Sex Differences in Serotonin 5-HT 1A Receptor Responses to Repeated Restraint Stress in Adult Male and Female Rats.

BACKGROUND: Male and female rats were exposed to repeated restraint to determine how changes in serotonin (5-hydroxytryptamine; 5-HT) 1A receptors associate with stress hypothalamic-pituitary-adrenal (HPA) axis habituation. METHODS: In response to 2-hour episodes of restraint, repeated daily for 5 consecutive days, males and females displayed reliable declines in HPA output, indicated by diminished adrenocorticotropin and corticosterone secretory responses. Using the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) as a pharmacological challenge for inducing hypothermia and elevations in plasma corticosterone, males displayed sensitized hypothermal responses after repeated restraint, whereas corticosterone responses to 8-OH-DPAT were enhanced in both sexes following single or repeated exposure. RESULTS: Only males showed elevations in 5-HT 1A receptor G-protein coupling responses in the dorsal raphe after repeated restraint, whereas only females showed an increase in 5-HT 1A receptor responses in the hippocampus following single or repeated exposure. G-protein coupling responses within both regions correlated positively with 5-HT 1A receptor binding capacity. Thus, despite expressing similar capacities for stress HPA axis habituation, males and females emerged from repeated restraint to show region-specific changes in 5-HT 1A receptor function that may be explained, at least in part, by changes in receptor availability. CONCLUSIONS: Based on the hypothermal and corticosteroid responses to 8-OH-DPAT, the present data suggest that stress habituation is met by an increase in the sensitivity of presynaptic 5-HT 1A receptors in males and by an increase in the sensitivity of a population of postsynaptic receptors in both sexes.

Digital Health Interventions for Delivery of Mental Health Care: Systematic and Comprehensive Meta-Review.

BACKGROUND: The COVID-19 pandemic has shifted mental health care delivery to digital platforms, videoconferencing, and other mobile communications. However, existing reviews of digital health interventions are narrow in scope and focus on a limited number of mental health conditions. OBJECTIVE: To address this gap, we conducted a comprehensive systematic meta-review of the literature to assess the state of digital health interventions for the treatment of mental health conditions. METHODS: We searched MEDLINE for secondary literature published between 2010 and 2021 on the use, efficacy, and appropriateness of digital health interventions for the delivery of mental health care. RESULTS: Of the 3022 records identified, 466 proceeded to full-text review and 304 met the criteria for inclusion in this study. A majority (52%) of research involved the treatment of substance use disorders, 29% focused on mood, anxiety, and traumatic stress disorders, and >5% for each remaining mental health conditions. Synchronous and asynchronous communication, computerized therapy, and cognitive training appear to be effective but require further examination in understudied mental health conditions. Similarly, virtual reality, mobile apps, social media platforms, and web-based forums are novel technologies that have the potential to improve mental health but require higher quality evidence. CONCLUSIONS: Digital health interventions offer promise in the treatment of mental health conditions. In the context of the COVID-19 pandemic, digital health interventions provide a safer alternative to face-to-face treatment. However, further research on the applications of digital interventions in understudied mental health conditions is needed. Additionally, evidence is needed on the effectiveness and appropriateness of digital health tools for patients who are marginalized and may lack access to digital health interventions.

Cellular and serotonergic correlates of habituated neuroendocrine responses in male and female rats.

Male and females appear equally capable of showing habituated hypothalamic-pituitary-adrenal (HPA) axis output responses to repeated exposures of the same challenge. Whether this reflects, within males and females, common mechanisms of decreased neuronal activity within stress responding, afferents to the paraventricular hypothalamic nucleus (PVH), the final common pathway to the HPA axis, has not been examined. Here we compared in adult male and female rats the extent to which declines in HPA axis responses to repeated restraint are met by habituated cellular (Fos) responses, in addition to changes in serotonin (5-hydroxytryptamine; 5-HT) expression and signaling, which normally stimulates the HPA axis. Thus, alterations in this component of HPA axis drive could provide an underlying basis for sex differences in adaptive responses. Males and females showed reliable declines in ACTH and corticosterone responses after 10 daily episodes of repeated restraint, recapitulated, in largest part, by similar regional patterns of Fos habituation, including within the PVH, several stress sensitive cell groups of the limbic forebrain, as well as within the raphe nucleus. Serotonin staining in the dorsal raphe and terminal profiles in the forebrain continued to reflect a higher pre-synaptic capacity for the 5-HT system in females. The sexual dimorphism encountered within the lateral septum and medial preoptic area of control animals was less distinguished in the repeat condition, however, whereas 5-HT varicosities in the PVH increased after repeated restraint only in females. Relative to their singly restrained counterparts, males displayed an increase in 5-HT 1 A receptor expression in the raphe nucleus after repeated restraint, whereas females showed a decrease in 5-HT 1 A mRNA levels in the hippocampus and in the zona incerta, representing the most proximal of cell groups expressing the 5-HT 1 A receptor in the vicinity of the PVH. In conclusion, similar regional profiles of cellular habituation in males and females suggest common CNS substrates of neuroendocrine adaptation. However, this process may be met by underlying sex differences in serotonergic control, given the respective roles for pre- and postsynaptic 5-HT 1 A receptors in mediating serotonin availability and signal transfer.