Oral Presentation 3rd Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity 2022

Targeting cognitive inflexibility to treat anorexia nervosa – insights into the effects of psilocybin in animal models (#24)

Laura K Milton 1 , Gabriella A Farrell 1 , Kyna-Anne Conn 1 , Alexander Reichenbach 1 , Brian J Oldfield 1 , Claire J Foldi 1
  1. Monash University, Clayton, VIC, Australia

Anorexia nervosa (AN) has one of the highest mortality rates of any psychiatric disorder and less than 50% of patients ever recover. Despite this, there are currently no effective medicinal treatments for AN. Psilocybin is currently being explored as a novel therapeutic for AN, and is proposed to act by “breaking down” cognitive inflexibility. To examine the effects of psilocybin on pathological weight loss and cognitive-behavioural flexibility, we used the activity-based anorexia (ABA) model and operant reinforcement tasks. Female Sprague-Dawley rats (n=23; 7 weeks old) were trained to run in wheels and administered psilocybin (1.5mg/kg) or saline 24h prior to the commencement of ABA, consisting of unlimited access to a running wheel paired with time-limited access to food. A separate cohort of rats (n=31) were trained to nose-poke into one of two operant ports in order to obtain a sucrose reward and administered psilocybin or saline 24h prior to reversal of the reward-paired port. Extinction and reinstatement of responding for sucrose rewards were also examined the day after treatment in naïve rats (n=22). Psilocybin attenuated the rapid weight loss elicited by ABA conditions, in a subpopulation of animals, by drastically reducing compulsive wheel running (F2,20=12.26, p=.0003). Psilocybin also improved reversal learning (F1,29=5.128, p=.031), by increasing the rate of learning but not by influencing learning strategy. Psilocybin had no effects extinction learning (F1,20=0.097, p=.758) either acutely (within 24h) or post-acutely (after 7 days), nor did it alter the reinstatement of responding for sucrose (F1,20=0.081, p=.779), suggesting a specific improvement in flexible learning. Using in vivo fiber photometry, we have also shown that dopamine release in the ventral striatum is augmented 24h after psilocybin, potentially providing a neurochemical substrate for enhanced reward learning. Taken together, these findings provide initial support for the therapeutic potential of psilocybin for treating cognitive inflexibility in AN.