Brain Behav Immun. 2017 Oct;65:210-221. doi: 10.1016/j.bbi.2017.05.004. Epub 2017 May 8.

HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function.

Kesby JP¹, Najera JA², Romoli B³, Fang Y², Basova L², Birmingham A⁴, Marcondes MCG⁵, Dulcis D⁶, Semenova S⁷.

Author information

1: Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA; Queensland Brain Institute, The University of Queensland, St. Lucia, Qld, Australia.
2: Department of Molecular and Cellular Neurosciences, The Scripps Research Institute, La Jolla, CA, USA.
3: Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA.
4: Center for Computational Biology and Bioinformatics, University of California San Diego, La Jolla, CA, USA.
5: Department of Molecular and Cellular Neurosciences, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: cmarcondes@SDBRI.ORG.
6: Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA. Electronic address: ddulcis@ucsd.edu.
7: Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA. Electronic address: ssemenova@ucsd.edu.

Abstract

Methamphetamine abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein TAT induces dysfunction of mesolimbic dopaminergic systems which may result in impaired reward processes and contribute to methamphetamine abuse. These studies investigated the impact of TAT expression on methamphetamine-induced locomotor sensitization, underlying changes in dopamine function and adenosine receptors in mesolimbic brain areas and neuroinflammation (microgliosis). Transgenic mice with doxycycline-induced TAT protein expression in the brain were tested for locomotor activity in response to repeated methamphetamine injections and methamphetamine challenge after a 7-day abstinence period. Dopamine function in the nucleus accumbens (Acb) was determined using high performance liquid chromatography. Expression of dopamine and/or adenosine A receptors (ADORA) in the Acb and caudate putamen (CPu) was assessed using RT-PCR and immunohistochemistry analyses. Microarrays with pathway analyses assessed dopamine and adenosine signaling in the CPu. Activity-dependent neurotransmitter switching of a reserve pool of non-dopaminergic neurons to a dopaminergic phenotype in the ventral tegmental area (VTA) was determined by immunohistochemistry and quantified with stereology. TAT expression enhanced methamphetamine-induced sensitization. TAT expression alone decreased striatal dopamine (D1, D2, D4, D5) and ADORA1A receptor expression, while increasing ADORA2A receptors expression. Moreover, TAT expression combined with methamphetamine exposure was associated with increased adenosine A receptors (ADORA1A) expression and increased recruitment of dopamine neurons in the VTA. TAT expression and methamphetamine exposure induced microglia activation with the largest effect after combined exposure. Our findings suggest that dopamine-adenosine receptor interactions and reserve pool neuronal recruitment may represent potential targets to develop new treatments for methamphetamine abuse in individuals with HIV.

KEYWORDS:

Adenosine receptors; Brain neurochemistry; Dopamine receptors; Gene expression microarrays; HPLC; Locomotor activity; Mice; Neurotransmitter respecification; TAT expression