Abstract
Motivational deficits (e.g., apathy) and dysregulation (e.g., addiction) in HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor β agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for motivational alterations, however, has yet to be systematically evaluated. Thus, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed and drug-seeking behavior. First, at the genotypic level, motivational deficits in HIV-1 Tg rats treated with vehicle were characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose. Motivational dysregulation was evidenced by enhanced drug-seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated both motivational deficits and dysregulation in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited lower levels of dendritic branching and a shift towards longer dendritic spines with decreased head diameter. Treatment with SE, however, led to long-term enhancements in dendritic spine morphology in HIV-1 Tg animals supporting a potential underlying basis by which SE exerts its therapeutic effects. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.
Highlights
Motivational deficits and dysregulation in human immunodeficiency virus type 1 (HIV-1) seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics
HIV-1 Tg animals treated with vehicle acquired autoshaping, earning at least 60 reinforcers for three consecutive days, significantly slower than control animals treated with vehicle (Fig. 2A)
HIV-1 Tg animals treated with vehicle exhibited a diminished reinforcing efficacy of sucrose relative to control animals treated with vehicle evidenced by a statistically significant genotype × concentration interaction for both the number of reinforcers (Fig. 2B; [F(4, 68) = 3.4, pGG ≤ 0.02, η2p = 0.165] with a prominent linear component [F(1,17) = 6.7, p ≤ 0.02, η2p = 0.282]) and “active” lever presses (Data Not Shown; [F(4, 68) = 2.9, pGG ≤ 0.05, η2p = 0.147] with a prominent linear component [F(1,17) = 6.0, p ≤ 0.03, η2p = 0.261]
Summary
Motivational deficits (e.g., apathy) and dysregulation (e.g., addiction) in HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. Etiologies, including human immunodeficiency virus type 1 (HIV-1; for r eview3), that target the neural substrates of the fronto-striatal circuit are commonly associated with prominent motivational alterations. There remains a critical need to develop innovative adjunctive therapeutics to mitigate the prominent motivational alterations in HIV-1 seropositive individuals. Long-term HIV-1 viral protein exposure induces a prominent distributional shift in the morphology of dendritic spines, characterized by decreased dendritic spine volume[21,22] and increased dendritic spine length[22]; morphological parameters which support synaptic dysfunction. MSNs have been implicated as a key structural locus for the actions of HIV-1 viral proteins on goal-directed behaviors[22] supporting a key target for the development of innovative therapeutics
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
