Nicotine has an agonistic action at the nicotinic receptor sites in the cholinergic nervous system. It binds with these receptors in a similar manner as acetylcholine (ACh), predominantly at the midbrain level, and influences various reflexes by excitation of chemoreceptors in the carotid body.

The effects of nicotine are described in terms of a sense of alertness, relaxation, pleasure, increased concentration, and stimulation of the autonomic nervous system.

Prolonged use of nicotine causes a significant increase in the number of nicotinic receptors, and in the accumulation of ACh by enzymatic induction and/or repression of choline acetyltransferase (CAT) and acetylcholinesterase (AChE). The overall result is biochemical tolerance, and physiological and psychological dependence.

During nicotine abstinence in chronic smokers, the biochemical interpretation of withdrawal is through the elimination of the nicotine blockade at nicotinic sites. Withdrawal symptoms result from excessive ACh intersynaptic stimulation of predominately muscarinic receptors in the Nucleus Accumbens and Ventral Tegmental Area. The responses may result in excitation or inhibition, and the clinical symptoms can include decreased heart rate and blood pressure, gastrointestinal disturbances, fatigue, nausea, headache, and electroencephalogram changes, along with increased irritability, nervousness, and decreased concentration.

Injections of scopolamine and atropine provide effective levels of anticholinergic activity to block the attachment of ACh to these receptors, thereby reducing and eliminating physical nicotine withdrawal symptoms during their most pronounced period - the first 24 to 48 hours of abstinence.

Although nicotine is eliminated from the body by urination in approximately three days, the normalization of ACh concentrations to non-smoker status can take up to two weeks. Consequently, oral and transdermal anticholinergic treatment is prescribed during this two week period to maintain lower, yet therapeutically effective, levels while withdrawal symptoms subside.

Treatment is supported by an interactive program of self-help behavioral changes to maintain nicotine abstinence permanently.

Research on the efficacy of different smoking cessation programs with no follow-up behavioral modification assistance indicates the following results immediately following treatment regimen and after treatment:

The authors of some of the above studies noted that 12-month results demonstrated the need for follow-up emotional support, after initial success of smoking cessation, to reduce recidivism. The challenge for motivated smokers to remain smoke-free is to continue to pursue the available support groups to which they are referred in order to modify the emotional side of their smoking behavior.

REFERENCES:

1. Principles of Medicinal Chemistry, Foye, W.O., et. al. Williams & Wilkins. 4th Edition, 1995.
2. The RBI Handbook of Receptor Classification and Signal Transduction, K.J Waitling. RBI. 3rd Edition, 1998
3. The Pharmacological Basis of Therapeutics, Goodman and Gilman. Macmillan, 10th Edition, 2001.
4. Studies on the Time Course and the Effect of Cholinergic and Adrenergic Receptor Blockers on the Stimulus Effect of Nicotine, Hirschhorn, I.D., Psychopharmocologia 40; 109-120, 1974.
5. The Effect of Chronic Nicotine and Withdrawal on Intra-Neuronal Dynamics of Acetylcholine and Related Enzymes in a Preganglionic Neuron System of the Rat, Dahlstrom, A. Acta Physio Scand 110; 13-20, 1980.
6. Inhibition by Drugs of Smoking Behavior in Monkeys, Glick, S.D., et. al. Nature 227; 967-971, 1970.
7. Non-nicotine Neuropharmacological Strategies for Nicotine Dependence: Beyond Bupropion, Cryan, J.F. Drug Discovery Today 8 (22); 1025-1034, 2003.
8. The Use of Anticholinergic Drugs for Smoking Cessation: A Pilot Study, Bachynski, N. The International Journal of The Addictions, 21 (7), 789-805, 1986.
9. Nicotinic Acetylcholine Receptors as Targets for Antidepressants, Shytle, R.D. Molecular Psychiatry 7 (6); 525-535, 2002.
10. Disruption of Nicotine Conditioning by Dopamine D(3) Receptor Ligands, Le Foll, B. Molecular Psychiatry 8 (2), 225 – 230, 2003.
11. Antidepressants for Smoking Cessation, Hughes, J.R. Cochrane Database System Review 1; CD000031, 2002.
12. Both Nicotinic and Muscarinic Receptors in Ventral Tegmental Area Contribute to Brain-Stimulation Reward, Yeomans, J. Pharmacological Biochemistry Behavior 57 (4); 915-921, 1997.
13. Atropine Pretreatment Interferes with The Development of Tolerance to The Depressant Effect of Nicotine, Ebenezer, I.S. IRCS Medical Science Biochemistry 11 95); 474-475, 1983.
14. Atropine Pretreatment Reverses the Initial Depressant Effect of Nicotine on The Spontaneous Activity of Naïve Rats, Ebenezer, I.S. IRCS Medical Science Biochemistry 11 (5); 472-473, 1983.
15. A Controlled Trial of Sustained-Release Bupropion, a Nicotine Patch, or Both for Smoking Cessation, Jorenby, D. E. The New England Journal of Medicine 340 (9); 685-691, 1999.
16. A Prospective, Randomized, Double-Blind Study Comparing Nortriptyline to Placebo, da Costa, C.L. Chest 122 (2); 403-408, 2002.
17. Psychological Intervention and Antidepressant Treatment in Smoking Cessation, Hall, S.M. Archive of General Psychiatry 59; 930-936, 2002.