Androgen depletion increases sensitivity to effort-related costs and alters mesoaccumbal circuit function in male mice

Background: Androgen deficiency in males is associated with reduced motivation, fatigue, and decreased goal-directed behavior, yet the neural mechanisms underlying these changes remain poorly understood. Dopamine signaling within the nucleus accumbens (NAc) plays a central role in regulating effort-based decision making. Here, we tested the hypothesis that loss of testicular hormones alters mesoaccumbal dopamine function to increase sensitivity to effort-related costs. Methods: Male mice underwent orchiectomy (ORX) either before puberty onset or in adulthood. Effort-based decision making was assessed using a progressive ratio 1 closed economy (PR1-CE) task. Dopamine-related function was assessed using systemic haloperidol administration and high-performance liquid chromatography to measure dopamine and metabolites, while whole-cell recordings were used to assess intrinsic excitability of NAc spiny projection neurons (SPNs). Results: ORX increased sensitivity to effort costs, reflected by a shift toward energy-efficient responding while maintaining overall food intake. These behavioral changes were accompanied by reduced responsiveness to haloperidol. Adult ORX increased dopamine content and reduced metabolite-to-dopamine ratios in the NAc, consistent with reduced dopamine turnover, whereas prepubertal ORX did not affect dopamine measures. Prepubertal ORX selectively reduced excitability of NAc core D1R+ SPNs, while adult ORX increased excitability across both D1R+ and D1R- populations. Conclusions: Androgen depletion increases effort cost sensitivity and is associated with alterations in mesoaccumbal circuit function. Although behavioral effects were similar following pre- or postpubertal ORX, distinct neurochemical and cellular adaptations were observed, suggesting developmental timing influences neural adaptations to androgen depletion. These findings provide insight into neural mechanisms linking androgen deficiency to motivational deficits.

Westbrook, S. R., Wang, Q., Jensen, A., Klappenbach, C., Touretsky, K., Delevich, K.

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