Pharmacological Action of Nicotine

Nicotine binds selectively to the nicotinic receptors that are present in the adrenal medulla, brain, autonomic ganglia, and neuromuscular junctions. It causes the release of several neurotransmitters and hormones such as acetylcholine, norepinephrine, dopamine, serotonin, arginine vasopressin, j3-endorphin, adrenocorticotropic hormone, and cortisol (187). This neuro-regulatory effect of nicotine is dose-dependent and occurs as plasma nicotine level rises when tobacco is smoked. The neurotransmitters released in the brain medi ate the behavior modulating effects and positive reinforcing effects of nicotine and other habit-forming drugs. Neurological Basis of Nicotine Dependence. In the brain, nicotine exerts a multitude of psychological and behavioral effects. At low doses, it exerts a predominantly stimulating effect, which occurs in the cortex through locus ceruleus and is mediated by norepinephrine. At high doses, a dopaminergic reward effect predominates (184, 188). The reward and positive reinforcement effects of nicotine are responsible for the drug-seeking behavior in tobacco smokers. A common effect of many drugs of abuse, as well as natural rewards (e.g., food, sex), is the elevation of extracellular dopamine levels (189). The mesolim-

neurons in the midbrain are thought to be the final common pathway for reward, and the reward effect occurs as a result of the elevated dopamine level. Although there have been some recent challenges to the dopamine reward theory (190-193), it is still unequivocally agreed that dopamine plays a crucial role in the reward system and drug-seeking habit formation. An alternative view to the classical dopaminergic reward theory is that the dopaminergic-neuron activation functions as a learning signal (189,194), and that the neuroadaptive changes (up-regula-of the dopaminergic neurons with the chronic use of tobacco (or other drugs of abuse) might result in the generation of a deficit state that enhances drug craving and hence drug-seeking behavior (189). Other neurotransmitters such as norepinephrine and 5-HT have been implicated in the reward and positive reinforcement effects of nicotine.

Nicotine is an agonist to the neuronal nic-otinic acetylcholine receptors (nAChR). These receptors are the likely site at which nicotine exerts its central actions. Evidence supports the involvement of the central nAChR in neurotransmitter release (195), and a large body of evidence indicates that dopamine release from dopaminergic neurons is mediated by activation of the brain nAChRs (196). It has also been shown that both nicotinic receptors and muscarinic receptors in the ventral tegmental area (VTA) activate the dopaminergic neurons and thus play a role in the reward effect of nicotine (197). In addition, animal data sug gest an involvement of the 5-HT (2C) receptor in mediating the mesolimbic-dopaminergic system (198).

These positive reinforcement effects of nicotine include anxiolytic effect, antinocicep-tive/analgesic effects, enhanced vigilance, and improved cognitive function. Tolerance to many of these effects occurs rapidly, leading to substance dependence (199, 200). In animal studies, a single pretreatment with nicotine results in acute tolerance to the subsequent dose (201,202). The role of norepinephrine in the positive reinforcement effects of nicotine is not clear, but it has been suggested that nicotine's effects on concentration and attention are mediated by a noradrenergic mechanism (182). The noradrenergic system is also implicated in mediating the effects of nicotine withdrawal. 5-HT receptors in the dorsal raphe nucleus (DRN) are implicated in the anxiolytic effect of nicotine (203). Changes to these receptors mediate the development of tolerance to the anxiolytic effect and hence the anx-iogenic response during nicotine withdrawal (203).The antinociceptive/analgesic effect of nicotine is believed to be mediated by a cholin-ergic pathway through the neuronal nicotinic acetylcholine receptors (204, 205). 5-HT receptors are also implicated in the antinocicep-tive effect of nicotine, possibly through an interaction between the nicotinic and serotonergic systems (206). Acetylcholine is known to play a crucial role in nicotine's effects on the cognitive function. Peripheral Pharmacological Actions ofNicotine. Nicotine effects on the cardiovascular system include tachycardia and peripheral vasoconstriction, which leads to elevated blood pressure. Because the cardiovascular effects are mainly caused by elevated levels of catecholamines and cortisol, tolerance to these effects does not occur. Other pharmacological actions of nicotine include increased gastrointestinal motility caused by parasym-pathetic ganglionic stimulation and skeletal muscle contraction caused by the effect on nic-otinic receptors in the neuromuscular junction (184).

7.2.2 Bupropion Mechanism of Action. Bupropion is a monocyclic non-MAO inhibitor antidepressant with both dopaminergic and noradrenergic activities. It is a weak inhibitor of dopamine, norepinephrine, and serotonin but it has a greater effect on the neuronal reuptake of catecholamines than of serotonin. Some studies suggest that bupro-pion is entirely selective for catecholamines and is devoid of any serotonergic activity

(185). Bupropion's effectiveness as a smoking cessation agent is not related to its antidepressant effect. The drug is equally effective in smokers with current depression, past depression, or no depression (168). The mechanism by which bupropion enhances the ability for smoking cessation is believed to be related to its dopaminergic and noradrenergic activity

(186). In addition, it has been shown recently that bupropion is a potent inhibitor of central and that it blocks nicotine activation of these receptors in a dose-dependent non-competitive fashion (208). This suggests that the nicotinic antagonist effect contributes to bupropion mechanism of action in smoking cessation.

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