327. 5-HT2B RECEPTORS MODULATE THE ANTIDEPRESSANT-LIKE RESPONSE OF THE PSYCHEDELIC LSD IN RAT BUT NOT IN MICE

Abstract Background Recent clinical trials show that serotonergic psychedelics, including the prototypical hallucinogen lysergic acid diethylamide (LSD), present a great promise for treating affective disorders. While the hallucinogenic activities of LSD are commonly attributed to stimulation of 5-HT2A receptors, their role in LSD’s antidepressant response is still in debate. Interestingly, LSD is a potent 5-HT receptors ligand endowed with high affinity for most of all 5-HT subtypes (Ki between 1 and 100 nM) and is regularly used as a valuable pharmacological tool to characterize 5-HT1A and 5-HT2A receptor mediations [1]. However, using a FLIPR calcium assay in recombinant human 5-HT2 receptors in CHO-K1 cells, it has been reported in vitro that several tryptamines, including LSD, displayed a rank order of potency of 5-HT2B > 5-HT2C > 5-HT2A receptors [2]. Notably, a crystal structure of LSD in complex with the human 5-HT2B receptor has been recently described [3]. Aims & Objectives Using behavioral paradigms in rodents, the present work was aimed to evaluate the involvement of the 5-HT2B receptor mediation in the action of LSD in modulating both rat and mice head twitch response (hallucinatory-like response) and the active coping behaviour (despair-like response). Method - Rats and mice were placed in an observation cage and the cumulative number of head twitches (counted during a 30-min period). LSD (i.p.) was injected immediately before the observation while the potent 5-HT2B receptor antagonist RS 127445 (i.p.) was administered prior to LSD administration. RS-127445 is one of the most selective antagonists with nanomolar affinity for the 5-HT2B receptor and has 1000-fold selectivity for this receptor as compared to other receptors [4]. - In the forced swimming test (FST), rats experienced a pre-test session (15 min) followed 24 h later by a test session (5 min) while mice experienced directly the test session (5 min). Vehicle or RS 127445 (i.p.) were injected acutely before vehicle or LSD (i.p.) that were administered one month before the test session. Results - Acute administration of LSD induced an increase of the head twitch response in both in rat and mice but the latter actions of LSD were significantly counteracted by a prior administration of RS 127445 only in rat. - One month after the acute administration of LSD, a significant decrease of immobility time was observed only in rat and this action was significantly counteracted by the pre-administration of RS 127445. - The preventing effects of other 5-HT2B receptor ligands will be presented at the meeting. Discussion & Conclusions Collectively, the present results suggest for the first time that 5-HT2B receptors play a permissive role in the long-lasting antidepressant effects of serotonergic psychedelics in rat.