Sex-specific effects of psychedelic drug exposure on central amygdala reactivity and behavioral responding.

Psilocybin and its active metabolite psilocin have been shown to elicit rapid and long-lasting symptom improvements in a variety of affective psychiatric illnesses. However, the region-specific alterations underlying these therapeutic effects remain relatively unknown. The central amygdala (CeA) is a primary output region within the extended amygdala that is dysregulated in affective psychiatric disorders. Here, we measured CeA activity using the activity marker c-Fos and CeA reactivity using fiber photometry paired with an aversive air-puff stimulus. We found that psilocin administration acutely increased CeA activity in both males and females and increased stimulus specific CeA reactivity in females, but not males. In contrast, psilocin produced time-dependent decreases in reactivity in males, but not in females, as early as 2 days and lasting to 28 days post administration. We also measured behavioral responses to the air-puff stimulus and found sex-dependent changes in threat responding but not exploratory behavior or general locomotion. Repeated presentations of the auditory component of the air-puff were also performed and sex-specific effects of psilocin on CeA reactivity to the auditory-alone stimulus were also observed. This study provides new evidence that a single dose of psilocin produces sex-specific, time-dependent, and enduring changes in CeA reactivity and behavioral responding to specific components of an aversive stimulus.

The effects of electronic nicotine vapor on voluntary alcohol consumption in female and male C57BL/6 J mice.

SIGNIFICANCE: Alcohol drinking and nicotine vaping often co-occur and dependence on both substances is common. However, the impact of nicotine vaping on alcohol consumption is not fully understood. METHODS: We examined the effects of nicotine vaping on ethanol drinking in female and male C57BL/6 J mice using an electronic nicotine delivery system and intermittent access two-bottle choice (IA-2BC) drinking. Mice were exposed to electronic nicotine vapor (3%) or propylene glycol/vegetable glycerol (PG/VG) control for 3 h sessions daily for 4 weeks and voluntary alcohol consumption was monitored. Nicotine vapor exposure was stopped and voluntary alcohol drinking was measured for a 2 week abstinence period. We also examined the effects of alcohol and nicotine on locomotion, temperature, and nicotine metabolism. RESULTS: Following acute nicotine vapor exposure, alcohol drinking was increased in males but not in females. Thermoregulation was disrupted following nicotine vapor exposure and voluntary drinking. Male and female mice displayed increased locomotor activity immediately following chronic nicotine vapor exposure, and an anxiolytic effect was seen in males. In nicotine vapor abstinence, female mice displayed increased alcohol consumption. Locomotor activity and anxiolytic effects remained elevated in male but not female mice. Female mice displayed higher levels of serum nicotine and hydroxycotinine, suggesting impaired metabolism following chronic drinking and nicotine vapor exposure. CONCLUSION: Collectively, these results suggest that while both male and female ethanol-drinking mice experience the stimulatory effects of nicotine vapor, only in males is there a parallel increase in ethanol drinking and only females display impairments in nicotine metabolism after drinking.

Sex differences in affective states and association with voluntary ethanol intake in Sprague-Dawley rats.

Alcohol use disorders (AUDs) are a major problem across the USA. While AUD remains a complex human condition, it is difficult to isolate the directionality of anxiety and ethanol (EtOH) drinking from outside influences. The present study sought to investigate the relationship between affective states and EtOH intake using male and female Sprague-Dawley rats. Using complementary tests of anxiety- and depressive-like behavior, we found sex- and test-specific differences in basal affective behavior such that females displayed enhanced anxiety-like behavior in the splash test and males displayed enhanced anxiety-like behavior in the novelty-suppressed feeding test. Although, there were no sex differences in EtOH intake and no correlation between baseline anxiety-like behavior and subsequent EtOH intake, we did find that depressive-like behavior predicted future EtOH intake in female rats only. In addition, we observed an increase in depressive-like behavior is male rats in both the water and EtOH drinking groups (compared to baseline levels). Furthermore, post-drinking anxiety-like behavior, but not depressive-like behavior predicted subsequent EtOH intake in female rats. Lastly, we found a history of EtOH intake decreased pain thresholds in male and female rats, but increased anxiety-like and depressive-like behavior was associated with decreased thermal sensitivity only in EtOH-drinking males. Together, these experiments provide important information on the complex interaction between negative affect and EtOH intake and how these two contexts reciprocally do, or do not, influence each other in a sex-specific manner.