Although declining in the United States, tobacco addiction remains the most prevalent addiction of all drugs of abuse. Nicotine is an alkaloid derived from the Nicotiana tabacum (common tobacco) plant, which has been cultivated for centuries for ceremonial and medicinal uses. The dried leaves of the plant are generally smoked, although oral administration in the form of snuff or chewing tobacco is also widespread. Cigarettes began to be manufactured in the mid-19th century. Since 1940, they have been the most prevalent form of administration.

Nicotine produces euphoria characterized by arousal and a stimulant effect, including cognitive activation, autonomic activation, and increases in heart rate and blood pressure. Paradoxically, it also reduces perceived tension and stress. Nicotine also produces analgesia and decreases appetite. Animal studies have shown that nicotine lowers brain reward thresholds, increases locomotor activity, and is intravenously self-administered. Nicotine can produce anxiolytic-like effects in various animal models of anxiety. It is rapidly absorbed by smoking and oral administration and has a short half-life of 2 hours. Tobacco smoke produces high carboxyhemoglobin levels and has significant amounts of carcinogens that have been linked to the toxic effects of smoking.

The behavioral mechanism of action of nicotine is linked to its mood titration effects via Nesbitt’s paradox, in which smokers maintain a certain blood nicotine level over the course of a smoking bout that is extended to waking hours in dependent smokers. The boundary model explains such titration, in which the upper boundary delimits the aversive effects of high nicotine doses, and the lower boundary delimits the aversive effects of nicotine withdrawal.

Much information has been gleaned from animal work about the neurobiology of the acute reinforcing and stimulant effects of nicotine. Nicotine binds to nAChRs and activates the mesocorticolimbic dopamine system, including the ventral tegmental area and nucleus accumbens. The molecular site of action for the acute reinforcing effects of nicotine involves interactions with the α4β2 and α6β2 subunits. Mutant mice that lack the b2 subunit do not self-administer nicotine. In the ventral tegmental area, nAChRs are localized to dopaminergic cell bodies and GABAergic and glutamatergic afferents. The combination of effects of nicotine on nAChRs at these locations facilitates the actions of dopamine neurons. There is evidence of opioid peptide interactions with nicotine reinforcement. μ Opioid receptor knockout mice show no nicotine-induced conditioned place preference. The neurobiological bases for the dependence-inducing properties of nicotine involves within-system decreases in reward-related neurotransmitter function, including dopamine, opioid peptides, and serotonin, and the recruitment of the between-system brain CRF stress system, similar to other drugs of abuse.

At the molecular level, differential receptor desensitization may underlie negative reinforcement, in which self-medication is used to control the functional recovery of nAChRs. At the neurocircuitry level, decreases in dopaminergic neurotransmission in the ventral tegmental area and nucleus accumbens are associated with the malaise associated with acute nicotine withdrawal. Losses of the functional activity of glutamate, serotonin, and likely opioid peptides and the recruitment of the brain stress systems (CRF) are also associated with nicotine withdrawal and by extrapolation also drive negative reinforcement. Chronic nAChR activation alters CREB activity. Decreased CREB activity has been observed in the amygdala, nucleus accumbens, and prefrontal cortex during withdrawal. These changes may alter gene expression and trigger long-term neuroadaptive responses that are similar to other drugs of abuse.

Back to top