Biomolecular
Pre-existing cognitive and mood disorders may influence the development and maintenance of nicotine dependence.[22] Nicotine is a parasympathomimetic stimulant[23] that binds to and activates nicotinic acetylcholine receptors in the brain, which subsequently causes the release of dopamine and other neurotransmitters, such as norepinephrine, acetylcholine, serotonin, gamma-aminobutyric acid, glutamate, endorphins,[24] and several neuropeptides.[25] Repeated exposure to nicotine can cause an increase in the number of nicotinic receptors, which is believed to be a result of receptor desensitization and subsequent receptor upregulation.[24] This upregulation or increase in the number of nicotinic receptors significantly alters the functioning of the brain reward system. With constant use of nicotine, tolerance occurs at least partially as a result of the development of new nicotinic acetylcholine receptors in the brain.[24] After several months of nicotine abstinence, the number of receptors go back to normal.[26] Nicotine also stimulates nicotinic acetylcholine receptors in the adrenal medulla, resulting in increased levels of adrenaline and beta-endorphin.[24] Nicotine alters neural responses of the amygdala. [27] Its physiological effects stem from the stimulation of nicotinic acetylcholine receptors, which are located throughout the central and peripheral nervous systems.[28] Chronic nicotinic acetylcholine receptor activation from repeated nicotine exposure can induce strong effects on the brain, including changes in the brain's physiology, that result from the stimulation of regions of the brain associated with reward, pleasure, and anxiety.[29] These complex effects of nicotine on the brain are still not well understood.[29]
When these receptors are not occupied by nicotine, they are believed to produce withdrawal symptoms.[30] These symptoms can include cravings for nicotine, anger, irritability, anxiety, depression, impatience, trouble sleeping, restlessness, hunger, weight gain, and difficulty concentrating.[31]
Neuroplasticity within the brain's reward system occurs as a result of long-term nicotine use, leading to nicotine dependence.[32] There are genetic risk factors for developing dependence. For instance, genetic markers for a specific type of nicotinic receptor (the α5-α3-β4 nicotine receptors) have been linked to increased risk for dependence.[33][34] The most well-known hereditary influence related to nicotine dependence is a mutation at rs16969968 in the nicotinic acetylcholine receptor CHRNA5, resulting in an amino acid alteration from aspartic acid to asparagine.[35] The single-nucleotide polymorphisms (SNPs) rs6474413 and rs10958726 in CHRNB3 are highly correlated with nicotine dependence. Many other known variants within the CHRNB3–CHRNA6 nicotinic acetylcholine receptors are also correlated with nicotine dependence in certain ethnic groups.[36] There is a relationship between CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptors and complete smoking cessation. Increasing evidence indicates that the genetic variant CHRNA5 predicts the response to smoking cessation medicine.[37]
