Effects of Conditional Central Expression of HIV-1 Tat Protein to Potentiate Cocaine-Mediated Psychostimulation and Reward Among Male Mice

Abstract

As a major neuropathogenic factor associated with human immunodeficiency virus (HIV) infection, HIV-1 Tat protein is known to synergize with psychostimulant drugs of abuse to cause neurotoxicity and exacerbate the progression of central nervous system pathology. However, the functional consequences of the interaction between HIV-1 Tat and abused drugs on behavior are little known. We tested the hypothesis that HIV-1 Tat expression in brain would modulate the psychostimulant effects of cocaine. Using the GT-tg bigenic mouse model, where brain-selective Tat expression is induced by activation of a doxycycline (Dox) promotor, we tested the effects of Tat on cocaine (10 mg/kg, s.c.) induced locomotion and conditioned place preference (CPP). Compared with uninduced littermates or C57BL/6J controls, cocaine-induced hyperlocomotion was sustained for a significantly longer duration among Tat-induced mice. Moreover, although all groups displayed similar saline-CPP, Tat-induced GT-tg mice demonstrated a three-fold increase in cocaine-CPP over the response of either uninduced littermates or Dox-treated C57BL/6J control mice. Induction of Tat also increased the magnitude of a previously established cocaine-CPP after an additional cycle of cocaine place-conditioning. Despite Tat-induced potentiation, extinction of place preference occurred within 21 days, commensurate with cocaine-extinction among saline-treated littermates and C57BL/6J controls. Re-exposure to cocaine produced reinstatement of an equivalent place preference in Tat-induced GT-tg or C57BL/6J mice; however, induction of Tat protein after the extinction of CPP also produced reinstatement without additional exposure to cocaine. Together, these data suggest that central HIV-1 Tat expression can potentiate the psychostimulant behavioral effects of cocaine in mice.

Progesterone protects normative anxiety-like responding among ovariectomized female mice that conditionally express the HIV-1 regulatory protein, Tat, in the CNS

“…The expression of Tat 1–86 protein in the GT-tg brain is dependent on the dose- and duration of doxycycline treatment (Carey et al, 2012; Paris et al, 2013). Tat expression in this model recapitulates clinical findings of HIV characterized by central macrophage/monocyte infiltration, T-lymphocyte infiltration, neuronal cell death (Kim et al, 2003), as well as dose-dependent reductions in limbic gray matter density (Carey et al, 2013), reductions in cognitive performance (Carey et al, 2012), increased anxietylike responding among males (Paris et al, 2013), and enhancement of psychostimulant reward (Paris et al, 2014). …”

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

“…TAT expression has been shown to increase the rewarding effects of methamphetamine (Kesby et al 2016b), ethanol (McLaughlin et al 2015) and cocaine (Paris et al 2014c). However, the effects of TAT exposure on psychostimulant-induced locomotor sensitization are mixed.…”

“…However, the effects of TAT exposure on psychostimulant-induced locomotor sensitization are mixed. For example, TAT−expressing mice and rats with intra-Acb TAT injections show an increased locomotor response to acute cocaine (Harrod et al 2008; Paris et al 2014c). However, intra-Acb injections of TAT before or after acquisition of cocaine sensitization have been shown to decrease sensitized locomotor responses (Ferris et al 2010; Harrod et al 2008).…”

Repeated Cocaine Treatment Enhances HIV-1 Tat-induced Cortical Excitability via Over-activation of L-type Calcium Channels

“…Using transgenic mice with an inducible Tat gene, McLaughlin and colleagues revealed that cocaine-induced hyperlocomotion and conditioned place preference were enhanced with brain expression of Tat (Paris et al 2014). Conditioned place preference is an associative learning task that provides an indirect measure of the cocaine-mediated reward.…”