Abstract
Methamphetamine abuse and human immunodeficiency virus (HIV) are common comorbidities. HIV-associated proteins, such as the regulatory protein TAT, may contribute to brain reward dysfunction, inducing an altered sensitivity to methamphetamine reward and/or withdrawal in this population. These studies examined the combined effects of TAT protein expression and, chronic and binge methamphetamine regimens on brain reward function. Transgenic mice with inducible brain expression of the TAT protein were exposed to either saline, a chronic, or a binge methamphetamine regimen. TAT expression was induced via doxycycline treatment during the last week of methamphetamine exposure. Brain reward function was assessed daily throughout the regimens, using the intracranial self-stimulation procedure, and after a subsequent acute methamphetamine challenge. Both methamphetamine regimens induced withdrawal-related decreases in reward function. TAT expression substantially, but not significantly increased the withdrawal associated with exposure to the binge regimen compared to the chronic regimen, but did not alter the response to acute methamphetamine challenge. TAT expression also led to persistent changes in adenosine 2B receptor expression in the caudate putamen, regardless of methamphetamine exposure. These results suggest that TAT expression may differentially affect brain reward function, dependent on the pattern of methamphetamine exposure. The subtle effects observed in these studies highlight that longer-term TAT expression, or its induction at earlier stages of methamphetamine exposure, may be more consequential at inducing behavioral and neurochemical effects.
Highlights
The disproportionately higher levels of methamphetamine dependence among human immunodeficiency virus (HIV)+ individuals compared to the general population [1] are suggestive of altered sensitivity to methamphetamine reward and/or withdrawal in this population
Animal models that replicate important aspects of the HIV infection, in the brain, allow us to investigate the neurobiological mechanisms underlying methamphetamine dependence in the context of HIV, and estimate mechanisms occurring in HIV+ humans under controlled laboratory conditions
Mesocorticolimbic reward circuits are crucial for the initiation and maintenance of drug use [2] mediated by the dopaminergic system [3] and appear vulnerable to both methamphetamine and HIV disease
Summary
The disproportionately higher levels of methamphetamine dependence among HIV+ individuals compared to the general population [1] are suggestive of altered sensitivity to methamphetamine reward and/or withdrawal in this population. HIV and methamphetamine target the dopamine system in the basal ganglia in a synergistic manner [4], suggesting this may be one common neural substrate for altered reward function after combined methamphetamine dependence and HIV disease [3]. The TaT protein, for instance, is the first critically produced protein, with a role in regulating viral replication It is produced by infected cells following the formation of the proviral DNA, even in the presence of antiretroviral drugs. TAT plays a key role in the dysfunction of the dopamine system associated with HIV disease, and when combined with methamphetamine, has both synergistic or additive effects in dopaminergic function [7, 11]. HIV-associated proteins, such as the regulatory protein TAT, may contribute to brain reward dysfunction, inducing an altered sensitivity to methamphetamine reward and/or withdrawal in this population
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