317. PSILOCYBIN DOES NOT INDUCE CONDITIONED PLACE PREFERENCE, BUT MODIFIES BEHAVIORAL PATTERNS IN SPRAGUE-DAWLEY RATS

Abstract Background Recent years have seen renewed scientific interest in psychedelics, including psilocybin, for their potential in treating neuropsychiatric disorders. However, the reward-related properties and behavioral impacts of a high dose of psilocybin remain insufficiently explored. Aims & Objectives Assessing the potential rewarding properties of a high dose of psilocybin (10 mg/kg i.p.) in the conditioned place preference (CPP) paradigm (McKendrick et al., Front. Behav. Neurosci., 2020) and analyze its effects on rat behavior. Method Twenty adult male Sprague Dawley rats (225–340 g) were subjected to CPP paradigm. On day 1, they were habituated to the apparatus, and on day 2, a preconditioning test assessed baseline compartment preference. Over 8 days, rats were conditioned (CT) by alternating between drug/vehicle conditioning on odd days (CT1,3,5,7) and vehicle conditioning on even days (CT2,4,6,8). After drug/vehicle administration, rats were confined to one CPP compartment. The potential rewarding effect of psilocybin was evaluated on the following day (postconditioning). Behavioral assessments, including head-twitch, dog-shaking, grooming, body licking, defecation, and rearing, were conducted during the CT sessions and on the postconditioning day. Results RM two-way ANOVA showed no significant difference in time spent in the psilocybin-paired compartment compared to vehicle, indicating that psilocybin did not produce rewarding effects in the CPP paradigm. Psilocybin administration led to modifications in the behavioral profile. Principal component analysis (explained variance>70%) indicated that head-twitching, dog-shaking, and defecation were more strongly associated with psilocybin, while grooming, body licking, and rearing were more characteristic of the vehicle group. For behavioral assessment, RM two-way ANOVA showed that on CT1, the psilocybin-treated group exhibited higher scores on head-twitching (p<0.0001), dog-shaking (p<0.05), and defecation (p<0.01), but lower scores on grooming (p<0.05), body licking (p<0.01), and rearing (p<0.01) compared to the vehicle group. These differences were even more pronounced on CT7 for head-twitching, dog-shaking, grooming, and body licking (p<0.0001), but not for rearing or defecation. Importantly, on the post-conditioning day (48 hours after the last psilocybin injection), the unpaired Student’s t-test revealed no behavioral differences. Discussion & Conclusions Our findings show that psilocybin is not linked to rewarding properties in the CPP paradigm. Psychedelics primarily act through serotonergic mechanisms, primarily via 5-HT2AR, with mild effects on 5-HT2CR. Activation of 5-HT2CR has been shown to mitigate drug craving and reduce dopamine-related reinforcing effects, suggesting a potential mechanism for their limited addiction liability (Canal et al., J Psychopharmacology, 2017).. Behavioral analysis revealed that psilocybin increased head-twitch and dog-shaking behaviors, key markers of psychedelic effects; but decreased grooming, rearing and body licking behaviors, which could reflect anxiolytic/anti-repetitive effects. No long-term behavioral changes were found, aligning with evidence that psychedelics do not cause physical dependence or withdrawal symptoms. These findings support the safety profile of psilocybin and its therapeutic potential, even if more studying assessing reward (i.e. self administration) should be conducted.