Both HIV and Tat expression decrease prepulse inhibition with further impairment by methamphetamine

Abstract

HIV infection and methamphetamine (METH) use are highly comorbid and represent a significant public health problem. Both conditions are known to negatively impact a variety of brain functions. One brain function that may be affected by HIV and METH use is sensorimotor gating, an automatic, pre-conscious filtering of sensory information that is thought to contribute to higher order cognitive processes. Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in both humans and animals, thereby enabling cross-species translational studies. While previous studies suggest HIV and METH may individually impair PPI, little research has been conducted on the effects of combined HIV and METH on PPI. The goal of this cross-species study was to determine the effects of METH on PPI in the inducible Tat (iTat) mouse model of HIV and in people with HIV. PPI was measured in the iTat mouse model before, during, and after chronic METH treatment and after Tat induction. Chronic METH treatment decreased PPI in male but not female mice. PPI normalized with cessation of METH. Inducing Tat expression decreased PPI in male but not in female mice. No interactions between chronic METH treatment and Tat expression were observed in mice. In humans, HIV was associated with decreased PPI in both men and women. Furthermore, PPI was lowest in people with HIV who also had a history of METH dependence. Overall, these results suggest HIV and METH may additively impair early information processing in humans, potentially affecting downstream cognitive function.

Keywords: HIV; Methamphetamine; Prepulse inhibition; Sensorimotor gating.

Figure 1.. Schematic of experimental design.

A.) WT and iTat mice were assessed for PPI at baseline (Phase 1: pre-METH and pre-DOX) and matched into four groups (WT+saline, WT+METH, Tat+saline, Tat+METH; n=15/group) based on percent PPI and startle reactivity. Two days later, mice began a 25 day regimen of injections with either saline or METH. Mice were assessed again for PPI on the 23^rd day of METH treatment (Phase 2: during METH and pre-DOX). The next day, a 7 day DOX treatment (85 mg/kg) was started. Mice were assessed for PPI a final time (Phase 3: post-METH and DOX) two days after completion of the DOX regimen. B.) METH was administered four times per day in an escalating manner, starting with 1 mg/kg and ending at 6 mg/kg. Injections were given for four days, followed by three days of no injections. This pattern was repeated a total of four times. C.) Participants with or without HIV and with or without a history of METH dependence were recruited for the human studies.

Figure 2.. PPI testing in mice pre-METH and pre-DOX, during METH and pre-DOX, and post-METH and post-DOX.

A.) WT and iTat male and female mice (n=30/group) were assessed for PPI prior to METH or DOX treatment. B.) Mice then received a 25-day regimen of either saline or METH injections and were assessed for PPI on the 23^rd day of METH treatment. C.) Mice then received a 7-day course of DOX injections overlapping by two days with the 25 day METH treatment. Two days after the last DOX injection, mice were assessed for PPI. Data are presented as mean ± S.E.M. * = main effect of METH (ANOVA, p<0.05). ** = main effect of Tat induction (ANOVA, p<0.05)

Figure 3.. Effects of HIV and a history of METH dependence on PPI in male participants.

Four groups of human men with or without HIV and with or without a history of METH dependence (HIV−/METH−: n=42, HIV−/METH+: n=29, HIV+/METH−: n=47, HIV+/METH+: n=42) were recruited and assessed for PPI at three different prepulse intensities. Average PPI for each group at each prepulse intensity are shown in panel A. PPI averaged across prepulse intensities are shown in panel B. Data are presented as mean ± S.E.M. * = main effect of HIV (Two-way ANOVA, p=0.003); † = significantly different compared to HIV−/METH− group (p=0.019, Dunnett’s posthoc test).