Serotonin in Adolescence: Role in Behavioral Inhibition

Background: Adolescents are impulsive and novelty seeking, normal behaviors that engage the adolescents in the world outside the home but also increase involvement in risky behaviors. Immaturity of frontal cortex circuits involved in executive function may be the main reason for this behavioral profile. As serotonergic innervation of the frontal cortex is critical for behavioral inhibition, we investigated the hypothesis that immaturity in serotonergically-mediated behavioral inhibition contributes to the adolescent behavioral profile. Design: To investigate the role of serotonergic innervation, we evaluated the behavioral and neurochemical effects of fluoxetine in adolescent (PN 28) and adult male rats (PN 70). Rats were treated with fluoxetine (0, 10 mg/kg) and tested in the light/dark anxiety test. In addition, the ability of fluoxetine (0, 2.5, 5 and 10 mg/kg at hourly intervals) to increase extracellular serotonin in the prefrontal cortex was measured using microdialysis. Finally, the ability of fluoxetine (10 mg/kg) to activate the immediate early gene c-fos relative to vehicle control was determined to investigate downstream effects of the increase in extracellular serotonin. Results: Fluoxetine did not inhibit behavior in the light/dark anxiety test in adolescents relative to vehicle control, but it did so in adults. However, the neurochemical effects of fluoxetine were comparable in adolescents and adults: fluoxetine elicited comparable increases in extracellular 5-HT in adolescents and adults. To examine the contribution of postsynaptic mechanisms, we evaluated the behavioral effects of the 5 HT1a agonist 8-OHDPAT and the 5 HT2 agonist mCPP. mCPP (0.5 or 1 mg/kg) produced comparable behavioral inhibition relative to vehicle control in adolescents and adults, but 8-OHDPAT (0.25, 0.5 mg/kg) did not. To determine if neural circuit activation by postsynaptic mechanisms was functional in adolescents, we tested the ability of fluoxetine (10 mg/kg) and 8-OHDPAT (0.5 mg/kg) to activate C-fos. Neither drug activated C-fos in amygdala or PVN of the hypothalamus. Conclusions: These results suggest that cortical inhibition of stress circuitry is immature in adolescents.