The reinforcing property of d-amphetamine and related psychostimulants has been attributed to their ability to block dopamine (DA) uptake and to increase DA release. Through the same mechanisms and by affecting feedback pathways of DA neurons, these drugs also inhibit DA cell firing. However, when DA-mediated feedback inhibition is blocked, d-amphetamine is found to powerfully excite DA cells, in part, through adrenergic alpha1 receptors. Thus, d-amphetamine produces two opposite effects on DA cells mediated by DA- and non-DA mechanisms, respectively. The non-DA-mediated excitation is mimicked by all psychostimulants tested and not by antidepressants, suggesting that it may have an important role in behaviors induced by psychostimulants. To further understand the significance of the non-DA effects, especially the alpha1-mediated increase in DA cell bursting, two series of studies are proposed. The first series will investigate further the mechanisms through which the alpha1 effect is produced by d-amphetamine. Selective antagonists will be used to identify the alpha1 receptor subtype responsible for the effect. DA neurons will be recorded in slices to confirm that the effect is not due to activation of alpha1 receptors on DA cells. Both in vivo and in vitro techniques will be used to test whether the effect involves areas, such as the prefrontal cortex and the raphe nucleus, known to express alpha1 receptors and to project to DA cells. The second series of studies will assess how the alpha1-mediated excitation may contribute to the acute and chronic effects of d- amphetamine on DA cells. The alpha1 effect will be blocked to see whether the blockade enhances the ability of d-amphetamine to inhibit DA cells. The response of DA cells to d-amphetamine will be examined in non-anesthetized rats to determine whether chronic treatment with d-amphetamine converts the response from an inhibition to an excitation, as reported previously. Studies will be carried out to further determine whether the conversion occurs with a time course parallel the development of behavioral sensitization and whether the excitation is alpha1-mediated. The proposed work will provide crucial information for a complete understanding of how psychostimulants may act through central DA neurons to produce their behavioral effects and may also provide information leading to the development of novel and effective treatments for drug abuse.
