Estrous Cycle and HIV-1 Tat Protein Influence Cocaine-Conditioned Place Preference and Induced Locomotion of Female Mice

Abstract

The HIV-1 trans-activator of transcription (Tat) protein, interacts with psychostimulants to potentiate cocaine-reward in rodents. Sex steroids may protect against Tat-induced deficits. Female GT-tg transgenic mice conditionally-expressed Tat protein targeted to brain via a doxycycline-dependent, GFAP-linked promoter. Mice were tested for cocaine-conditioned place preference (CPP) and cocaine-induced locomotion when in the proestrous (high-hormone) or diestrous (low-hormone) phases of their estrous cycle. Cocaine-CPP was potentiated by Tat induction via 50, 100, or 125 (but not 25) mg/kg doxycycline daily treatment for 7 days. Diestrous mice exposed to Tat protein demonstrated significantly greater cocaine-CPP than did proestrous mice. Tat induction interacted with estrous cycle to decrease acute cocaine-induced locomotion among Tat-induced diestrous mice, but not their uninduced or proestrous counterparts, and attenuated cocaine-sensitization. In a cocaine-challenge, previously cocaine-sensitized mice demonstrated greater cocaine-locomotion over cocaine-naive counterparts and Tat-induction attenuated locomotion. Altogether, data demonstrate Tat and circulating sex steroid influences over cocaine-reward and psychostimulation.

Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

“…The concentration of Dox that was previously demonstrated to optimally express Tat protein in the GT-tg brain (100 mg/kg, i.p. [8,23]), concurrent with impaired learning [23], enhanced anxiety-like behavior [8,9], and potentiated drug reward [31–33] was also the most efficacious concentration observed herein. Notably, effects on ASR and PPI were not linear; rather, acute Tat induction (after 1 day of Dox) or prolonged exposure (after 7 days of Dox) equally potentiated startle and impaired PPI.…”

[3H]Dopamine Uptake through the Dopamine and Norepinephrine Transporters is Decreased in the Prefrontal Cortex of Transgenic Mice Expressing HIV-1 Transactivator of Transcription Protein

“…The optimized dose of Dox was chosen because it has been previously proven efficacious for induction of Tat (Zou et al, 2007;Carey et al, 2012;Paris et al, 2014b), and findings have shown that iTat so induced is biologically active during the period of behavioral testing (Zou et al, 2007). The 7-or 14-day Dox or saline treatment paradigm was chosen for the kinetic analysis of DA uptake based on the previous behavior studies (Carey et al, 2012(Carey et al, , 2013Paris et al, 2014a). In addition, based on the previous report that showed no significant difference in Tat immunoreactivity in whole brain of iTat-tg mice after 7 or 14 days' administration of Dox (Paris et al, 2014b), and because no difference in the inhibitory effects of Tat on DA uptake were observed between these time points, only the 7-day administration paradigm was used in the subsequent studies.…”

Sex differences and Tat expression affect dopaminergic receptor expression and response to antioxidant treatment in methamphetamine-sensitized HIV Tat transgenic mice

“…All mice (Tat− and Tat+) were administered 100 mg/kg Dox (doxycycline hyclate; Sigma-Aldrich, St. Louis, MO, USA) by intraperitoneal injection once a day for 7 days. This regimen was previously shown to induce Tat effectively [43][44][45] . Specifically, Tat expression increases during Dox administration and wanes significantly over 14 days after the termination of Dox treatment 45 .…”