SRI-32743, a novel allosteric modulator, attenuates HIV-1 Tat protein-induced inhibition of the dopamine transporter and alleviates the potentiation of cocaine reward in HIV-1 Tat transgenic mice

Zhu, Jun; Quizon, Pamela M.; Wang, Yingying; Adeniran, Charles; Strauss, Matthew J.; Torres, Ana Jimenez; Patel, Palak; Cirino, Thomas J.; Eans, Shainnel O.; Hammond, Haylee R.; Deliscar, Laure S.; O'Hara, Priscilla; Saini, Surendra Kumar; Ofori, Edward; Vekariya, Rakesh H.; Zhang, Sixue; Moukha-Chafiq, Omar; Nguyen, Theresa; Ananthan, Subramaniam; Augelli‐Szafran, Corinne E.; Zhan, Chang‐Guo; McLaughlin, Jay P.

doi:10.1016/j.neuropharm.2022.109239

Cited by 13 publications

(15 citation statements)

References 85 publications

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“…Previous research into cocaine-related behavior in preclinical models of HIV has been largely limited to males. Our nding showing similar magnitude of CPP may result from differential effects of HIV-1 on cocaine preference in this model as compared to the use of Tat transgenic animals (Zhu et al, 2022), however, these previous ndings were restricted to male mice. Substantial sex differences in cocainerelated behaviors have been reported, including development of cocaine CPP at lower doses in females (Zakharova et al, 2009) and reinstatement in females (Bobzean et al, 2010).…”

Section: Discussionmentioning

confidence: 46%

“…A majority of the work has employed transgenic models to investigate outcomes in a cocaine conditioned place preference (CPP) paradigm which assesses the development and expression of drug-context associations. In HIV-1 Tat transgenic (Tg) mice, Tat expression potentiates cocaine CPP (Paris et al, 2014;Mediouni et al, 2015a;Zhu et al, 2022). Inducing Tat expression is also su cient to drive the reinstatement of cocaine CPP (Paris et al, 2014;Mediouni et al, 2015) following extinction, suggesting that HIV-1 proteins can act to alter cocaine-related behavior, potentially through in ammatory effects or effects on the dopamine transporter (Miller et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation

Barker,

Buck,

Xie

et al. 2023

Preprint

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Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between HIV infection and cocaine use disorder is likely bidirectional, with cocaine use directly impacting immune function while HIV infection alters addiction-related behavior. To better characterize the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilized a humanized mouse model to investigate the outcomes of HIV-1 infection on cocaine-related behaviors in a conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection selectively impaired cocaine CPP extinction without effecting reinstatement or cocaine seeking under conflict were observed. Behavioral alterations were accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes were observed in both mouse and human cytokines, including HIV-induced reductions in mouse IL-1α and G-CSF and human TNFα, and cocaine induced alterations in mouse GM-CSF. Together these data provide new insights into the unique neurobehavioral outcomes of HIV infection and cocaine exposure and how they interact to effect immune responses.

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Section: Discussionmentioning

confidence: 46%

Section: Introductionmentioning

confidence: 99%

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation

Barker,

Buck,

Xie

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Adult male inducible Tat transgenic (iTat-tg) mice and G-tg (Tat-null) mice [ 8 ] were obtained from colonies at the University of Florida as reported previously [ 6 ]. Both the iTat-tg and Tat-null mice genetically expresses a “tetracycline-on (TETON)” system, but only iTat-tg mice possess the Tat 1–86 coding gene [ 8 ].…”

Section: Methodsmentioning

confidence: 99%

“…Among these proteins, transactivation of transcription (Tat), is known to act as a negative allosteric modulator of the dopamine transporter (DAT), inhibiting dopamine (DA) uptake [ 4 , 5 ]. Our recent study demonstrates that the disruption of DAT-mediated dopaminergic transmission caused by Tat contributes to Tat-induced potentiation of cocaine reward and deficits in learning and memory seen in HAND [ 5 ], making Tat an attractive pharmacologic target [ 6 ]. Our previous study reported that SRI-30827, a closely related analog of SRI-32743, attenuated Tat-induced inhibition of [ 3 H]WIN35428 binding through its influence on tyrosine470 and tyrosine88 residues in the EL6 region of hDAT [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…These two hDAT residues are critical for Tat protein’s allosteric modulation of DAT [ 4 ]. Furthermore, SRI-32743 dose-dependently reversed Tat-induced potentiation of cocaine-CPP and impairment of novel object recognition (NOR) in mice [ 6 ]. The doses of SRI-32743 tested were without effect on cocaine-CPP or NOR in mice lacking Tat protein expression.…”

Section: Introductionmentioning

confidence: 99%

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SRI-30827, a novel allosteric modulator of the dopamine transporter, alleviates HIV-1 Tat-induced potentiation of cocaine conditioned place preference in mice

Hammond,

Eans,

Cirino

et al. 2023

NeuroImmune Pharmacology and Therapeutics

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Objectives HIV-1 Tat (transactivator of transcription) protein disrupts dopaminergic transmission and potentiates the rewarding effects of cocaine. Allosteric modulators of the dopamine transporter (DAT) have been shown to reverse Tat-induced DAT dysfunction. We hypothesized that a novel DAT allosteric modulator, SRI-30827, would counteract Tat-induced potentiation of cocaine reward. Methods Doxycycline (Dox)-inducible Tat transgenic (iTat-tg) mice and their G-tg (Tat-null) counterparts were tested in a cocaine conditioned place preference (CPP) paradigm. Mice were treated 14 days with saline, or Dox (100 mg/kg/day, i.p.) to induce Tat protein. Upon induction, mice were place conditioned two days with cocaine (10 mg/kg/day) after a 1-h daily intracerebroventricular (i.c.v.) pretreatment with SRI-30827 (1 nmol) or a vehicle control, and final place preference assessed as a measure of cocaine reward. Results Dox-treatment significantly potentiated cocaine-CPP in iTat-tg mice over the response of saline-treated control littermates. SRI-30827 treatment eliminated Tat-induced potentiation without altering normal cocaine-CPP in saline-treated mice. Likewise, SRI-30827 did not alter cocaine-CPP in both saline- and Dox-treated G-tg mice incapable of expressing Tat protein. Conclusions These findings add to a growing body of evidence that allosteric modulation of DAT could provide a promising therapeutic intervention for patients with comorbid HIV-1 and cocaine use disorder (CUD).

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Molecular mechanisms of dopaminergic transmission in NeuroHIV

Zhu,

Davis,

Zhan

et al. 2024

HIV-Associated Neurocognitive Disorders

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SRI-32743, a novel allosteric modulator, attenuates HIV-1 Tat protein-induced inhibition of the dopamine transporter and alleviates the potentiation of cocaine reward in HIV-1 Tat transgenic mice

Cited by 13 publications

References 85 publications

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation

SRI-30827, a novel allosteric modulator of the dopamine transporter, alleviates HIV-1 Tat-induced potentiation of cocaine conditioned place preference in mice

Molecular mechanisms of dopaminergic transmission in NeuroHIV

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