Role of β-Arrestin2 Signaling in Neuropharmacological Effects of Psychedelic Drugs

Current research into the actions of psychedelic drugs is focused on 5-HT2A receptor-coupled signaling pathways, particularly β-arrestin2 signaling. Here, we investigated the involvement of β-arrestin2 in psychedelic drug-induced mouse markers of hallucinogenic effects, molecular plasticity, and structural plasticity; specifically, the head-twitch response, cortical expression of plasticity-related genes (cFos, Egr1, Egr2, and Arc), and dendritogenesis (primary cortical neuron cultures), respectively. Psilocin-induced head-twitches, plasticity gene expression, and dendritogenesis were all blocked by the 5-HT2A receptor antagonist MDL-100,907. The head-twitch response to psilocin was not different between wildtype and β-arrestin2 knockout (KO) mice, and the head-twitch responses to 2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) were similarly unaffected by β-arrestin2 KO. Psilocin-evoked gene expression showed a trend to be less in β-arrestin2 KO compared to wildtype mice, but the gene expression response to DOI was clearly not altered by β-arrestin2 KO. Finally, psilocin-induced dendritogenesis was attenuated in β-arrestin2 KO versus wild-type cultured neurons, and similar findings were obtained with DOI. In summary, the current study found no convincing evidence to support a role for β-arrestin2 signaling in either the head-twitch or plasticity-related gene responses to the psychedelic drugs tested. However, our data suggest a role for the β-arrestin2 pathway in psychedelic drug-evoked dendritogenesis of cultured neurons. Thus, the β-arrestin2 pathway unlikely mediates the hallucinogenic effects of psychedelic drugs but may contribute to neural plasticity changes in certain models.