The atypical antipsychotic clozapine induces 5‐HT2ARmediated signaling and behavioral events in a beta‐arrestin2‐ independent but Akt‐dependent manner

Abstract

The G protein‐coupled serotonin 2A receptor (5‐HT2AR) is a prominent target for atypical antipsychotic drugs, such as clozapine. Although clozapine is known to inhibit 5‐HT2AR mediated G protein coupling, it differs from classic GPCR antagonists in that it also induces 5‐HT2AR internalization and activates Akt signaling via a 5‐HT2AR‐mediated event. The cognate neurotransmitter at the 5‐HT2AR, serotonin, also induces 5‐HT2AR internalization and Akt phosphorylation, events which require the interaction between the receptor and the intracellular scaffolding and regulatory protein, beta‐arrestin2 (βarr2). Moreover, the 5‐HT2AR/βarr2/Akt interaction is critical for serotonin‐induced, 5‐HT2AR‐mediated behavioral responses in mice. Therefore, we hypothesized that clozapine also utilizes a βarr2‐mediated mechanism to induce 5‐HT2AR signaling and regulatory events, as well as its behavioral effects in mice. Here, we demonstrate that, unlike serotonin, clozapine‐mediates 5‐ HT2AR internalization and Akt phosphorylation independent of receptor interactions with βarr2. Moreover, clozapine‐mediated suppression of MK‐801 and PCP‐induced hyperlocomotion is βarr2 independent, although it is dependent upon Akt. These results demonstrate that serotonin and clozapine utilize differential mechanisms to in the induction of similar events downstream of the 5‐HT2AR. The further elucidation of these mechanisms in vivo may allow for the development of more effective atypical antipsychotic drugs.Funding from NIDA: DA025158