The disproportionally higher levels of nicotine dependence among HIV-infected individuals compared to the general population may indicate altered sensitivity to nicotine and nicotine withdrawal in smokers with HIV. Altered sensitivity to nicotine may result from HIV-induced damage to corticolimbic brain structures and dysregulation of major transmitter systems critically involved in reward processes, in particular dopaminergic (DA) transmission. Thus, there is a critical need to investigate the neurobiological mechanisms underlying nicotine dependence in HIV-infected humans. HIV-induced neurodegeneration involves, in part, neurotoxic viral products including the HIV-1 TAT, a viral nonstructural protein that is critical for viral replication and is secreted by HIV-infected cells. TAT has been found in the brain of HIV-1 post-mortem brain tissue. The proposed studies will be conducted on a doxycycline (Dox)-inducible and brain targeted HIV-1 TAT transgenic mouse model, TAT- induced (iTAT) mice. This mouse model with induced TAT expression is a well-accepted animal model of HIV- related pathology. The TAT protein induces neurodegeneration and dysfunction in the mesocorticolimbic DA system in mice similar to HIV-induced pathology seen in humans. Importantly, the iTAT mouse model allows one to expose mice to nicotine before the induction of TAT expression, and continue nicotine exposure concurrently with TAT expression to mimic the human condition of smoking before and during HIV infection. Limited evidence indicates that TAT expression potentiates cocaine reward and leads to increased DA transporter levels in the striatum, suggesting altered sensitivity to drug reward. The role of TAT expression in nicotine reward and nicotine withdrawal is unknown. There are several sources of motivation that contribute to the maintenance of nicotine dependence including the environment or conditioned cues associated with nicotine reward and the negative consequences of nicotine withdrawal. The proposed studies will characterize two aspects of nicotine dependence in iTAT mice such as the conditioned rewarding effects of nicotine (Specific Aim 1) and affective/somatic aspects of nicotine withdrawal (Specific Aim 2). Neurochemical studies will investigate changes in DA transmission in corticolimbic brain areas in response to nicotine and nicotine withdrawal (Specific Aim 3). It is predicted that iTAT mice will show higher sensitivity to conditioned rewarding effects of nicotine and exacerbated affective/somatic aspects of nicotine withdrawal. TAT-expression will also result in DA terminal damage as reflected in altered levels of biomarkers of DA transmission (DA transporter and tyrosine hydroxylase). This pattern of results will support the hypothesis that HIV-infected individuals may have altered DA transmission resulting in enhanced sensitivity to the reinforcing effects of nicotine and more pronounced withdrawal symptoms during abstinence from nicotine, leading to the high smoking rates in this population. Understanding the effects of TAT expression may help identify a target for development of preventative or adjunct therapies for the treatment of nicotine dependence in the HIV-infected population.
The high prevalence of tobacco smoking in HIV-infected humans may be attributed to brain damage induced by neurotoxic HIV-related TAT protein leading to altered sensitivity to nicotine and nicotine withdrawal. The proposed project will characterize the development of nicotine dependence and neurochemical changes in the brain reward systems in transgenic mice that express TAT protein in the brain. Thus, the proposed work will improve our understanding of neurobiological mechanisms underlying nicotine dependence in HIV positive humans and provide a platform for future work to identify effective therapies to treat nicotine dependence in the HIV-infected population.
|Kesby, James P; Najera, Julia A; Romoli, Benedetto et al. (2017) HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function. Brain Behav Immun 65:210-221|
|Kesby, James P; Markou, Athina; Semenova, Svetlana (2016) The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice. Neuropharmacology 109:205-215|
|Tatro, Erick T; Soontornniyomkij, Benchawanna; Letendre, Scott L et al. (2014) Cytokine secretion from brain macrophages infected with human immunodeficiency virus in vitro and treated with raltegravir. BMC Infect Dis 14:386|
|Tatro, Erick T (2014) Brain-wide imaging of neurons in action. Front Neural Circuits 8:31|