Age‐Dependent Effects of Nicotine or Fluoxetine on 5‐HT1A Receptor Activity

Abstract

Initiation of smoking and onset of psychiatric diseases often emerge during adolescence, a sensitive developmental period. Clinical data indicates that teen smokers are more likely to develop psychiatric disorders and substance abuse. Preclinical data reveals that nicotine, the main psychoactive component of tobacco, elicits lasting changes in adolescent brain development, neuronal signaling, and motivated behavior. Our lab has shown that nicotine enhances behavioral sensitivity to cocaine reward in adolescents but not adults (Dao et al., 2011). This effect is mimicked by endogenous activation of the 5‐HT system with fluoxetine, a selective serotonin reuptake inhibitor commonly prescribed for teen depression. Furthermore, both co‐administration of 5‐HT1AR antagonist WAY‐100,635 (during drug exposure) and acute administration of WAY‐100,635 (after drug exposure) blocked nicotine and fluoxetine's enhancement effects, indicating that these drugs increase adolescent 5‐HT1AR signaling. Thus, this study examines whether nicotine or fluoxetine age‐dependently alters 5‐HT1AR activity, particularly in brain areas regulating drug reward. Adolescent or adult rats received nicotine (60µg/kg, i.v.) or fluoxetine (1mg/kg, i.v.) for 4 consecutive days. Next day, brains were collected and processed via agonist‐stimulated [35S]GTPγS binding to determine 5‐HT1AR activity. Preliminary data indicate that adolescent nicotine or fluoxetine exposure may increase 5‐HT1AR activity in brain regions mediating executive function and addiction‐related behaviors. ​These results provide region‐specific understanding of nicotine and fluoxetine's effects on brain development and clarify underlying mechanisms in which 5‐HT1ARs mediate sensitization of cocaine reward during adolescence.