metabolite 5-HIAA was elevated after 3 days of Hx, but levels of DA metabolites were not different from control. Locomotion, a behavior thought to be related to DA transmission, was elevated following Hx treatment, as were presynaptic markers of the DA system such as DAT and TH protein levels. The persistent reduction in TH positive cell numbers suggests that Hx damages or kills DA neurons. The increase in intracellular DA at early time points suggests that Hx might interfere with DA release, possibly by temporarily inactivating DA neurons. These findings are consistent with the hypothesis that Hx, a purine significantly elevated in blood and CSF of Lesch-Nyhan patients, maybe involved in DA dysfunction. / Studies on alcohol abuse have focused on the mesolimbic DA pathway and the serotonergic influence within this pathway. Here we report that abstinent binge-drinking monkeys have significant reductions of SERT binding, and to a lesser extent, DAT binding in the midbrain region, while abstinent heavy-drinking subjects have elevated levels of DAT binding, as compared to controls. Both mesolimbic and nigrostriatal pathways are affected. CSF levels of both HVA and 5-HIAA substantiate the neuroanatomical differences between binge- and heavy-drinking vervets. Taken together, these findings provide a neurochemical profile with which to further distinguish subtypes of alcohol-preferring vervet monkeys.

No description available.