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PhD Thesis: Susan McQuown

Dissertation Abstract: Neural Mechanisms Underlying Nicotine as a ‘Gateway’ Drug

By Susan McQuown
Doctor of Philosophy in Pharmacology and Toxicology
University of California, Irvine, 2009
Professor Frances M. Leslie, Chair

Epidemiological studies have established that drug use in adolescence is initiated with tobacco and alcohol and progresses to marijuana and other illicit drugs. These findings have led to the hypothesis that tobacco is a ‘gateway’ drug that sensitizes central reward pathways to the effects of illicit substances. Despite strong epidemiological evidence, few preclinical studies have examined whether there is a biological basis for this pattern of drug use and the underlying mechanism. This dissertation evaluated whether nicotine, the main psychoactive constituent of tobacco, during adolescence alters subsequent drug-reinforced behavior and the neural circuitry mediating this response.

In order to test the ‘gateway’ theory, I have developed a novel method to model the early, initiation phase of teenage smoking in rats.  This exposure paradigm is brief, only four days, and delivers the equivalent nicotine in 2-4 cigarettes each day, and more closely mimics the pharmacokinetics of smoking. Using this model, I tested the ‘gateway’ hypothesis that adolescent nicotine treatment has unique effects on reward-related behavior.

Nicotine pretreatment increased self-administration of cocaine in adolescent, but not adult, rats.  Enhanced acquisition of drug-taking behavior was also found for ethanol and methamphetamine. Furthermore, the enhanced responding is not generalized to natural reinforcers, since pretreatment had no effect on sucrose operant reponse. These experiments demonstrate that adolescent nicotine treatment sensitizes the brain to drugs of abuse.

When examining cocaine’s locomotor activating properties, prior nicotine treatment did not alter acute cocaine-induced activity.   However, adolescent nicotine pretreatment did enhance behavioral plasticity in response to repeated cocaine. Findings from these experiments demonstrate that adolescent nicotine exposure uniquely enhances cocaine-induced behavioral plasticity.

Neurochemical studies showed that forebrain monoamine systems are immature during adolescence and nicotine exposure accelerates their development. To further demonstrate serotonin’s role, the selective 5-HT1a receptor antagonist, WAY 100635, pretreatment was shown to block nicotine-induced enhancement of cocaine and methamphetamine self-administration, but had no effect on behavior in saline-pretreated controls. These findings suggest that nicotine-induced changes in serotonergic maturation may underlie enhancement of reward behavior. Together, this dissertation provides strong biological evidence for the ‘gateway’ hypothesis and identifies a potential neural mechanism.