Sex-Specific Effects of Psychedelic Drug Exposure on Central Amygdala Reactivity and Behavioral Responding

Abstract

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 specific mechanisms behind these therapeutic effects remain relatively unknown. The central amygdala (CeA) is a primary output region within the extended amygdala that is heavily dysregulated in affective psychiatric disorders. Here, we utilized fiber photometry to measure changes in CeA reactivity to an aversive air puff stimulus after psilocin administration, both acutely and at varying prolonged time points. We found that administration of psilocin increased reactivity acutely in females, but not males. Additionally, we show that one dose of psilocin produced decreases in reactivity in males, but not females, 28-days post administration, with decreases seen as early as 2-days post administration. We further report stimulus-specific changes in CeA reactivity after psilocin with differential responsivity to an aversive air puff stimulus and an auditory stimulus. We also measured changes in behavioral response to the air puff stimulus and report sex differences in threat responding but not exploratory behavior or general locomotion. This study provides evidence that a single dose of psilocin can elicit sex-specific, dynamic, and enduring changes in CeA reactivity to an aversive stimulus. These data are an important step towards dissecting circuit-based mechanisms underlying the effects of psychedelics.

Increased reactivity of the paraventricular nucleus of the hypothalamus and decreased threat responding in male rats following psilocin administration

“…Here, we showed that psilocin administration produced increases in reactivity within the PVN in males, but no significant effects were seen in females, and no differences in either sex were seen at more prolonged time points. Interestingly, these effects are in contrast to previous findings from our group, wherein we found acute sex-specific effects of psilocin administration causing increased CeA reactivity in females only 30 . One potential mechanism for this could involve known inhibitory PVN→CeA circuitry, wherein oxytocinergic projections from the PVN to the CeA activate GABAergic cells in the lateral CeA (CeL) that then inhibit output neurons of the CeA located in the medial CeA (CeM) 43 .…”

“…Given the observed persistent effects of psychedelics in clinical trials and previously published work 30 , we assessed PVN reactivity at multiple time points following injection. In males, acutely elevated PVN reactivity to the air puff following injection was restored at the 2-and 7-day follow-up time points.…”

“…1C). Group sizes were determined based on previous work 30 . After 3 weeks to allow for viral transfection and recovery, fiber photometry recordings were performed in conjunction with exposure to an air-puff stimulus (Figs.…”

Psilocybin prevents activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms

“…It is important to note that female animals were used exclusively in these studies and that psilocybin has been shown to have effects that differ based on biological sex in rats and mice in terms of behaviour 95 , regional brain reactivity 96 and structural neuroplasticity 46 . Future studies should aim to examine how psilocybin influences serotoninergic tone via other (i.e.…”

“…The key outcomes of this study underline the fact that animal studies are required for understanding the mechanisms that underlie the therapeutic efficacy of psilocybin because they allow detailed interrogation of behaviour and brain function in the absence of effects of expectancy. It is important to note that female animals were used exclusively in these studies and that psilocybin has been shown to have effects that differ based on biological sex in rats and mice in terms of behaviour 93 , regional brain reactivity 94 and structural neuroplasticity 46 . Future studies should aim to examine how psilocybin influences serotoninergic tone via other (i.e.…”