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5ht2a receptor may not be necessary for antidepressant effect in psilocybin: ampa/nmda receptor ratio appears more influential


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Our results provide evidence that psilocybin exerts a rapid beneficial action in well-studied and well-validated models of chronic stress-induced deficits in depression-relevant hedonic behaviors. Although depression is a uniquely human disease, findings from animal experiments can provide insights into psilocybin’s mechanisms of action that are challenging to obtain in humans, such as receptor pharmacology. Indeed, our results recapitulate the rapid antidepressant actions of psilocybin in humans (3, 4) and alterations in brain functional connectivity that outlast the presence of the drug, as reported previously (32). Although psilocybin has been reported to have delayed antidepressant-like effects in the forced swim test in some, but not all, strains of rats (13, 33), we were unable to replicate this finding in mice.
Psychedelic compounds alter consciousness through activation of 5-HT2ARs. The prevailing view in developing psychedelic compounds for psychiatry is that the mind-altering effects of these compounds contribute to, or are responsible for, the therapeutic benefits (2, 9, 10). This assumption has never been tested, however. Our test of this hypothesis requires that the pretreatment with ketanserin sufficiently attenuated the activation of 5-HT2ARs at the time we administered psilocybin. We present two lines of evidence that indicate this is true. We observed that ketanserin blocked 5-HT2AR–dependent head twitching (Fig. 2A) and 5-HT2AR–dependent decreases in low-frequency oscillatory activity (Fig. 2 C and D). Our preclinical results suggest that 5-HT2ARs, and thus psychedelic responses, may not be required for an antidepressant response to psilocybin. We also found that mice with little or no evidence of psilocybin-induced head twitches, indicative of a lack of 5-HT2AR activation (12, 17), still exhibited a robust psilocybin-induced antianhedonic effect (Fig. 2B). Our preclinical results therefore suggest that 5-HT2ARs, and thus psychedelic responses in humans, may not be required for an antidepressant response to psilocybin, although that can only be definitively established with tests in human TRD. We cannot exclude that 5-HT2AR activation is required for some antidepressant activity at postpsilocybin time points longer than the 24 to 48 h we examined here. If 5-HT2AR activation is not necessary, then the combination of psilocybin and a 5-HT2R antagonist safe for human use, such as ketanserin, offers a potential means to eliminate, attenuate, or shorten the duration of psilocybin-induced alterations of perception while retaining its therapeutic benefits. This would reduce barriers hindering psilocybin’s widespread clinical use and perhaps increase its acceptance and utility. Use of nonhallucinogenic derivatives of psychedelic compounds (14) is another potential approach, although an antianhedonic response to these compounds has not yet been demonstrated.
Resetting synaptic strength within cortico-mesolimbic circuits responsible for integration of reward and emotion, such as those demonstrated here, could provide a neurobiological substrate for lasting improvements in psychological and cognitive processing. In this study, we found a significant correlation between synaptic strength and change in hedonic state after psilocybin. Indeed, human studies with healthy volunteers and TRD patients reveal persistent increases in functional connectivity in these same circuits after psilocybin administration (11, 32, 35). The 5-HTRs underlying this synaptic response to psilocybin remain to be determined, but their definition could reveal a strategy for developing alternatives to psilocybin that are biased toward synaptic strengthening relative to perceptual alteration. Our previous work has suggested that 5-HT1BRs contribute to the synaptic and behavioral antidepressant-like actions of SSRIs (36). It is possible that psilocin and novel ibogaine analogs, which both have a high affinity for 5-HT1BRs (6, 14), exert their beneficial actions through activation of 5-HT1BRs. Although animal models cannot provide insight into the potential synergistic effects of the psychedelic experience and traditional psychotherapy, the effectiveness of these interactions may be improved with a better preclinical understanding of the pharmacological and physiological basis of psilocybin’s actions.

https://www.pnas.org/doi/10.1073/pnas.2022489118

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