Brain region-specific abnormalities in serotonergic transmission appear to underlie suicidal behavior. Alterations of RNA editing on the serotonin receptor 2C (HTR2C) pre-mRNA in the brain of suicides produce transcripts that attenuate 5-HT_2CR signaling by impairing intracellular G-protein coupling and subsequent intracellular signal transduction. In brain, the distribution of RNA-editing enzymes catalyzing deamination (A-to-I modification) shows regional variation, including within the cerebral cortex. We tested the hypothesis that altered pre-mRNA 5-HT_2CR receptor editing in suicide is region-specific. To this end, we investigated the complete 5-HT_2CR mRNA-editing profile in two architectonically distinct cortical areas involved in mood regulation and decision-making in a clinically well-characterized cohort of age- and sex-matched non-psychiatric drug-free controls and depressed suicides. By using an original biochemical detection method, that is, capillary electrophoresis single-stranded conformational polymorphism (CE-SSCP), we corroborated the 5-HT_2CR mRNA-editing profile previously described in the dorsolateral prefrontal cortex (Brodmann area 9 (BA9)). Editing of 5-HT_2CR mRNA displayed clear regional difference when comparing dorsolateral prefrontal cortex (BA9) and anterior cingulate cortex (BA24). Compared with non-psychiatric control individuals, alterations of editing levels of 5-HT2CR mRNA were detected in both cortical areas of depressed suicides. A marked increase in editing on 5-HT_2CR was especially observed in the anterior cingulate cortex in suicides, implicating this cortical area in suicide risk. The results suggest that region-specific changes in RNA editing of 5-HT_2CR mRNA and deficient receptor function likely contribute to the etiology of major depressive disorder or suicide.

The in vivo behavior of 4‐(2′‐methoxyphenyl)‐1‐[2′‐[N‐(2″‐pyridinyl)‐p‐[¹⁸F]fluorobenzamido]ethyl]‐piperazine (p‐[¹⁸F]MPPF), a new serotonin 5‐HT_1A antagonist, was studied in awake, freely moving rats. Biodistribution studies showed that the carbon‐fluorine bond was stable in vivo, that this compound was able to cross the blood‐brain barrier, and that a general diffusion equilibrium could account for the availability of the tracer. The great quantity of highly polar metabolites found in plasma did not contribute to the small amounts of metabolites found in hippocampus, frontal cortex, and cerebellum. Exvivo p‐[¹⁸F]MPPF and in vitro 8‐hydroxy‐2‐(di‐n‐[³H]propylamino)tetralin autoradiography were compared both qualitatively and quantitatively. Qualitative evaluation proved that the same brain regions were labeled and that the p‐[¹⁸F]MPPF labeling is (a) in total agreement with the known distribution of 5‐HT_1A receptors in rats and (b) characterized by very low nonspecific binding. Quantitative comparison demonstrated that the in vivo labeling pattern obtained with p‐[¹⁸F]MPPF cannot be explained by differences in regional blood flow, capillary density, or permeability. The 5‐HT_1A specificity of p‐[¹⁸F]MPPF and binding reversibility were confirmed in vivo with displacement experiments. Thus, this compound can be used to evaluate parameters characterizing 5‐HT_1A binding sites in the brain.