title: Clozapine-induced locomotor suppression is mediated by 5-HT2A receptors in the forebrain.
abstract: The need for safer, more effective therapeutics for the treatment of schizophrenia is widely acknowledged. To optimally target novel pharmacotherapies, in addition to establishing the mechanisms responsible for the beneficial effects of antipsychotics, the pathways underlying the most severe side effects must also be elucidated. Here we investigate the role of serotonin 2A (5-HT(2A)), serotonin 2C (5-HT(2C)), and dopamine 2 receptors (D₂) in mediating adverse effects associated with canonical first- and second-generation antipsychotic drugs in mice. Wild-type (WT) and 5-HT(2A) knockout (KO) mice treated with haloperidol, clozapine, and risperidone were assessed for locomotor activity and catalepsy. WT mice showed a marked reduction in locomotor activity following acute administration of haloperidol and high-dose risperidone, which was most likely secondary to the severe catalepsy caused by these compounds. Clozapine also dramatically reduced locomotor activity, but in the absence of catalepsy. Interestingly, 5-HT(2A) KO mice were cataleptic following haloperidol and risperidone, but did not respond to clozapine's locomotor-suppressing effects. Restoration of 5-HT(2A) expression to cortical glutamatergic neurons re-instated the locomotor-suppressing effects of clozapine in the open field. In sum, we confirm that haloperidol and risperidone caused catalepsy in rodents, driven by strong antagonism of D₂. We also demonstrate that clozapine decreases locomotor activity in a 5-HT(2A)-dependent manner, in the absence of catalepsy. Moreover, we show that it is the cortical population of 5-HT(2A) that mediate the locomotor-suppressing effects of clozapine.
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, 1051 Riverside Drive, New York, NY 10032, USA. cem2185@columbia.edu
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: McOmish
authors.forename: Alena
authors.initials: A
authors.lastname: Lira
authors.forename: James B
authors.initials: JB
authors.lastname: Hanks
authors.forename: Jay A
authors.initials: JA
authors.lastname: Gingrich
mesh_terms: D000818:Animals; D003024:Clozapine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D016548:Prosencephalon / Q000187:drug effects / Q000502:physiology*; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D003024:Clozapine