HIV‐1 protein Tat inhibits vesicular monoamine transporter‐2 activity in rat striatum

Theodore, Shaji; Cass, Wayne A.; Dwoskin, Linda P.; Maragos, William F.

doi:10.1002/syn.21564

Cited by 19 publications

(12 citation statements)

References 9 publications

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“…Tat-induced conformational changes in DAT also increase the affinity of cocaine for the transporter protein [78]. Thus, Tat has the capacity to significantly enhance extracellular concentrations of dopamine through multiple mechanisms [81]. Excessive extracellular dopamine over-actives dopaminergic receptors and drives the reward-motivation known to underlie cocaine-mediated behaviors.…”

Section: Common Pathways For Cocaine and Tat Effects In Mpfcmentioning

confidence: 99%

Cortical Consequences of HIV-1 Tat Exposure in Rats are Enhanced by Chronic Cocaine

Wayman

Chen²,

Persons³

et al. 2015

CHR

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The life span of individuals that are sero-positive for human immunodeficiency virus (HIV) has greatly improved; however, complications involving the central nervous system (CNS) remain a concern. While HIV does not directly infect neurons, the proteins produced by the virus, including HIV transactivator of transcription (Tat), are released from infected glia; these proteins can be neurotoxic. This neurotoxicity is thought to mediate the pathology underlying HIV-associated neurological impairments. Cocaine abuse is common among HIV infected individuals, and this abuse augments HIV-associated neurological deficits. The brain regions and pathophysiological mechanisms that are dysregulated by both chronic cocaine and Tat are the focus of the current review.

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Section: Common Pathways For Cocaine and Tat Effects In Mpfcmentioning

confidence: 99%

Cortical Consequences of HIV-1 Tat Exposure in Rats are Enhanced by Chronic Cocaine

Wayman

Chen²,

Persons³

et al. 2015

CHR

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“…Transgenic mice that express the TAT protein in the brain, under the glial fibrillary acidic protein (GFAP) promoter and inducible by treatment with doxycycline, show neuropathology that is similar to that observed in HIV-infected humans (Kim et al 2003), therefore providing a useful in vivo model to study the temporal impact of TAT protein on brain function. Moreover, TAT-induced dysfunction in corticolimbic dopaminergic neurotransmission (Ferris et al 2009; Kesby et al 2016b; Midde et al 2012; Theodore et al 2012; Zhu et al 2009) may lead to alterations in reward function (Kesby et al 2016b; Koob and Volkow 2010). We have previously shown that the expression of HIV-associated proteins, such as gp120 and TAT, increase the sensitivity to methamphetamine reward (Kesby et al 2016b; Kesby et al 2014).…”

Section: Introductionmentioning

confidence: 99%

HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function

Kesby

Najera

Romoli

et al. 2017

Brain, Behavior, and Immunity

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Methamphetamine abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein TAT induces dysfunction of mesolimbic dopaminergic systems which may result in impaired reward processes and contribute to methamphetamine abuse. These studies investigated the impact of TAT expression on methamphetamine-induced locomotor sensitization, underlying changes in dopamine function and adenosine receptors in mesolimbic brain areas and neuroinflammation (microgliosis). Transgenic mice with doxycycline-induced TAT protein expression in the brain were tested for locomotor activity in response to repeated methamphetamine injections and methamphetamine challenge after a 7-day abstinence period. Dopamine function in the nucleus accumbens (Acb) was determined using high performance liquid chromatography. Expression of dopamine and/or adenosine A receptors (ADORA) in the Acb and caudate putamen (CPu) was assessed using RT-PCR and immunohistochemistry analyses. Microarrays with pathway analyses assessed dopamine and adenosine signaling in the CPu. Activity-dependent neurotransmitter switching of a reserve pool of non-dopaminergic neurons to a dopaminergic phenotype in the ventral tegmental area (VTA) was determined by immunohistochemistry and quantified with stereology. TAT expression enhanced methamphetamine-induced sensitization. TAT expression alone decreased striatal dopamine (D1, D2, D4, D5) and ADORA1A receptor expression, while increasing ADORA2A receptors expression. Moreover, TAT expression combined with methamphetamine exposure was associated with increased adenosine A receptors (ADORA1A) expression and increased recruitment of dopamine neurons in the VTA. TAT expression and methamphetamine exposure induced microglia activation with the largest effect after combined exposure. Our findings suggest that dopamine-adenosine receptor interactions and reserve pool neuronal recruitment may represent potential targets to develop new treatments for methamphetamine abuse in individuals with HIV.

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“…Recent imaging studies have revealed reduced gray matter density and cerebral fractional anisotropy abnormalities in multiple brain areas in TAT-expressing mice (Carey et al, 2013, Carey et al, 2015). TAT protein induces dysfunction of dopaminergic neurotransmission in corticolimbic brain circuits (Ferris et al, 2009b, Zhu et al, 2009, Midde et al, 2012, Theodore et al, 2012) that are involved in reward function (Koob and Volkow, 2010). However, it is not known if TAT-induced alterations in dopaminergic function in corticolimbic circuits result in changes in reward processes.…”

Section: Introductionmentioning

confidence: 99%

The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice

2016

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Depression and psychostimulant abuse are common comorbidities among humans with immunodeficiency virus (HIV) disease. The HIV regulatory protein TAT is one of multiple HIV-related proteins associated with HIV-induced neurotoxicity. TAT-induced dysfunction of dopamine and serotonin systems in corticolimbic brain areas may result in impaired reward function, thus, contributing to depressive symptoms and psychostimulant abuse. Transgenic mice with doxycycline-induced TAT protein expression in the brain (TAT+, TAT− control) show neuropathology resembling brain abnormalities in HIV+ humans. We evaluated brain reward function in response to TAT expression, nicotine and methamphetamine administration in TAT+ and TAT− mice using the intracranial self-stimulation procedure. We evaluated the brain dopamine and serotonin systems with high-performance liquid chromatography. The effects of TAT expression on delay-dependent working memory in TAT+ and TAT− mice using the operant delayed nonmatch-to-position task were also assessed. During doxycycline administration, reward thresholds were elevated by 20% in TAT+ mice compared with TAT− mice. After the termination of doxycycline treatment, thresholds of TAT+ mice remained significantly higher than those of TAT− mice and this was associated with changes in mesolimbic serotonin and dopamine levels. TAT+ mice showed a greater methamphetamine-induced threshold lowering compared with TAT− mice. TAT expression did not alter delay-dependent working memory. These results indicate that TAT expression in mice leads to reward deficits, a core symptom of depression, and a greater sensitivity to methamphetamine-induced reward enhancement. Our findings suggest that the TAT protein may contribute to increased depressive-like symptoms and continued methamphetamine use in HIV-positive individuals.

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HIV‐1 protein Tat inhibits vesicular monoamine transporter‐2 activity in rat striatum

Cited by 19 publications

References 9 publications

Cortical Consequences of HIV-1 Tat Exposure in Rats are Enhanced by Chronic Cocaine

Cortical Consequences of HIV-1 Tat Exposure in Rats are Enhanced by Chronic Cocaine

HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function

The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice

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