The role of the 5-HT(2C) receptor in anxiety-like behavior: An fMRI and genetics study.

摘要

Activation of the serotonin 5-hydroxytryptamine-2C (5-HT 2C) receptor is anxiogenic in humans and animals. The 5-HT2C receptor is expressed in limbic brain regions associated with anxiety, including the amygdala, the hippocampus, and the hypothalamus, therefore suggesting that the 5-HT2C receptor is an integral component of an anxiety circuit. In this thesis, the effects of m-CPP, a 5-HT2 receptor agonist, were compared with the anxiogenic GABAA inverse agonist FG-7142 on both anxiety-like behavior and regional brain activation using functional Magnetic Resonance Imaging (fMRI) in the rat. I also determined if the selective 5-HT2C receptor antagonist SB 242084 would blunt m-CPP or FG-7142-induced neuronal activation. Both m-CPP (3mg/kg, ip) and FG-7142 (10mg/kg, ip) elicited anxiety-like behavior when measured in the social interaction test, and pretreatment with SB 242084 (1 mg/kg, ip) blocked the behavioral effects of both anxiogenic drugs. Regional brain activation in vivo in response to anxiogenic drug challenge was determined by Blood Oxygen Level Dependent (BOLD) fMRI. Region of interest analyses revealed that m-CPP and FG-7142 significantly increased BOLD signals in brain regions that have been linked to anxiety, including the amygdala, dorsal hippocampus, and medial hypothalamus. These BOLD signal increases were blocked by pretreatment with SB 242084. In addition to pharmacological manipulation of 5-HT2C receptor activity, 5-HT2C receptor function is modified by RNA editing, a postranscriptional process that changes the genetic code at the level of RNA. Increases in 5-HT2C receptor RNA editing correlated with a higher proportion of receptor isoforms with reduced signaling capacity and decreased anxiety-like behavior in inbred mouse strains. I confirmed the strain anxiety differences using light ↔ dark exploration, and discovered that BALB/cJ and DBA/2J are each characterized by a higher functioning RNA editing profile than C57BL/6J. Taken together, these findings indicate that decreases in 5-HT2C receptor function resulting from either increased RNA editing or blockade with a selective antagonist promote anxiolysis, which suggests that agents that increase 5-HT2C receptor editing and/or block 5-HT2C receptor function might be therapeutic in the treatment of anxiety disorders.