Neurobehavioral alterations in HIV-1 transgenic rats: Evidence for dopaminergic dysfunction

Abstract

Clinical studies have provided evidence that the progression of HIV-1-associated neurocognitive disorders (HAND) involves alterations in dopamine (DA) systems. Drugs of abuse that act on the brain DA system, such as cocaine (Coc), may exacerbate HIV-1 infection and consequent behavioral and neurological manifestations. In the present study, we used the HIV-1 transgenic (Tg) rat, which constitutively expresses 7 of the 9 HIV-1 genes, to assess potential DA system alterations in three behavioral assays: prepulse inhibition (PPI) of the auditory startle response (ASR), novelty and habituation/retention, and sensitization to Coc across repeated administration. Adult female Sprague-Dawley rats were tested in each experiment. The HIV-1 Tg animals were hyperreactive to auditory startle stimuli and displayed a leftward shift in the temporal window for maximal PPI, suggesting an alteration in sensorimotor gating. All animals displayed an initial robust locomotor response to a novel environment which dissipated with repeated testing; however, the HIV-1 Tg rats, relative to controls, consistently showed a weaker novelty response across monthly-spaced assessments. The HIV-1 Tg animals also showed decreased intrasession habituation of motor activity across 3-day periods that emerged across monthly-spaced locomotor activity sessions; a pattern consistent with impaired long-term episodic memory. Furthermore, the HIV-1 Tg group displayed differential cocaine-induced sensitization, observed both in initiation across the 10-day cocaine treatment, and in expression following a cocaine rechallenge after a 7-day abstinence. Collectively, the present data implicate that the non-infectious HIV-1 Tg rat, which resembles the complete suppression of infection in HIV-1 positive individuals under CART, displays sustained, if not permanent, alterations in the brain DA system.

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

“…In contrast with previous findings ( Moran et al, 2013b ), planned analysis of vehicle data alone during THC testing ( Figure 3A )—and a main effect of genotype across all doses of CBD ( Figure 4A )—revealed a previously undetected general PPI deficit of the HIVtg rat. Critically, this deficit was driven by the 68-dB prepulse condition, as indicated by a significant prepulse × genotype interaction during the THC assessment ( Figure 3C ) and a similar near-significant trend during the CBD assessment ( Figure 4C ).…”

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

“…In contrast with previous findings ( Moran et al, 2013b ), planned analysis of vehicle data alone during THC testing ( Figure 3A )—and a main effect of genotype across all doses of CBD ( Figure 4A )—revealed a previously undetected general PPI deficit of the HIVtg rat. Critically, this deficit was driven by the 68-dB prepulse condition, as indicated by a significant prepulse × genotype interaction during the THC assessment ( Figure 3C ) and a similar near-significant trend during the CBD assessment ( Figure 4C ).…”

Sex Matters: Robust Sex Differences in Signal Detection in the HIV-1 Transgenic Rat

“…The non-infectious nature of the HIV-1 Tg rat makes it unsuitable for studies of infectivity or viral replication, however, it has been promoted for investigating the neurocognitive deficits commonly observed in HAND (e.g., Vigorito et al, 2007 ; Moran et al, 2013a ; Repunte-Canonigo et al, 2014 ; Reid et al, 2016 ; McLaurin et al, 2017a ). HIV-1 Tg rats in the present study displayed no significant health disparities, consistent with our previous studies (Moran et al, 2012 , 2013b ; Roscoe et al, 2014 ; McLaurin et al, 2017a ). Strong evidence for the integrity of visual system function through the majority of the animal’s functional lifespan has been reported in visual PPI, suggesting that animals are capable of detecting brightness (Moran et al, 2013a ; McLaurin et al, 2017a ).…”

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

“…Our results demonstrated that HIV‐1Tg rats showed significant up‐regulation of genes involved in dopaminergic, cholinergic, and glutamatergic signaling in the NAc. These results are consistent with previous findings showing that HIV‐1 proteins alter excitatory neurotransmitter systems, mainly by changing the expression of NMDA receptors and by impairing dopaminergic and cholinergic function (Moran et al., ; Neri et al., ; Nesil et al., ; Potter et al., ). These alterations lead to dysfunction in neurotransmission between synapses and, ultimately, to neuronal cell death in the brains’ mesolimbic system (Avdoshina et al., ).…”

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

“…In contrast with previous findings ( Moran et al, 2013b ), planned analysis of vehicle data alone during THC testing ( Figure 3A )—and a main effect of genotype across all doses of CBD ( Figure 4A )—revealed a previously undetected general PPI deficit of the HIVtg rat. Critically, this deficit was driven by the 68-dB prepulse condition, as indicated by a significant prepulse × genotype interaction during the THC assessment ( Figure 3C ) and a similar near-significant trend during the CBD assessment ( Figure 4C ).…”

Sex Matters: Robust Sex Differences in Signal Detection in the HIV-1 Transgenic Rat

“…The non-infectious nature of the HIV-1 Tg rat makes it unsuitable for studies of infectivity or viral replication, however, it has been promoted for investigating the neurocognitive deficits commonly observed in HAND (e.g., Vigorito et al, 2007 ; Moran et al, 2013a ; Repunte-Canonigo et al, 2014 ; Reid et al, 2016 ; McLaurin et al, 2017a ). HIV-1 Tg rats in the present study displayed no significant health disparities, consistent with our previous studies (Moran et al, 2012 , 2013b ; Roscoe et al, 2014 ; McLaurin et al, 2017a ). Strong evidence for the integrity of visual system function through the majority of the animal’s functional lifespan has been reported in visual PPI, suggesting that animals are capable of detecting brightness (Moran et al, 2013a ; McLaurin et al, 2017a ).…”

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

“…Our results demonstrated that HIV‐1Tg rats showed significant up‐regulation of genes involved in dopaminergic, cholinergic, and glutamatergic signaling in the NAc. These results are consistent with previous findings showing that HIV‐1 proteins alter excitatory neurotransmitter systems, mainly by changing the expression of NMDA receptors and by impairing dopaminergic and cholinergic function (Moran et al., ; Neri et al., ; Nesil et al., ; Potter et al., ). These alterations lead to dysfunction in neurotransmission between synapses and, ultimately, to neuronal cell death in the brains’ mesolimbic system (Avdoshina et al., ).…”

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

“…In contrast with previous findings ( Moran et al, 2013b ), planned analysis of vehicle data alone during THC testing ( Figure 3A )—and a main effect of genotype across all doses of CBD ( Figure 4A )—revealed a previously undetected general PPI deficit of the HIVtg rat. Critically, this deficit was driven by the 68-dB prepulse condition, as indicated by a significant prepulse × genotype interaction during the THC assessment ( Figure 3C ) and a similar near-significant trend during the CBD assessment ( Figure 4C ).…”

Sex Matters: Robust Sex Differences in Signal Detection in the HIV-1 Transgenic Rat

“…The non-infectious nature of the HIV-1 Tg rat makes it unsuitable for studies of infectivity or viral replication, however, it has been promoted for investigating the neurocognitive deficits commonly observed in HAND (e.g., Vigorito et al, 2007 ; Moran et al, 2013a ; Repunte-Canonigo et al, 2014 ; Reid et al, 2016 ; McLaurin et al, 2017a ). HIV-1 Tg rats in the present study displayed no significant health disparities, consistent with our previous studies (Moran et al, 2012 , 2013b ; Roscoe et al, 2014 ; McLaurin et al, 2017a ). Strong evidence for the integrity of visual system function through the majority of the animal’s functional lifespan has been reported in visual PPI, suggesting that animals are capable of detecting brightness (Moran et al, 2013a ; McLaurin et al, 2017a ).…”

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

“…Our results demonstrated that HIV‐1Tg rats showed significant up‐regulation of genes involved in dopaminergic, cholinergic, and glutamatergic signaling in the NAc. These results are consistent with previous findings showing that HIV‐1 proteins alter excitatory neurotransmitter systems, mainly by changing the expression of NMDA receptors and by impairing dopaminergic and cholinergic function (Moran et al., ; Neri et al., ; Nesil et al., ; Potter et al., ). These alterations lead to dysfunction in neurotransmission between synapses and, ultimately, to neuronal cell death in the brains’ mesolimbic system (Avdoshina et al., ).…”