The role of VMAT-2 in mediating the impact of HIV-1 protein Tat and methamphetamine on dopamine neurotransmission and behavior

点击翻译按钮获取中文摘要

Project Summary Dysregulation of dopaminergic function due to the HIV-1 transactivator of transcription (Tat) protein has been implicated in the progression of HIV-1 associated neurocognitive disorders (HAND). Tat mediates increases in dopamine (DA) release and acts as a negative allosteric modulator for the dopamine transporter (DAT). In addition to DAT, previous work has identified Tat as a negative allosteric modulator for the vesicular monoamine transporter (VMAT-2). VMAT-2 functions to repackage DA into vesicles for subsequent release. Inhibition of VMAT-2 causes dysregulation of DA neurotransmission which can lead to autooxidation of DA and apoptosis. The psychostimulant methamphetamine (METH), in addition to Tat, inhibits VMAT-2 function. METH is a highly abused psychostimulant among HIV-1 infected persons. Expression of the Tat protein has been shown to potentiate METH induced neurotoxicity and behavior. Considering the respective interactions between Tat or METH and VMAT-2, we hypothesize that the Tat and METH effects on extracellular DA and behavior are mediated by VMAT-2. We will address this hypothesis by first, determining the role for VMAT-2 in mediating Tat- induced increases in DA release (Tat alone). We will use fast scan cyclic voltammetry to quantify DA release in Tat expressing mice. Specifically, we will profile the pharmacological response to a VMAT-2 inhibitor to determine whether Tat expression alters VMAT-2 function. Second, we will use two different METH administration models (acute and chronic) and profile the response to the VMAT-2 inhibitor as in the first aim. Lastly, we will determine whether a VMAT-2 specific inhibitor attenuates Tat-potentiated METH-conditioned place preference behavior. This will give insight whether VMAT-2 mediates Tat-potentiated METH behavior. The findings from this proposal will provide key insight into the molecular mechanism by which Tat increases extracellular DA and determine whether VMAT-2 is a suitable drug target for future therapeutic intervention in the treatment of METH abuse in HIV-1 infected persons. .