Serotonin 5-HT_2A receptor expression and functionality in postmortem frontal cortex of subjects with schizophrenia: Selective biased agonism via G_αi1-proteins

Serotonin 5-HT_2A receptors (5-HT_2ARs) have been implicated in schizophrenia. However, postmortem studies on 5-HT_2ARs expression and functionality in schizophrenia are scarce. The 5-HT_2AR mRNA and immunoreactive protein expression were evaluated in postmortem tissue from dorsolateral prefrontal cortex (DLPFC) of antipsychotic-free (n = 18) and antipsychotic-treated (n = 9) subjects with schizophrenia, and matched controls (n = 27). Functional coupling of 5-HT_2AR to G-proteins was tested by measuring the activation induced by the agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride ((±)DOI) in antibody-capture [³⁵S]GTPγS scintillation proximity assays (SPA). In antipsychotic-free schizophrenia subjects, 5-HT_2AR mRNA expression and protein immunoreactivity in total homogenates was similar to controls. In contrast, in antipsychotic-treated schizophrenia subjects, lower mRNA expression (60±9% vs controls) and a trend to reduced protein immunoreactivity (86±5% vs antipsychotic-free subjects) just in membrane-enriched fractions was observed. [³⁵S]GTPγS SPA revealed a significant ~6% higher stimulation of G_αi1-protein by (±)DOI in schizophrenia, whereas activation of the canonical G_αq/11-protein pathway by (±)DOI remained unchanged. Expression of G_αi1- and G_αq/11-proteins did not differ between groups. Accordingly, in rats chronically treated with clozapine, but not with haloperidol, a 30–40% reduction was observed in 5-HT_2AR mRNA expression, 5-HT_2AR protein immunoreactivity and [³H]ketanserin binding in brain cortical membranes. Overall, the data suggest a supersensitive 5-HT_2AR signaling through inhibitory G_αi1-proteins in schizophrenia. Together with previous results, a dysfunctional pro-hallucinogenic agonist-sensitive 5-HT_2AR conformation in postmortem DLPFC of subjects with schizophrenia is proposed. Atypical antipsychotic treatment would contribute to counterbalance this 5-HT_2AR supersensitivity by reducing receptor expression.