Tobacco smoking prevalence among the HIV-positive population is approximately 50%-70%, which is 2 to 3 times higher than that in non-HIV population (Centers for Disease Control and Prevention, 2005). Nicotine (NIC), the primary reinforcing agent in tobacco, stimulates the mesolimbic dopamine (DA) system through activation of nicotinic acetylcholine receptors (nAChRs) in the brain. The DA projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) plays a critical role in NIC-mediated behaviors that may contribute to NIC craving in humans. Compared to non-HIV individuals, HIV-positive smokers are more likely to develop NIC dependence, suffer from depression and experience more difficulty to quit smoking. Taken together, tobacco smoking presents an elevated health hazard to HIV-positive individuals, and HIV infection may increase the risk of NIC dependence. Currently, little is known about the neurobehavioral mechanisms through which HIV-positive individuals show increased vulnerability to NIC dependence. Infection with HIV is associated with a variety of neurological impairments that result from the presence of the viral proteins. HIV-1 trans-activator of transcription (Tat) protein is essential for efficient viral replication and plays a crucial role in pathogenesis of HIV-1-associated dementia and synergistic neurotoxicity in the dopaminergic system. Our recent studies indicate that intra-striatal infusion of Tat decreases K+evoked DA levels in rats (Ferris et al., 2008) and that intra-accumbal Tat alters the acute and sensitized response to cocaine (Harrod et al., 2008). The preliminary results show that in vitro exposure to the Tat protein decreases DA transporter (DAT) function in rat striatum. Thus, the major experimental question of this proposal is: Does microinjection of Tat into either the NAc or VTA produce neural changes that alter sensitivity to acute and/or repeated intravenous (IV) NIC administration? The proposed research will test the following hypothesis: HIV-1 Tat protein alters functioning of the mesolimbic dopamine system, thereby resulting in NIC-mediated behavioral changes. The experiments proposed here are designed to focus on two specific aims: 1) To determine the effects of microinjected Tat on IV NIC-mediated locomotor sensitization, 2) To determine the effects of microinjected Tat on DAT activity and nAChRs expression in rats with acute or repeated IV NIC administration. The long-term experimental goal of the present research proposal will be to elucidate the underlying neurobiological mechanisms of Tat-induced dysfunction of mesolimbic DA system contributing to NIC dependence. Such research will provide new insights into developing effective smoking cessation programs in HIV-positive population.

Public Health Relevance

These results will provide new insights into the underlying neurobehavioral mechanisms through which HIV- positive individuals show increased vulnerability to NIC dependence. Understanding this mechanism will have the potential to facilitate the development of effective smoking cessation programs in HIV-positive population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
5R03DA026721-02
Application #
7787099
Study Section
Special Emphasis Panel (ZRG1-AARR-F (53))
Program Officer
Lynch, Minda
Project Start
2009-04-01
Project End
2012-06-30
Budget Start
2010-01-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$142,560
Indirect Cost
Name
University of South Carolina at Columbia
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Zhu, Jun; Yuan, Yaxia; Midde, Narasimha M et al. (2016) HIV-1 transgenic rats display an increase in [(3)H]dopamine uptake in the prefrontal cortex and striatum. J Neurovirol 22:282-92
Midde, Narasimha M; Yuan, Yaxia; Quizon, Pamela M et al. (2015) Mutations at tyrosine 88, lysine 92 and tyrosine 470 of human dopamine transporter result in an attenuation of HIV-1 Tat-induced inhibition of dopamine transport. J Neuroimmune Pharmacol 10:122-35
Gomez, Adrian M; Altomare, Diego; Sun, Wei-Lun et al. (2015) Prefrontal microRNA-221 Mediates Environmental Enrichment-Induced Increase of Locomotor Sensitivity to Nicotine. Int J Neuropsychopharmacol 19:
Gomez, Adrian M; Sun, Wei-Lun; Midde, Narasimha M et al. (2015) Effects of environmental enrichment on ERK1/2 phosphorylation in the rat prefrontal cortex following nicotine-induced sensitization or nicotine self-administration. Eur J Neurosci 41:109-19
Zhu, Jun; Midde, Narasimha M; Gomez, Adrian M et al. (2015) Intra-ventral tegmental area HIV-1 Tat1-86 attenuates nicotine-mediated locomotor sensitization and alters mesocorticolimbic ERK and CREB signaling in rats. Front Microbiol 6:540
Roscoe Jr, Robert F; Mactutus, Charles F; Booze, Rosemarie M (2014) HIV-1 transgenic female rat: synaptodendritic alterations of medium spiny neurons in the nucleus accumbens. J Neuroimmune Pharmacol 9:642-53
Midde, Narasimha M; Huang, Xiaoqin; Gomez, Adrian M et al. (2013) Mutation of tyrosine 470 of human dopamine transporter is critical for HIV-1 Tat-induced inhibition of dopamine transport and transporter conformational transitions. J Neuroimmune Pharmacol 8:975-87
Gomez, Adrian M; Midde, Narasimha M; Mactutus, Charles F et al. (2012) Environmental enrichment alters nicotine-mediated locomotor sensitization and phosphorylation of DARPP-32 and CREB in rat prefrontal cortex. PLoS One 7:e44149
Midde, Narasimha M; Gomez, Adrian M; Zhu, Jun (2012) HIV-1 Tat protein decreases dopamine transporter cell surface expression and vesicular monoamine transporter-2 function in rat striatal synaptosomes. J Neuroimmune Pharmacol 7:629-39
Midde, Narasimha M; Gomez, Adrian M; Harrod, Steven B et al. (2011) Genetically expressed HIV-1 viral proteins attenuate nicotine-induced behavioral sensitization and alter mesocorticolimbic ERK and CREB signaling in rats. Pharmacol Biochem Behav 98:587-97

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