HIV-1-induced apathy: Mitigation by the gut metabolite, S-Equol

ABSTRACT The persistence of motivational alterations, including apathy, in older 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 apathy, however, has yet to be systematically evaluated. Thus, beginning at approximately seven to nine months of age, 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 behavior. First, at the genotypic level, apathetic behavior in older HIV-1 Tg rats treated with vehicle was characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose and enhanced drug seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated alterations in goal-directed behaviors and reduced drug seeking behavior in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited prominent decreases in dendritic branching and a shift towards longer dendritic spines with decreased head diameter; synaptic dysfunction that was partially restored by SE treatment. 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.