Differential effects of psilocybin and lisuride on serotonin and dopamine neuronal activity and behavior

Psilocybin and lisuride are 5-HT2A receptor agonists, but only psilocybin elicits the head twitch response (HTR) in rodents, a behavior commonly used as a proxy for hallucinogenic activity. This study aimed to compare their effects on serotonin (5-HT) and dopamine (DA) neuronal activity, as well as related behavioral outcomes, to elucidate the mechanisms underlying their divergent effects. Adult male C57BL/6N mice were administered intraperitoneal injections of psilocybin (0.3–3 mg/kg), lisuride (0.1–0.5 mg/kg), or vehicle. In vivo electrophysiological recordings were performed in the dorsal raphe nucleus (DRN) and substantia nigra (SN) to monitor 5-HT and DA neuronal firing. MDL 100907 (0.2 mg/kg) pretreatment was used to determine 5-HT2A receptor specificity. Behavioral assessments included HTR testing 10 min post-injection, followed by either the forced swim test (FST), open field test (OFT), or elevated plus maze (EPM) at 20 min post-injection. Psilocybin-induced inhibition, but not lisuride-induced inhibition, of 5-HT neuron firing was blocked by MDL 100907. Both drugs reduced DA neuron firing, however, lisuride's effect was more sensitive to 5-HT2A receptor antagonism. Psilocybin elicited HTR, while lisuride did not. In the FST, only high-dose lisuride reduced immobility time. Both drugs reduced locomotor activity in the OFT and EPM. Principal Component Analysis (PCA) sufficiently separated the effects of each drug from each other, indicating distinct effect profiles. Although both drugs target 5-HT2A receptors, they engage distinct neurobiological pathways. Psilocybin produces psychedelic-like, 5-HT–dominant effects, whereas lisuride displays DA-linked improvements in coping behavior, informing future development of serotonergic therapeutics.