Methamphetamine Augments HIV-1 gp120 Inhibition of Synaptic Transmission and Plasticity in Rat Hippocampal Slices: Implications for Methamphetamine Exacerbation of HIV-Associated Neurocognitive Disorders.

Background: Methamphetamine (Meth) abuse and human immunodeficiency virus type 1(HIV-1) infection are two major public health problems worldwide. Being frequently comorbid with HIV-1 infection, Meth abuse exacerbates neurocognitive impairment in HIV-1-infected individuals even in the era of combined antiretroviral therapy. While a large body of research have studied the individual effects of Meth and HIV-1 envelope glycoprotein 120 (gp120) in the brain, far less has focused on their synergistic influence. To uncover the underlying mechanisms for increased incidence and severity of HIV-1-associate neurocognitive disorders (HAND) in HIV-1-infected patients with Meth abuse, we investigated acute individual and combined effects of Meth and gp120 on synaptic transmission and plasticity in CA1 region of rat hippocampus, a brain region known to be vulnerable to HIV-1 infection. Methods: Experiments were conducted on the hippocampal slices prepared from 15-30 d-old male Spraque-Dawley rats. Field excitatory postsynaptic potentials were generated by electric stimulation of Schaffer collateral fibers and recorded in the CA1 region. Long-term potentiation (LTP) was induced by high frequency stimulation (HFS) or theta-burst stimulation (TBS). The individual and combined effects of acutely applied methamphetamine and HIV-1 gp120 synaptic physiology and underlying mechanisms were examined via electrophysiology, western blotting and immunohistochemistry. One-way and two-way ANOVA, followed by Tukey’s multiple comparisons tests were employed for statistical analyses. Results: Acute and localized application of Meth and gp120 each alone reduced short-term dynamics of input-output responses and frequency facilitation, and LTP induced by either HFS or TBS. A synergistic augmentation on activity-dependent synaptic plasticity was observed when Meth and gp120 were applied in combination. Paired-pulse facilitation results exhibited an altered facilitation ratio, suggesting a presynaptic site of action. Further studies revealed an involvement of microglia NLRP3 inflammasome activation in Meth augmentation of gp120-mediated attenuation of LTP. Conclusions: Our results demonstrated Meth augmented gp120 attenuation of LTP in the hippocampus via microglial inflammasome activation. Since LTP is the accepted experimental analog of learning at the synaptic level, such augmentation may underlie Meth exacerbation of HAND observed clinically.