HIV Transgenic Rats Demonstrate Impaired Sensorimotor Gating But Are Insensitive to Cannabinoid (Δ9-Tetrahydrocannabinol)-Induced Deficits

Abstract

Background HIV-associated Neurocognitive Disorder (HAND) is commonly observed in persons living with HIV (PWH), and is characterized by cognitive deficits implicating disruptions of fronto-striatal neurocircuitry. Such circuitry is also susceptible to alteration by cannabis and other drugs of abuse. PWH use cannabis at much higher rates than the general population, thus prioritizing the characterization of any interactions between HIV and cannabinoids on cognitively relevant systems. Prepulse inhibition (PPI) of the startle response, the process by which the motor response to a startling stimulus is attenuated by perception of a preceding non-startling stimulus, is an operational assay of fronto-striatal circuit integrity that is translatable across species. PPI is reduced in PWH. The HIV transgenic (HIVtg) rat model of HIV infection mimics numerous aspects of HAND, although to date the PPI deficit observed in PWH has yet to be fully recreated in these animals. Methods PPI was measured in male and female HIVtg rats and wildtype (WT) controls following acute, nonconcurrent treatment with the primary constituents of cannabis—Δ 9-tetrahydrocannabinol (THC; 1 & 3 mg/kg, s.c) and cannabidiol (CBD; 1, 10, & 30 mg/kg, i.p.). Results HIVtg rats exhibited a significant PPI deficit relative to WT controls. THC reduced PPI in controls, but not HIVtg rats. CBD exerted only minor, genotype-independent effects on PPI. Conclusions HIVtg rats exhibit a relative insensitivity to the deleterious effects of THC on the fronto-striatal function reflected by PPI, which may partially explain the higher rates of cannabis use amongst PWH.

Acute nicotine vapor normalizes sensorimotor gating and reduces locomotor activity deficits in HIV-1 transgenic rats

“…In these studies, we demonstrated that acute nicotine vapor can normalize the PPI deficits of HIV-1Tg rat model of HIV. Consistent with previously published findings (Roberts et al, 2021a), HIV-1Tg rats exhibited deficient PPI relative to F344 controls at the lower prepulse intensities. Importantly, within the lowest prepulse intensity condition (PP3), nicotine normalized PPI in HIV-1Tg rats to levels observed in F344 control rats.…”

“…IIa], where every louder prepulse resulted in increased PPI relative to every quieter prepulse ( p s <0.001). Given deficits of HIV-1Tg rats at lower prepulses in prior publications (Roberts et al, 2021a), specific a priori hypotheses analyses were conducted at PP3.…”

“…IIa], where every louder prepulse resulted in increased PPI relative to every quieter prepulse (ps <0.001). Given deficits of HIV-1Tg rats at lower prepulses in prior publications (Roberts et al, 2021a), specific a priori hypotheses analyses were conducted at PP3. Pairwise comparisons revealed that within VEH-treated rats, HIV-1Tg rats exhibited lower prepulse levels relative to their WT controls (p=0.019; Fig.…”

“…Among NCI-diagnosed PWH, sensorimotor gating (SG) deficits, as measured by prepulse inhibition (PPI), are observed (Minassian et al, 2013), though recent data indicates PPI deficits in PWH irrespective of NCI status (Walter et al, 2021). These PPI deficits are replicated in the Fischer 344 HIV-1 Transgenic (HIV-1Tg) rat model of HIV at lower prepulse intensities (Roberts et al, 2021a). HIV-1Tg rats are a reliable manipulation relevant to HIV, as these animals consistently express the HIV-1 proviral genome (7 of 9 proteins except for gag and pol, responsible for viral replication and reverse transcriptase) throughout the animal's life (Reid et al, 2001).…”

Neurodegeneration Within the Amygdala Is Differentially Induced by Opioid and HIV-1 Tat Exposure

“…Thus, we anticipate that similar reductions in PPI will be apparent in our Tat-tg model with more prolonged exposure. Other preclinical models (HIV-tg rats and gp120-tg mice) also do not display consistent results, e.g., some studies show a HIV-protein-induced reduction in PPI, whereas others show no change ( Moran et al, 2013 ; Henry et al, 2014 ; Roscoe et al, 2014 ; Bachis et al, 2016 ; McLaurin et al, 2017a , b , 2018 ; Roberts et al, 2021 ). It is anticipated that our results would differ from these because of the involvement of different HIV proteins (or different combinations of proteins), and we predict each viral protein will affect PPI differently or not at all.…”