Postnatal Serotonin Type 2 Receptor Blockade Prevents the Emergence of Anxiety Behavior, Dysregulated Stress-Induced Immediate Early Gene Responses, and Specific Transcriptional Changes that Arise Following Early Life Stress

Background: Early life adverse experience contributes to an enhanced vulnerability for adult psychopathology. Recent evidence indicates that serotonin type 2 (5-HT(2)) receptor function, implicated in the pathophysiology of mood and anxiety disorders, is significantly enhanced in the maternal separation model of early life stress. We examined whether postnatal 5-HT(2) receptor blockade would prevent the consequences of maternal separation on anxiety behavior and dysregulated gene expression. Methods: Control and maternally separated litters received treatment with the 5-HT(2) receptor antagonist, ketanserin, or vehicle during postnatal life and were examined for effects on adult anxiety behavior, adult stress-induced immediate early gene expression responses, and transcriptional changes within the prefrontal cortex during postnatal life and in adulthood. Results: Treatment with ketanserin during postnatal life blocked the long-lasting effects of maternal separation on anxiety behavior in the open field test and the elevated plus maze. Further, the dysregulated adult stress-induced expression pattern of the immediate early gene, Arc, observed in maternally separated animals was also prevented by postnatal ketanserin treatment. Ketanserin treatment normalized the alterations in the expression of specific genes in the prefrontal cortex of maternally separated animals, including changes in serotonin type 2A receptor messenger RNA expression during postnatal life and in genes associated with G-protein signaling in adulthood. Conclusions: Postnatal treatment with the 5-HT(2) receptor antagonist, ketanserin, blocked specific consequences of maternal separation, including anxiety behavior and dysregulated gene expression in the prefrontal cortex. Our results suggest that enhanced 5-HT(2) receptor function may contribute to the emergence of anxiety behavior and perturbed stress responses following early life stress.