Elevated levels of serotonin 5-HT_2A receptors in the orbitofrontal cortex of antisocial individuals.

ABSTRACT: Antisocial behavior (ASB) is characterized by frequent violations of the rights and properties of others, as well as aggressive conduct. While ample evidence points to a critical role of serotonin in the emotional modulation of social responses, the implication of this neurotransmitter in ASB is unclear. Here, we performed the first-ever postmortem analysis of serotonergic markers in the orbitofrontal cortex (OFC) of male subjects with ASB (n = 9). We focused on this brain region, given its well-recognized role in social response and ASB pathophysiology. Given that all individuals also had a substance use disorder (SUD) diagnosis, two age-matched control groups were used: SUD only and unaffected controls. Tissues were processed for immunoblotting analyses on eight key serotonergic targets: tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of brain serotonin synthesis; serotonin transporter (SERT), the primary carrier for serotonin uptake; monoamine oxidase A (MAOA), the primary enzyme for serotonin catabolism; and five serotonin receptors previously shown to influence social behavior: 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C, and 5-HT₄. Our analyses documented a significant increase in 5-HT_2A receptor levels in the ASB + SUD group compared to SUD-only controls. Furthermore, TPH2 levels were significantly reduced in the SUD group (including SUD only and ASB + SUD) compared to unaffected controls. No difference was detected in the expression of any other serotonergic target. These results are in keeping with previous evidence showing high 5-HT_2A receptor binding in the OFC of pathologically aggressive individuals and point to this molecule as a potential target for ASB treatment.

SUBMITTER: Braccagni G 

PROVIDER: S-EPMC10831872 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature