Interactive Effects of Ethanol and HIV‐1 Proteins on Novelty‐Seeking Behaviors and Addiction‐Related Gene Expression

Abstract

Background Novelty-seeking behavior is related to the reward system in the brain and can predict the potential for addiction. Alcohol use is prevalent in HIV-1-infected patients and adversely affects anti-retroviral medication. The difference in vulnerability to alcohol addiction between HIV-1 infected and non-infected populations has not been fully investigated. This study was designed to determine whether HIV-1 proteins alter the effects of ethanol on novelty-seeking behavior using the HIV-1 transgenic (HIV-1Tg) rat as the study model and to examine the molecular mechanisms responsible for this behavior. Methods Both HIV-1Tg and F344 control rats were tested for baseline novelty-seeking behavior, then received either ethanol (1g/kg) at a concentration of 20% v/v or saline treatment for 13 days and then were re-tested for novelty seeking. Quantitative real-time PCR was conducted to examine the differences in expression of 65 genes implicated in novelty-seeking and alcohol addiction between strains and treatment groups. Results The HIV-1 proteins significantly enhanced baseline novelty-seeking behaviors in both the hole-board and open field tests. Chronic ethanol treatment significantly increased baseline novelty-seeking behavior in both strains, but the effects of ethanol appeared to be more robust and prominent in HIV-1Tg rats. Strain-specific patterns of altered gene expression were observed for dopaminergic, cholinergic, and glutamatergic signaling in the nucleus accumbens (NAc), suggesting the effects of HIV-1 proteins on the brain’s reward system. Chronic ethanol treatment was shown to greatly modulate the effects of HIV-1 proteins in these neurotransmitter systems. Conclusions Taken together, our findings indicate that HIV-1 proteins could modify novelty-seeking behavior at the gene expression level, and ethanol treatment may enhance this behavior in both strains but to a greater extent in HIV-1Tg rats.

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

“…Behavioral control is the ability to override impulses and adjust behavior to respond appropriately to different stimuli ( Diamond, 2013 ; Kliethermes and Crabbe, 2006 ). Two to eight weeks of Tat exposure increased novelty-exploration in response to a novel environment, flavor, or food—coinciding with findings in HIV-1 transgenic rats (expressing multiple HIV proteins including Tat, Nef, and Vpr) demonstrating increased exploration in a novel environment ( Wingo et al, 2016 ; Yang et al, 2017 ), and extending prior findings by revealing that increased novelty-exploration seen in preclinical HAND models is observed across the presentation of different novel stimuli. Thus, exposure to Tat alone (versus other viral proteins or protein combinations) is sufficient to increase novelty-exploration.…”

MR brain volumetric measurements are predictive of neurobehavioral impairment in the HIV-1 transgenic rat

“…This is also in line with previous reports of dopaminergic dysfunction in the Tg rats ( Webb et al, 2010 , Moran et al, 2013b , Moran et al, 2012 , Silvers et al, 2007 ) which probably parallels known susceptibility of the dopaminergic system to HIV in infected patients ( Kumar et al, 2011 , Kumar et al, 2009 , Chang et al, 2008 , Gelman et al, 2006 ). It again draws attention to the compounding effects of addiction drugs on a system that is already compromised, with worse damage seen in the Tg rats compared to WT rats under the effect of nicotine ( Yang et al, 2017 , Yang et al, 2016 , Song et al, 2016 , Cao et al, 2016 , Nesil et al, 2015 ), ethanol ( Wingo et al, 2016 , Sarkar et al, 2013 ), methamphetamine ( Moran et al, 2012 , Pang et al, 2013 , Henry et al, 2013 , Kass et al, 2010 , Liu et al, 2009 ) or cocaine administration ( Moran et al, 2013b , McIntosh et al, 2015 ).…”

Analysis of the Association of Nonsynonymous Polymorphisms in ADH Genes with Hazardous Drinking in HIV‐1‐Positive Individuals

“…Although specific antiviral treatments allow control of the HIV‐1 replication process, Tat protein is still present in the body and can act by reinforcing the harmful effects of alcohol (Lawson et al., ). In addition, HIV‐1 proteins can modify the effects of alcohol on the brain by changing patterns of gene expression for neurotransmitter systems (dopaminergic, cholinergic, and glutamatergic) (Wingo et al., ).…”