Nicotine withdrawal

Nicotine Delivery Systems. For all transdermal nicotine products, the hypothesis is that continuous deflvery of nicotine [34-11-3] ne t trough levels during smoking should alleviate physical nicotine withdrawal symptoms and allow the smoker to concentrate on eliminating the behavioral aspects of addiction. 

Cionidine. Clonidine dampens sympathetic activity originating at the locus coeruleus by stimulation of presynaptic a2-adrenergic receptors in the sympathetic chain (Covey and Classman 1991 Hughes 1994). It appears to have some efficacy for alcohol and opioid withdrawal and thus was evaluated for treatment of nicotine withdrawal as well (Covey and Classman 1991 Hughes 1994). Several clinical trials used oral or transdermal clonidine in doses of 0.1—0.4 mg/day for 2—6 weeks with or without behavior therapy. Three meta-analytic reviews reported that clonidine improved quit rates (Covey and Classman 1991 Courlay and Benowitz 1995 Law and Tang 1995). 

Epping-Jordan, M.P., Watkins, S.S., Koob, G.F., Markou, A. Dramatic decreases in brain reward function during nicotine withdrawal. Nature. 393 76, 1998. 

Markou, A., Paterson, N.E. The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat. Nicotine Tob. Res. 3 361, 2001. 

Cohen, C., Perrault, G., Griebel, G., Soubrie, P. Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology. 30 145, 2005. 

Boyadjieva, N.I.S.D. The secretory response of hypothalamic beta-endorphin neurons to acute and chronic nicotine treatments and following nicotine withdrawal. Life Sci. 61 PL59, 1997. 

Rasmussen, K.C.J. Nicotine withdrawal leads to increased sensitivity of serotonergic neurons to the 5-HT1A agonist 8-OH-DPAT. Psychopharmacology. 133 343, 1997. 

Since nicotine has wide ranging effects on the central nervous system it seems likely that pharmacogenomic effects on the development of nicotine dependence will span several neurotransmitter systems. One study found an association between a polymorphism in dopamine /1-hydroxylase and level of tobacco consumption [20]. This enzyme is important in noradrenaline synthesis and it is tempting to speculate that genetically regulated variations in activity might influence susceptibility to nicotine withdrawal symptoms mediated by noradrenergic pathways, but more information is required on the molecular effects of the polymorphism. 

Dissection of the molecular mechanisms underlying tobacco addiction should lead to new and better treatments to achieve nicotine withdrawal. It seems clear that the dopamine D2 receptor is involved in nicotine dependence and drugs that block this receptor, such as tiapride, could be useful in the treatment of tobacco dependence. Tiapride has been shown to be successful in alcohol withdrawal [58] but would represent a new avenue for tobacco addiction therapy. 

Similarly opioid peptides are important in nicotine addiction and may have a role in causing nicotine withdrawal symptoms in some smokers [35]. Opioid antagonists such as naltrexone are licensed treatments for dependence syndromes arising from other addictive drugs and could also be of use in some smokers to aid nicotine withdrawal [59] although there is no definitive evidence overall that they are beneficial [60]. 

Alternative pharmacological approaches Clonidine, an o2 adrenergic agonist, has been employed as adjunctive therapy to assist in smoking cessation. However, results have been mixed or the effects small (Gourlay et al. 1994 Hilleman et al. 1993 Franks et al. 1989). Buspirone (BuSpar) is a 5-HTlA partial agonist with anxiolytic effects. It has been tested as a treatment for smoking cessation because anxiety is a prominent feature of nicotine withdrawal (Farid and Abate 1998). To date, results have been mixed and more controlled research is needed. 

Shiftman S, Paty JA, Gnys M, Kassel JD, Elash C. (1995). Nicotine withdrawal in chippers and regular smokers subjective and cognitive effects. Health Psychol. 14(4) 301-9. 

Hildebrand BE, Nomikos GG, Hertel P, SchEstrom B, Svensson TH. 1998. Reduced dopamine output in the nucleus accumbens but not in the medial prefrontal cortex in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome. Brain Res 779(1—2) 214-225. 

Panagis G, Hildebrand BE, Svensson TH, Nomikos GG. 2000. Selective c-fos induction and decreased dopamine release in the central nucleus of amygdala in rats displaying a meca-mylamine-precipitated nicotine withdrawal syndrome. 

The methods discussed above have been widely used to assess the effect of either continuous or intermittent nicotine on nAChR functions and brain biochemistry (Matta et al. 2007). For models of nicotine withdrawal, see the chapter by Malin in this volume. Given the intrinsic advantages and limitations of each approach, the non-contingent nature of most administration regimes and the absence of associated cues, it is important that these paradigms are not assumed to model tobacco addiction per se. Sometimes, the experiments are conducted in concert with behavioural measures (e.g. precipitation of withdrawal with somatic signs), which give more credibility to the assertion that a state of nicotine dependence has been achieved (Kenny and Markou 2005). 

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