iTat transgenic mice exhibit hyper-locomotion in the behavioral pattern monitor after chronic exposure to methamphetamine but are unaffected by Tat expression

Ayoub, Samantha; Kenton, Johnny A.; Milienne-Petiot, Morgane; Deben, Debbie S.; Achim, Cristian L.; Geyer, Mark A.; Perry, William; Grant, Igor; Young, Jared W.; Minassian, Arpi

doi:10.1016/j.pbb.2022.173499

Cited by 3 publications

(2 citation statements)

References 64 publications

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“…However, sex differences are not typically observed in BPM studies cross-species (Minassian et al, 2016; Risbrough et al, 2006; Roberts et al, 2021b). Contradictory to our current findings, one recent BPM study in mice found that males had increased motor activity, exploratory behavior, and more linear movement (Ayoub et al, 2023). Although these findings are in a different rodent species, this highlights the need to consider interacting factors when interpreting sex differences, notably estrogen/testosterone pathways, each of which mediates spontaneous activity in both rats and mice (Datta et al, 2019; Miller et al, 2021; Roy & Wade, 1975; Broida & Svare, 1983).…”

Section: Discussionsupporting

confidence: 76%

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

Jha,

Ayoub,

Flesher

et al. 2024

Preprint

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RationaleDespite improved life expectancy of people with HIV (PWH), HIV-associated neurocognitive impairment (NCI) persists, alongside deficits in sensorimotor gating and neuroinflammation. PWH exhibit high smoking rates, possibly due to neuroprotective, anti-inflammatory, and cognitive-enhancing effects of nicotine, suggesting potential self-medication.ObjectivesHere, we tested the effects of acute nicotine vapor exposure on translatable measures of sensorimotor gating and exploratory behavior in the HIV-1 transgenic (HIV-1Tg) rat model of HIV.MethodsMale and female HIV-1Tg and F344 control rats (n=57) were exposed to acute nicotine or vehicle vapor. Sensorimotor gating was assessed using prepulse inhibition (PPI) of the acoustic startle response, and exploratory behavior was evaluated using the behavioral pattern monitor (BPM).ResultsVehicle-treated HIV-1Tg rats exhibited PPI deficits at low prepulse intensities compared to F344 controls, as seen previously. No PPI deficits were observed in nicotine-treated HIV-1Tg rats, however. HIV-1Tg rats were hypoactive in the BPM relative to controls, whilst nicotine vapor increased activity and exploratory behavior across genotypes. Cotinine analyses confirmed comparable levels of the primary metabolite of nicotine across genotypes.ConclusionsPrevious findings of PPI deficits in HIV-1Tg rats were replicated and, importantly, attenuated by acute nicotine vapor. Evidence for similar cotinine levels suggest a nicotine-specific effect in HIV-1Tg rats. HIV-1Tg rats had reduced exploratory behavior compared to controls, attenuated by acute nicotine vapor. Therefore, acute nicotine may be beneficial for remediating sensorimotor and locomotor activity deficits in PWH. Future studies should determine the long-term effects of nicotine vapor on similar HIV/NCI-relevant behaviors.

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Section: Discussionsupporting

confidence: 76%

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

Jha,

Ayoub,

Flesher

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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“…In patients treated with anti-retroviral therapies, low levels of Tat have been detected in the cerebrospinal fluid which has been correlated with HIV-associated neurocognitive disorders (HAND) (King et al, 2006;Bagashev and Sawaya, 2013;Zhu et al, 2018) which affects more than 50% of patients (Heaton et al, 2010). Several studies have suggested that Tat causes neurological disorders by interacting with monoamine transporters (DAT, serotonin, norepinephrine) as well as with N-methyl-D-Aspartate (NMDA) receptors in the central nervous system impairing their functional activity (Aksenova et al, 2006;Kumar et al, 2011;Purohit et al, 2011;Adeniran et al, 2021;Ayoub et al, 2023). Several experiments have confirmed that Tat protein interacts with DAT and decreases dopamine uptake activity leading to CNS neurotoxicity (Zhu et al, 2009).…”

Section: Interactions Of Dat With Tatmentioning

confidence: 99%

Overview of the structure and function of the dopamine transporter and its protein interactions

Nepal

Das²,

Reith³

et al. 2023

Front. Physiol.

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The dopamine transporter (DAT) plays an integral role in dopamine neurotransmission through the clearance of dopamine from the extracellular space. Dysregulation of DAT is central to the pathophysiology of numerous neuropsychiatric disorders and as such is an attractive therapeutic target. DAT belongs to the solute carrier family 6 (SLC6) class of Na+/Cl− dependent transporters that move various cargo into neurons against their concentration gradient. This review focuses on DAT (SCL6A3 protein) while extending the narrative to the closely related transporters for serotonin and norepinephrine where needed for comparison or functional relevance. Cloning and site-directed mutagenesis experiments provided early structural knowledge of DAT but our contemporary understanding was achieved through a combination of crystallization of the related bacterial transporter LeuT, homology modeling, and subsequently the crystallization of drosophila DAT. These seminal findings enabled a better understanding of the conformational states involved in the transport of substrate, subsequently aiding state-specific drug design. Post-translational modifications to DAT such as phosphorylation, palmitoylation, ubiquitination also influence the plasma membrane localization and kinetics. Substrates and drugs can interact with multiple sites within DAT including the primary S1 and S2 sites involved in dopamine binding and novel allosteric sites. Major research has centered around the question what determines the substrate and inhibitor selectivity of DAT in comparison to serotonin and norepinephrine transporters. DAT has been implicated in many neurological disorders and may play a role in the pathology of HIV and Parkinson’s disease via direct physical interaction with HIV-1 Tat and α-synuclein proteins respectively.

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Using cross-species behavioral tools to determine mechanisms contributing to HIV-associated neurocognitive disorder and comorbid substance use

Ayoub,

Noback,

Ahern

et al. 2024

HIV-Associated Neurocognitive Disorders

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iTat transgenic mice exhibit hyper-locomotion in the behavioral pattern monitor after chronic exposure to methamphetamine but are unaffected by Tat expression

Cited by 3 publications

References 64 publications

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

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

Overview of the structure and function of the dopamine transporter and its protein interactions

Using cross-species behavioral tools to determine mechanisms contributing to HIV-associated neurocognitive disorder and comorbid substance use

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