Abstract

Repeated exposure to psychostimulant drugs leads to changes in the synaptic connectivity and dendritic arborization of neurons in the terminal regions of the mesolimbic dopamine system. The morphology of the dopaminergic neurons themselves, however, has not been characterized following psychostimulant exposure. Thus, the present study was designed to investigate whether repeated amphetamine administration would affect the morphology of dopaminergic neurons in the ventral tegmental area (VTA). In Chapter 1, a novel adaptation of the in vitro whole-cell patch-clamp method is introduced, allowing for the identification and morphological analysis of dopamine neurons. In Chapter 2, male Wistar rats were treated with amphetamine (2 mg/kg, s.c.) or saline on postnatal days 10, 12, and 14. Whole cell electrophysiological recordings from dopamine neurons were obtained from acute VTA slices taken from 21 to 42 day-old saline- or amphetamine-treated rats. Subsequent staining and visualization of these neurons revealed that amphetamine treatment induces a large increase in the total dendritic length of dopaminergic neurons in the VTA as compared to saline treatment. In Chapter 3, following amphetamine or saline treatment, the VTA of postnatal day 21 or 30 rats was examined for basic fibroblast growth factor (bFGF, or FGF-2) immunoreactivity. Amphetamine treatment induced a transient increase in astrocytic bFGF expression in the VTA of postnatal day 21 rats as compared to saline treatment. In Chapter 4, rats received either amphetamine or saline co-administered with a bFGF antibody or control IgG on postnatal days 10, 12, and 14. Amphetamine induced significant dendritic growth in VTA dopamine neurons when co-administered with a control IgG, but neutralization of bFGF prevented amphetamine-induced dendritic growth of VTA dopamine neurons. Early postnatal administration of human recombinant bFGF, however, did not induce changes in dendritic arborization. It can be concluded that early postnatal amphetamine exposure induces marked morphological alterations in VTA dopamine neurons in young rats, an effect that is dependent on the actions of endogenous bFGF. The amphetamine-induced elaboration of the dendritic arbor of dopaminergic neurons is proposed to account for, in part, increased excitability within the mesolimbic dopamine system observed after exposure to psychostimulant drugs.