S-Equol mitigates motivational deficits and dysregulation associated with HIV-1

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.

Synaptic Dysfunction Underlies Alterations in the Initiation of Goal-Directed Behaviors: Implications for Hiv-1 Associated Apathy

“…Of specific note is the decreased number of meters run per session in HIV-1 Tg animals during the maintenance phase of nocturnal voluntary wheel running; an observation that supports a decreased reinforcing efficacy of voluntary wheel running in HIV-1 rats. Notably, the HIV-1 Tg rat also exhibited a diminished reinforcing efficacy of sucrose (Bertrand et al, 2018;McLaurin et al, 2021b) supporting a generalizable decrease in motivation for natural rewards. At the microstructural level, HIV-1 Tg animals exhibited a decreased number of running bouts relative to controls supporting a profound alteration in the self-initiation of spontaneous behaviors, one of the key steps for goal-directed behaviors.…”

“…One of the notable advantages of the HIV-1 Tg rat is its utility for investigating the debilitating neurocognitive impairments (e.g., Vigorito et al, 2007;Moran et al, 2014;Repunte Canonigo et al, 2014;McLaurin et al, 2019) and affective (e.g., Nemeth et al, 2014;Bertrand et al, 2018;Denton et al, 2021;McLaurin et al, 2021b) alterations associated with HIV-1. The HIV-1 Tg rat, developed by Reid et al (2001), constitutively expresses seven of the nine HIV-1 viral proteins (the gag and pol genes are deleted) under the control of the natural HIV-1 promoter.…”

“…Critically, chronic HIV-1 viral protein exposure induces decreased dopamine levels in the NAc (e.g., Jenuwein et al, 2004;Javadi-Paydar et al, 2017;Denton et al, 2019;for review, McLaurin et al, 2021a) and alters MSNs (Roscoe et al, 2014;Schier et al, 2017;McLaurin et al, 2018a;McLaurin et al, 2021b) supporting a potential neural mechanism underlying HIV-1 associated apathy.…”

HIV-Associated Apathy/Depression and Neurocognitive Impairments Reflect Persistent Dopamine Deficits

“…In clinical studies, apathy is most commonly [250] assessed using either the Apathy Evaluation Scale [251] or the Neuropsychiatric Inventory [252], scales which exhibit both strong reliability and validity [250]. Furthermore, preclinical studies have utilized operant and Pavlovian conditioning as a method to evaluate how willing an animal is to "work" for reinforcement [198,253,254]. Understanding apathy from both a clinical and preclinical perspective is vital, given its prevalence in many neurological disorders (e.g., Alzheimer's disease [255], Parkinson's disease [256], HIV-1 [27,257]).…”

“…Understanding apathy from both a clinical and preclinical perspective is vital, given its prevalence in many neurological disorders (e.g., Alzheimer's disease [255], Parkinson's disease [256], HIV-1 [27,257]). Indeed, chronic HIV-1 viral protein exposure induces prominent alterations in goal-directed behaviors [198,254]. The clinical significance of apathy in HIV-1 seropositive individuals cannot be understated, as increased apathy is significantly associated with greater impairments in activities of daily living [27,258], decreased medication adherence [259] and decreased quality of life [260].…”