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Dryad

Psychedelic drug effects on reactivity of the paraventricular nucleus of the hypothalamus and threat responding behavior

Abstract

Psychedelics have experienced renewed interest following studies suggesting potential therapeutic effects in patients with affective disorders. While clinical results look promising, the neurobiological mechanisms underlying acute and prolonged effects of psychedelics remain unclear. Many psychiatric disorders involve hypothalamic-pituitary-adrenal (HPA) axis dysfunction. The paraventricular nucleus of the hypothalamus (PVN) is a midline hypothalamic nucleus that plays an integral role in HPA stress reactivity, autonomic functioning, social behavior, and many other affective processes. We investigated the effect of psilocin, the psychoactive metabolite of psilocybin, on PVN reactivity in Sprague Dawley rats. Psilocin increased stimulus-independent activity as measured by c-Fos expression in the PVN of male and female rats. Psilocin also increased PVN reactivity (ΔF/F) to an aversive air-puff stimulus in males but not females. PVN reactivity was restored at 2- and 7-days post-injection with no group differences. Additionally, we found that prior psilocin injection did not affect PVN reactivity following acute restraint stress. Experimental groups were sub-classified by baseline threat responding and psilocin-induced increases in male PVN reactivity were found to be driven by baseline active threat responders. Overall, these data demonstrate that the PVN is a significant site of psychedelic drug action with implications for threat responding behavior.