Dysregulated 5-HT2A receptor binding in postmortem frontal cortex of schizophrenic subjects

Abstract

Previous postmortem and neuroimaging studies have repeatedly suggested alterations in serotonin 5-HT2A receptor (5-HT2AR) binding associated with the pathophysiology of schizophrenia. These studies were performed with ligands, such as ketanserin, altanserin and LSD, that may bind with high-affinity to different structural or functional conformations of the 5-HT2AR. Interpretation of results may also be confounded by chronic antipsychotic treatment and suicidal behavior in the schizophrenia group. We quantified 5-HT2AR density by radioligand binding assays in postmortem prefrontal cortex of antipsychotic-free (n=29) and antipsychotic-treated (n=16) schizophrenics, suicide victims with other psychiatric diagnoses (n=13), and individually matched controls. [3H]Ketanserin binding, and its displacement by altanserin or the LSD-like agonist DOI, was assayed. Results indicate that the number of [3H]ketanserin binding sites to the 5-HT2AR was increased in antipsychotic-free (128±11%), but not in antipsychotic-treated (92±12%), schizophrenic subjects. In suicide victims, [3H]ketanserin binding did not differ as compared to controls. Aging correlated negatively with [3H]ketanserin binding in schizophrenia, suicide victims and controls. The fraction of high-affinity sites of DOI displacing [3H]ketanserin binding to the 5-HT2AR was increased in antipsychotic-free schizophrenic subjects. Functional uncoupling of heterotrimeric G proteins led to increased fraction of high-affinity sites of altanserin displacing [3H]ketanserin binding to the 5-HT2AR in schizophrenic subjects, but not in controls. Together, these results suggest that the active conformation of the 5-HT2AR is up-regulated in prefrontal cortex of antipsychotic-free schizophrenic subjects, and may provide a pharmacological explanation for discordant findings previously obtained.

Region-Specific Regulation of the Serotonin 2a Receptor Expression in Development and Aging in Postmortem Human Brain

“…Thus, changes in HTR2A expression levels in postmortem brain have been detected in schizophrenia [18][19][20]. In line with these findings, a recent meta-analysis confirmed a significant association of the rs6311 HTR2A polymorphism with schizophrenia [21].…”

Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

“…DOI-induced head twitches are elicited by activation of 5-HT2ARs in the prefrontal cortex (PFC) (14,16,17). We find that DOI induces this behavior in MIA and control mice in a dose-dependent manner [F (1,28) = 75.6, P < 0.0001 and F (1, 33) = 116.4, P < 0.0001 for 1 and 2 mg/kg DOI, respectively; post hoc tests, P < 0.001 for both 1 and 2 mg/kg DOI for control and MIA offspring] (Fig. 1A).…”

“…Compared with controls, antipsychotic-free human schizophrenic subjects display an increased 5-HT2AR level in the PFC (28). Moreover, rodent models of schizophrenia, including MIA and prenatal or postnatal stress, yield offspring with elevated 5-HT2AR in the PFC, as well as a greater sensitivity to DOI (29)(30)(31).…”

Repressive Epigenetic Changes at themGlu2Promoter in Frontal Cortex of 5-HT2AKnockout Mice

“…Similar effects of chronic antipsychotic treatment have been reported in postmortem human brain of schizophrenic subjects. Thus, the number of [ 3 H]ketanserin binding sites to the 5-HT 2A receptor was increased in antipsychotic-free schizophrenic subjects, but not in schizophrenic subjects treated with atypical antipsychotic drugs (Gonzalez-Maeso et al, 2008;Muguruza et al, 2012). These results suggest that down-regulation of 5-HT 2A receptor binding by chronic treatment with atypical antipsychotics may be one of the mechanisms underlying their therapeutic effects.…”

“…Similarly, second generation, or atypical, antipsychotic drugs, such as clozapine, olanzapine, and risperidone, have in common a high affinity for the 5-HT 2A receptor and a lower affinity for the dopamine D2 receptor (Roth et al, 2004;Miyamoto et al, 2005;Lieberman et al, 2008). Radioligand binding assays in postmortem human brain samples and positron emission tomography (PET) studies suggest alterations in 5-HT 2A receptor binding and expression as potentially involved in neuropsychiatric disorders, such as schizophrenia (Gurevich and Joyce, 1997;Gonzalez-Maeso et al, 2008;Rasmussen et al, 2010;Muguruza et al, 2012), depression (Shelton et al, 2009), and suicidal behavior (Oquendo et al, 2006). The role of the 5-HT 2A receptor in these behavioral measures is further supported by previous observations showing that some of the effects of hallucinogenic and atypical antipsychotic drugs are absent in 5-HT 2A knockout (KO) mice (Gonzalez-Maeso et al, 2003, 2007Fribourg et al, 2011).…”