Nicotine Addiction: Why is it So Hard to Break the Habit?

• The effects of nicotine are mediated by nicotinic acetylcholine receptors (nAChRs), located throughout the nervous system.
• Two main types of brain nAChRs are the α7 homo-oligomer (fast activation, low affinity) and the α4β2 hetero-oligomer (high affinity, slow desensitization).
• nAChRs in mammals are composed of subunits encoded by 17 genes. Of these,12 are expressed in the brain. The various nAChR subunits differ in their pharmacology and localization. Areas of the brain involved in nicotine addiction are the midbrain, the hippocampus, the habenulo-interpeduncular system and the prefrontal cortex.

• Chronic nicotine exposure alters the brain reward system by increasesing dopamine release.
• At the cellular level, nicotine administration for 2 months causes hyperactivity of dopaminergic neurons in the brain.
• Neurological imaging in humans suggests that nicotine addiction may involve a disruption of prefrontal cortex and functions. This disruption can hinder attention, reasoning, planning and decision-making.
• Nicotine 'resets' dopamine reward circuits and increases sensitivity to subsequent nicotine intake.

The process of 'sensitisation' seems to be unique to nicotine, since other drugs of abuse cause decreased sensitivity of neural circuits. Sensitization is thought to be a key step in the process leading to addiction.

Wild-type (normal) mice and mice lacking specific nAChR subunits have different responses to nicotine. The mutant mice share features with genetic differences seen in humans, which makes them relevant models to investigate the molecular biology of nicotine addiction. Allowing mice to self administer nicotine (usually in their drinking water) has generated some useful findings, for example:

Mice lacking certain β subunits, but not α subunits, showed decreased nicotine consumption relative to wild-type (normal mice). However, after 3 weeks of nicotine access, the β deficient mice returned to normal levels of nicotine consumption, whereas the α deficient mice continued to show decreased nicotine consumption.

• The withdrawal syndrome that accompanies smoking cessation can involve gastrointestinal discomfort, irritability, anxiety and depression. In rodents, rearing, jumping, shaking, abdominal constrictions, chewing and scratching are seen.
• Withdrawal symptoms are mediated by different nAChR subunits. In rodent experiments, wild-type (normal) mice and those lacking certain nAChR subunits showed withdrawal behaviour, but mice lacking other subunits did not.
• The habenula system has been implicated in withdrawal from other drugs of addiction, including opiates, cocaine and alcohol. Activity in the habenula and interpeduncular nucleus increases during nicotine withdrawal.
• The pattern and distribution of nAChR subunits involved in the nicotine withdrawal syndrome might differ from those engaged in the short-term effects of nicotine.

The nAChR subunits involved in the transition from short-term to long-term effects of nicotine exposure requires further exploration. This is because most currently available stop smoking therapies primarily target the short-term effects of nicotine withdrawel.

Human genetic studies on nicotine dependence show an association of certain subunit polymorphisms with nicotine dependence. Therefore it would seem that some people's genetic make up makes them more vulnerable to nicotine addiction.

Hopefully this research will uncover new targets for stop smoking therapies. In addition, these studies may have relevance to diseases such as depression, Alzheimer's disease and Parkinson's disease.