Behavioral sensitization to stimulant drugs is an important animal model for the intensification of drug craving that characterizes drug addiction in humans. The purpose of this proposal is to determine if sensitization to amphetamine (Amph) involves changes in excitatory amino acid (EAA) transmission, particularly in ventral tegmental area- (VTA), where sensitization is initiated, and nucleus accumbens (NAc), where it is expressed. It is hypothesized that repeated elevation of EAA levels in VTA by Amph initiates sensitization by altering EAA receptor expression on VTA DA cells, resulting in increased excitatory drive to VTA DA cells. Increased excitatory drive to DA cells projecting to prefrontal cortex (PFC) is proposed to result in increased DA release in PFC, leading to tolerance of PFC cells to the inhibitory effects of DA; since PFC cells use EAA transmitters and project to VTA and NAc, this might result in tonic increases in EAA transmission in these regions. Resulting changes in EAA receptors in NAc, as well as Amph-stimulated EAA efflux in NAc, are proposed to contribute to the expression of sensitization.
Specific Aim 1 will use microdialysis to characterize Amph-stimulated increases in EAA efflux in VTA, focusing on the role of D1 receptors, the contribution of vesicular release vs. reversal of the glutamate transporter, and possible alterations in sensitized rats.
Specific Aim 2 will use microdialysis to determine whether Amph increases EAA efflux in NAc with a time course rapid enough to mediate sensitized behavioral responses to Amph challenge and thereby account for the ability of EAA antagonists to prevent expression of Amph sensitization.
Specific Aim 3 will determine, in both VTA and NAc, whether sensitization is accompanied by tonic changes in extracellular EAA levels or turnover using the """"""""no net flux"""""""" microdialysis technique.
Specific Aim 4 will test the hypothesis that tonic disinhibition of PFC cells projecting to VTA and NAc results in tonic increases in EAA levels or turnover in these brain regions.
Specific Aim 5 will determine whether Amph sensitization is accompanied by altered expression in VTA or NAc of the AMPA receptor subunits GluR1-4 or the NMDA receptor subunit NR1, at both mRNA and protein levels.
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