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

Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1 A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors (Htr2a and Htr1a, respectively), and a further reduction in the abundance of Htr2a transcripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.

Pre-training anandamide infusion within the basolateral amygdala impairs plus-maze discriminative avoidance task in rats.

Endocannabinoids (eCBs) modulate a variety of brain functions via activation of the widely expressed CB1 receptor. One site of high density of this receptor is the basolateral amygdala (BLA), a structure involved in the formation of aversive memories. The activation and blockade of CB1 receptors by systemic or hippocampal drug administrations have been shown to modify memory processing. However, little is known about the role of the BLA endocannabinoid system in aversive memories. Additionally, BLA endocannabinoid transmission seems to be related to emotional states, but the relevance of these effects to memory formation is still unknown. In this study we investigated the effects of the eCB anandamide (AEA) and the CB1 antagonist/inverse agonist AM251 infused into the BLA on the acquisition of an aversive memory task, concomitantly evaluating basal anxiety levels in rats. Male rats received pre-training micro-injection of AEA, AM251 or vehicle bilaterally into the BLA, and were studied with the plus-maze discriminative avoidance task (a paradigm that allows concomitant and independent evaluation of anxiety-like behavior and the memory of an aversive task). Our results showed that AEA into the BLA before training prevented memory retrieval 24 h later, as evaluated by exploration of the aversive arm of the maze, while AM251 into the BLA did not interfere with animals' performance. In addition, AEA had no effect on anxiety-like behavior (as evaluated by open arm exploration and risk assessment), while AM251 induced an anxiogenic effect. Our data indicate an important role of BLA CB1 receptors in aversive memory formation, and suggest that this involvement is not necessarily related to a possible modulation of anxiety states.

Basolateral amygdala inactivation impairs learned (but not innate) fear response in rats.

Numerous studies have suggested that the amygdala is involved in the formation of aversive memories, but the possibility that this structure is merely related to any kind of fear sensation or response could not be ruled out in previous studies. The present study investigated the effects of bilateral inactivation of the amygdaloid complex in rats tested in the plus-maze discriminative avoidance task. This task concomitantly evaluates aversive memory (by discrimination of the two enclosed arms) and innate fear (by open-arm exploration). Wistar rats (3-5 months-old) were implanted with bilateral guide cannulae into basolateral amygdala. After surgery, all subjects were given 1 week to recover before behavioral experiments. Afterwards, in experiment 1, 15 min prior to training, 0.5 µl of saline or muscimol (1 mg/ml) was infused in each side via microinjection needles. In experiment 2 the animals received injections immediately after the training session and in experiment 3 rats were injected prior to testing session (24 h after training). The main results showed that (1) pre-training muscimol prevented memory retention (evaluated by aversive arm exploration in the test session), but did not alter innate fear (evaluated by percent time in open arms); (2) post-training muscimol impaired consolidation, inducing increased percent in aversive arm exploration in the test session and (3) pre-testing muscimol did not affect retrieval (evaluated by aversive enclosed arm exploration in the test session). The results suggest that amygdala inactivation specifically modulated the learning of the aversive task, excluding a possible secondary effect of amygdala inactivation on general fear responses. Additionally, our data corroborate the hypothesis that basolateral amygdala is not the specific site of storage of aversive memories, since retention of the previously learned task was not affected by pre-testing inactivation.