Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia.

Subchronic administration of phencyclidine (PCP) to mice increases the sensitivity of serotonin 2A receptors (5-HT2A Rs) in the frontal cortex. Mice treated with PCP (10 mg/kg) for 10 days, followed by a 5-day washout, showed a stronger head-twitch response and greater expression of immediate-early genes (Arc, c-fos, egr-2) after a challenge with the 5-HT2A R agonist DOI, compared to saline-treated mice. These functional changes occurred without alterations in 5-HT2A R binding or in binding of the 5-HT1A receptor or serotonin transporter. Basal Arc mRNA levels were also elevated in the prefrontal cortex. The findings suggest that PCP-induced changes enhance 5-HT2A R-mediated neurotransmission, which may contribute to behavioral deficits in this schizophrenia model.

Study at a glance

Abstract

Prefrontal serotonin 2A receptors (5-HT2A Rs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5-HT2A R at clinical relevant doses, and activation of 5-HT2A receptors by lysergic acid diethylamide (LSD) and LSD-like drugs induces a schizophrenia-like psychosis in humans. Subchronic phencyclidine (PCP) administration is a well-established model for schizophrenia-like symptoms in rodents. The aim of the present study was to investigate whether subchronic PCP administration changes expression, binding, or functionality of cortical 5-HT2A Rs. As a measure of 5-HT2A R functionality, we used the 5-HT2A R agonist 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch response (HTR) and mRNA expression of the immediate-early genes (IEGs) activity-related cytoskeletal associated-protein (Arc), c-fos, and early growth response protein 2 (egr-2) in the frontal cortex. Mice were treated with PCP (10 mg/kg) or saline for 10 days, followed by a 5-day washout period. The PCP pretreatment increased the overall induction of HTR and frontal cortex IEG mRNA expression following a single challenge with DOI. These functional changes were not associated with changes in 5-HT2A R binding. Also, binding of the 5-HT1A R and the 5-HT transporter was unaffected. Finally, basal mRNA level of Arc was increased in the prefrontal cortex after subchronic PCP administration as revealed with in situ hybridization. Together these findings indicate that PCP administration produces changes in the brain that result in an increase in the absolute effect of DOI. Therefore, neurotransmission involving the 5-HT2A R could contribute to the behavioral deficits observed after PCP treatment. © 2013 Wiley Periodicals, Inc.