Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders.

Pregnane neuroactive steroids, notably allopregnanolone and pregnenolone, exhibit efficacy in mitigating inflammatory signals triggered by toll-like receptor (TLR) activation, thus attenuating the production of inflammatory factors. Clinical studies highlight their therapeutic potential, particularly in conditions like postpartum depression (PPD), where the FDA-approved compound brexanolone, an intravenous formulation of allopregnanolone, effectively suppresses TLR-mediated inflammatory pathways, predicting symptom improvement. Additionally, pregnane neurosteroids exhibit trophic and anti-inflammatory properties, stimulating the production of vital trophic proteins and anti-inflammatory factors. Androstane neuroactive steroids, including estrogens and androgens, along with dehydroepiandrosterone (DHEA), display diverse effects on TLR expression and activation. Notably, androstenediol (ADIOL), an androstane neurosteroid, emerges as a potent anti-inflammatory agent, promising for therapeutic interventions. The dysregulation of immune responses via TLR signaling alongside reduced levels of endogenous neurosteroids significantly contributes to symptom severity across various neuropsychiatric disorders. Neuroactive steroids, such as allopregnanolone, demonstrate efficacy in alleviating symptoms of various neuropsychiatric disorders and modulating neuroimmune responses, offering potential intervention avenues. This review emphasizes the significant therapeutic potential of neuroactive steroids in modulating TLR signaling pathways, particularly in addressing inflammatory processes associated with neuropsychiatric disorders. It advances our understanding of the complex interplay between neuroactive steroids and immune responses, paving the way for personalized treatment strategies tailored to individual needs and providing insights for future research aimed at unraveling the intricacies of neuropsychiatric disorders.

Acute, but not repeated, cocaine exposure alters allopregnanolone levels in the midbrain of male and female rats.

RATIONALE: Multiple psychiatric disorders are associated with altered brain and serum levels of neuroactive steroids, including the endogenous GABAergic steroid, allopregnanolone. Clinically, chronic cocaine use was correlated with decreased levels of pregnenolone. Preclinically, the effect of acute cocaine on allopregnanolone levels in rodents has had mixed results, showing an increase or no change in allopregnanolone levels in some brain regions. OBJECTIVE: We hypothesized that cocaine acutely increases allopregnanolone levels, but repeated cocaine exposure decreases allopregnanolone levels compared to controls. METHODS: We performed two separate studies to determine how systemic administration of 15 mg/kg cocaine (1) acutely or (2) chronically alters brain (olfactory bulb, frontal cortex, dorsal striatum, and midbrain) and serum allopregnanolone levels in adult male and female Sprague-Dawley rats. RESULTS: Cocaine acutely increased allopregnanolone levels in the midbrain, but not in olfactory bulb, frontal cortex, or dorsal striatum. Repeated cocaine did not persistently (24 h later) alter allopregnanolone levels in any region in either sex. However, allopregnanolone levels varied by sex across brain regions. In the acute study, we found that females had significantly higher allopregnanolone levels in serum and olfactory bulb relative to males. In the repeated cocaine study, females had significantly higher allopregnanolone levels in olfactory bulb, frontal cortex, and serum. Finally, acute cocaine increased allopregnanolone levels in the frontal cortex of females in proestrus, relative to non-proestrus stages. CONCLUSION: Collectively these results suggest that allopregnanolone levels vary across brain regions and by sex, which may play a part in differential responses to cocaine by sex.

Deleterious Interaction between the Neurosteroid (3α,5α)3-Hydroxypregnan-20-One (3α,5α-THP) and the Mu-Opioid System Activation during Forced Swim Stress in Rats.

The neurosteroid 3α,5α-THP is a potent GABAA receptor-positive modulator and its regulatory action on the HPA axis stress response has been reported in numerous preclinical and clinical studies. We previously demonstrated that 3α,5α-THP down-regulation of HPA axis activity during stress is sex-, brain region- and stressor-dependent. In this study, we observed a deleterious submersion behavior in response to 3α,5α-THP (15 mg/kg) during forced swim stress (FSS) that led us to investigate how 3α,5α-THP might affect behavioral coping strategies engaged in by the animal. Given the well-established involvement of the opioid system in HPA axis activation and its interaction with GABAergic neurosteroids, we explored the synergic effects of 3α,5α-THP/opiate system activation in this behavior. Serum ß-endorphin (ß-EP) was elevated by FSS and enhanced by 3α,5α-THP + FSS. Hypothalamic Mu-opiate receptors (MOP) were increased in female rats by 3α,5α-THP + FSS. Pretreatment with the MOP antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 2 mg/kg, IP) reversed submersion behavior in males. Moreover, in both males and females, CTAP pretreatment decreased immobility episodes while increasing immobility duration but did not alter swimming duration. This interaction between 3α,5α-THP and the opioid system in the context of FSS might be important in the development of treatment for neuropsychiatric disorders involving HPA axis activation.

Allopregnanolone Decreases Evoked Dopamine Release Differently in Rats by Sex and Estrous Stage.

Mesolimbic dopamine transmission is dysregulated in multiple psychiatric disorders, including addiction. Previous studies found that the endogenous GABAergic steroid (3α,5α)-3-hydroxy-5-pregnan-20-one (allopregnanolone) modulates dopamine levels in the nucleus accumbens and prefrontal cortex. As allopregnanolone is a potent positive allosteric modulator of GABAA receptors, and GABAA receptors can regulate dopamine release, we hypothesized that allopregnanolone would reduce phasic fluctuations in mesolimbic dopamine release that are important in learning and reward processing. We used fast-scan cyclic voltammetry in anesthetized female and male rats to measure dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area, before and after administration of allopregnanolone. Allopregnanolone (7.5-25 mg/kg, IP) reduced evoked dopamine release in both male and female rats, compared to ß-cyclodextrin vehicle. In males, all doses of allopregnanolone decreased dopamine transmission, with stronger effects at 15 and 25 mg/kg allopregnanolone. In females, 15 and 25 mg/kg allopregnanolone reduced dopamine release, while 7.5 mg/kg allopregnanolone was no different from vehicle. Since allopregnanolone is derived from progesterone, we hypothesized that high endogenous progesterone levels would result in lower sensitivity to allopregnanolone. Consistent with this, females in proestrus (high progesterone levels) were less responsive to allopregnanolone than females in other estrous cycle stages. Furthermore, 30 mg/kg progesterone reduced evoked dopamine release in males, similar to allopregnanolone. Our findings confirm that allopregnanolone reduces evoked dopamine release in both male and female rats. Moreover, sex and the estrous cycle modulated this effect of allopregnanolone. These results extend our knowledge about the pharmacological effects of neurosteroids on dopamine transmission, which may contribute to their therapeutic effects.

Association of Extracellular Vesicle Protein Cargo with Race and Clinical Markers of Mortality.

Differential mortality rates remain a significant health disparity in the United States, suggesting the need to investigate novel potential molecular markers associated with mortality. Extracellular vesicles (EVs), including exosomes, microvesicles and apoptotic bodies, are lipid-bound vesicles secreted by cells into the circulation. EVs mediate intercellular communication by shuttling functional signaling molecules as cargo. EV characteristics by race in the context of mortality risk factors have not been described. We isolated plasma EVs from a cross-sectional cohort of African Americans (AA) and whites and found no significant differences in EV size, distribution or concentration between race or by sex. However, EV cargo showed increased levels of phospho-p53, total p53, cleaved caspase 3, ERK1/2 and phospho-AKT in white individuals compared to AAs. phospho-IGF-1R levels were significantly higher in females compared to males. EV concentration was significantly associated with several clinical mortality risk factors: high-sensitivity C-reactive protein (hsCRP), homeostatic model assessment of insulin resistance (HOMA-IR), alkaline phosphatase, body mass index, waist circumference and pulse pressure. The association of EV proteins with mortality markers were dependent on race. These data suggest that EV cargo can differ by race and sex and is associated with mortality risk factors.