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.

Figure 1

Experimental design schematic.

Figure 2

The impact of the HIV-1 transgene on sucrose-maintained responding (A–C) and cocaine-maintained responding (D–F) is illustrated as a function of genotype (HIV-1 Tg Vehicle vs. Control Vehicle; ± 95% Confidence Intervals). HIV-1 Tg animals took significantly longer to successfully acquire autoshaping, supporting a profound deficit in stimulus-reinforcement learning (A). Under sucrose-maintained responding, apathetic behaviors in the HIV-1 Tg rat were characterized by a diminished sensitivity to (B), and reinforcing efficacy of (C), sucrose relative to control animals. Under cocaine-maintained responding, HIV-1 Tg animals exhibited an increased response vigor, independent of schedule of reinforcement (i.e., Fixed Ratio 1: D; Progressive Ratio: E and F), relative to control animals. Furthermore, an increased sensitivity to cocaine dose was observed in HIV-1 Tg animals relative to controls (F). Collectively, independent of differences in the unique response to either sucrose or cocaine self-administration, the HIV-1 Tg rat exhibits prominent alterations in goal-directed behaviors.

Figure 3

Following a history of cocaine self-administration, the impact of the HIV-1 transgene on dendritic branching (A; ± SEM) and dendritic spine morphology (B–C) in medium spiny neurons of the nucleus accumbens was examined and is illustrated as a function of genotype (HIV-1 Tg Vehicle vs. Control Vehicle). HIV-1 Tg animals exhibited a dramatic decrease in dendritic branching complexity (A) and a population shift towards longer dendritic spines (B) with decreased head diameter (C) relative to control animals.

Figure 4

The therapeutic efficacy of S-Equol (SE) as a novel therapeutic for apathetic behaviors under sucrose-maintained responding in the HIV-1 Tg rat is illustrated as a function of genotype (HIV-1 Tg vs. Control) and treatment (SE vs. Vehicle; ± 95% Confidence Intervals). The number of days required to successfully acquire autoshaping, an index of stimulus-reinforcement learning, for HIV-1 Tg animals treated with SE was statistically indistinguishable from either HIV-1 Tg animals treated with vehicle (A) or control animals treated with vehicle (B). Treatment with SE enhanced the reinforcing efficacy of sucrose (C–D) and ameliorated alterations in the sensitivity to sucrose (E–F) in HIV-1 Tg rats.

Figure 5

The therapeutic efficacy of S-Equol (SE) as a novel therapeutic for apathetic behaviors under cocaine-maintained responding in the HIV-1 Tg rat is illustrated as a function of genotype (HIV-1 Tg vs. Control) and treatment (SE vs. Vehicle; ± 95% Confidence Intervals). HIV-1 Tg animals treated with SE displayed an initial novelty response to cocaine self-administration followed by a rapid decay. At the end of the five day fixed ratio testing period, the number of cocaine infusions earned by HIV-1 Tg animals treated with SE were statistically indistinguishable from either HIV-1 Tg (A) or control animals (B) treated with vehicle. Treatment with SE reduced drug-seeking behavior in the HIV-1 Tg rat (C–D); an effect which generalized across cocaine dose (E–F).

Figure 6

The utility of S-Equol (SE) to modify neuronal (A; ± SEM) and dendritic spine morphology (B–E) in medium spiny neurons of the nucleus accumbens is illustrated as a function of genotype (HIV-1 Tg vs. Control) and treatment (SE vs. Vehicle; ± 95% Confidence Intervals). Although treatment with SE failed to alter dendritic branching (A), long-term modifications in dendritic spine morphology were observed in HIV-1 Tg animals, evidenced by a prominent population shift towards shorter dendritic spines (B) with increased head diameter (D) relative to HIV-1 Tg animals treated with vehicle. Treatment with SE shifted the morphological parameters of dendritic spines in MSNs of the NAc to a more mature phenotype relative to HIV-1 Tg animals treated with vehicle, evidenced by a prominent population shift towards shorter dendritic spines (Fig. 6B; [F(1,1538) = 79.6, p ≤ 0.01]) with increased head diameter (Fig. 6D; [F(1,1292) = 25.4, p ≤ 0.01]). Relative to control animals treated with vehicle, HIV-1 Tg animals treated with SE exhibited significantly longer dendritic spines (C), no statistically significant differences in head diameter (E) between the two groups were observed.