Psychedelics produce enduring enhancement of reward responsiveness in male rats

Abstract

Anhedonia, the blunted responsiveness to previously rewarding stimuli, is a core symptom of several psychiatric disorders. Ketamine and psilocybin have shown promising evidence in ameliorating anhedonic symptoms in clinical trials. The Probabilistic Reward Task (PRT) was developed to objectively quantify reward responsiveness in clinical populations and laboratory animals. Here, the PRT was used to explore acute and sustained effects of several psychedelics and relevant pharmacological comparators on reward responsiveness in rats ( n = 12/group, n = 84/total). Reward responsiveness was significantly increased following administration of psilocybin (0.1–1 mg/kg) or ketamine (10 mg/kg) acutely, and the effect persisted 24 hours after dosing. The effects of psilocybin, but not ketamine, on reward responsiveness were blocked in a dose-dependent manner by pretreatment with the 5-HT_2A receptor antagonist volinanserin. Both the 5-HT_2A-non-selective psychedelic DMT (1–10 mg/kg) and the relatively 5-HT_2A-selective psychedelic (±)-DOI (0.3–3 mg/kg) produced significant dose-related increases in reward responsiveness acutely; however, these effects were not sustained 24 hours later. Neither the non-psychedelic 5-HT_2A agonist lisuride (0.1–1 mg/kg) nor the SSRI fluoxetine (0.3–3 mg/kg) exerted positive effects in the PRT. These results suggest that psychedelics can produce acute and enduring increases in reward responsiveness and that this effect depends, at least in part, on the 5-HT_2A receptor. While positive effects on reward responsiveness may be common across psychedelics, differences in time course suggest that their enhancement of hedonic function may vary. The PRT is a useful tool to comparatively assess the effects of potential treatments for anhedonia, although the clinical implications of these data require further validation.