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Adolescence represents a sensitive developmental period characterized by heightened clinical vulnerability to tobacco, e-cigarettes, and antidepressants. While there are sociocultural influences, both clinical and preclinical data indicate that this adolescent sensitivity has strong neurobiological underpinnings. Although definitions of adolescence vary, the hallmark of this period is a profound reorganization of brain regions necessary for mature cognitive, executive, and emotional function, including serotonin (5-HT) and dopamine (DA) monoamine systems. However, as shown in this dissertation, perturbations of 5-HT systems during this time with nicotine or fluoxetine may have unique consequences on adolescent DA function. In this dissertation, I highlight that the distinct neurobiology of adolescent 5-HT and DA systems create unique behavioral vulnerabilities to drugs of abuse. The present studies demonstrate that changes in adolescent 5-HT systems and 5-HT1A receptor activation during brief, low-dose pretreatment sensitize D2 receptor-mediated behaviors. Using a pharmacological approach, I have shown that increasing endogenous 5-HT signaling with fluoxetine enhances quinpirole-induced locomotion and acquisition of self-administration during adolescence via sensitization of D2 receptor responses. These effects are age-specific and analogous to those observed after adolescent nicotine exposure. Furthermore, antagonist studies indicate that this enhanced sensitivity to quinpirole and cocaine is mediated by increased activation of postsynaptic 5-HT1A receptors and persists even after pretreatment has ended. To characterize the lasting alterations in 5-HT1A receptor function, neurochemical and anatomical analysis suggest that nicotine and fluoxetine have both distinct and common effects on regional 5-HT1A receptor activity. While fluoxetine alone targets prefrontal cortical neurocircuitry and nicotine alone targets the amygdala, both drugs enhance adolescent 5-HT1A receptor activity in the primary motor cortex (M1). Thus, within the adolescent M1, maladaptive changes in 5-HT signaling and 5-HT1A activity after nicotine or fluoxetine exposure may potentiate D2 receptor responsiveness to dopaminergic drugs and prime adolescent vulnerability for future substance abuse.