Serotonergic mechanisms underlying nicotine induced alterations in the dopamine system

Abstract

Clinical studies have shown that adolescent smoking is associated with a variety of health risk behaviors including the development of anxiety disorders, high‐risk sexual behavior and other types of illicit drug use. Neurotransmitter systems implicated in the modulation of these behaviors are not fully mature during this period, and can be critically altered by external stimuli, such as smoking. Given the importance of dopamine (DA) in central reward functions, the purpose of this study was to determine whether nicotine induces age‐specific alterations in mesocorticolimbic DA function. Using rat as an animal model, we found that four‐day pretreatment with a low dose of nicotine (60μg/kg; i.v.), equivalent to that found in 1‐2 cigarettes, significantly altered locomotion induced by direct DA agonists. Behavioral studies show that locomotor activity and erectile response induced by quinpirole (0.4mg/kg; i.p.) was increased after adolescent nicotine exposure, an effect not seen in adults. Neurochemical studies and double‐labeling in situ hybridization studies showed unique changes in limbic, sex and stress‐related systems. WAY 100,635, a selective 5‐HT1a receptor antagonist, blocked the enhancement of quinpirole‐induced locomotion when co‐administered with daily nicotine treatment. Pretreatment with 8‐OH‐DPAT, a 5‐HT1A agonist (10 μg/kg, i.v.), mimicked nicotine's pretreatment effects indicating that adolescent nicotine alters the 5‐HT system, critically impacting central reward pathways These findings provide evidence that nicotine administration causes unique neural adaptations within adolescence, and elucidates novel pathways altered by nicotine that may increase vulnerability to high‐risk behaviors.