Nicotine Gateway Effects on Adolescent Substance Use

Abstract

Given the rise in teenage use of electronic nicotine delivery systems ("vaping") in congruence with the increasing numbers of drug-related emergencies, it is critical to expand the knowledge of the physical and behavioral risks associated with developmental nicotine exposure. A further understanding of the molecular and neurochemical underpinnings of nicotine's gateway effects allows emergency clinicians to advise patients and families and adjust treatment accordingly, which may minimize the use of tobacco, nicotine, and future substances. Currently, the growing use of tobacco products and electronic cigarettes among teenagers represents a major public health concern. Adolescent exposure to tobacco or nicotine can lead to subsequent abuse of nicotine and other substances, which is known as the gateway hypothesis. Adolescence is a developmentally sensitive time period when risk-taking behaviors, such as sensation seeking and drug experimentation, often begin. These hallmark behaviors of adolescence are largely due to maturational changes in the brain. The developing brain is particularly vulnerable to the harmful effects of drugs of abuse, including tobacco and nicotine products, which activate nicotinic acetylcholine receptors (nAChRs). Disruption of nAChR development with early nicotine use may influence the function and pharmacology of the receptor subunits and alter the release of reward-related neurotransmitters, including acetylcholine, dopamine, GABA, serotonin, and glutamate. In this review, we emphasize that the effects of nicotine are highly dependent on timing of exposure, with a dynamic interaction of nAChRs with dopaminergic, endocannabinoid, and opioidergic systems to enhance general drug reward and reinforcement. We analyzed available literature regarding adolescent substance use and nicotine's impact on the developing brain and behavior using the electronic databases of PubMed and Google Scholar for articles published in English between January 1968 and November 2018. We present a large collection of clinical and preclinical evidence that adolescent nicotine exposure influences long-term molecular, biochemical, and functional changes in the brain that encourage subsequent drug abuse.

Figure 1

4-day nicotine pretreatment paradigm in testing the nicotine gateway hypothesis in rats. Two intravenous nicotine (0.03 mg/kg/0.1 ml, equivalent to 1–2 cigarettes) or saline injections, spaced one minute apart, are administered daily for 4 consecutive days during early adolescence (PND 28–31) or adulthood (PND 86–89). Experimentation following nicotine pretreatment (dashed lines) varies upon the drug administered, duration of drug administration, and contingent or non-contingent injections. The daily nicotine dose yields peak serum levels of approximately 30 ng/ml in both adolescents in adults, which is well within the range of the average smoker. PND, postnatal day; IV, intravenous; mg, milligram; kg, kilogram; ng, nanogram; ml, milliliter.