Neurobiological basis of the nicotine withdrawal reaction : an experimental analysis

The mesolimbocortical dopamine (DA) system is pivotal for the mediation of the reinforcing effects of many dependence-producing drugs. It consists of cell bodies in the ventral tegmental area (VTA) that project to e.g. the nucleus accumbens (NAC), the central nucleus of amygdala (CNA) and the medial prefrontal cortex. In experimental animals, nicotine increases DA output in the NAC, exerts a locomotor stimulatory effect and is readily self-administered. These effects of systemic nicotine appear largely mediated via nicotinic receptors (nAChRs) in the VTA. Moreover, recently the a7 nAChR subtype has been implicated in some of the acute effects of nicotine.

The effects of nicotine withdrawal on behavior and mesolimbocortical dopaminergic neurotransmission in rats have remained largely unknown. Therefore, utilizing behavioral methods, in vivo microdialysis, intracerebral drug injections and immunohistochemistry, we explored in detail the effects of nicotine withdrawal on these parameters. Rats were, by means of subcutaneously implanted minipumps, treated chronically with a dose of nicotine that yielded plasma levels similar to those encountered in heavy smokers.

A somatic nicotine abstinence reaction was induced through removal of the infusion pump or through administration of a nAChR antagonist, acting either centrally and peripherally or peripherally only. Administration of nicotine or of a peripherally acting nAChR agonist both reversed the withdrawal reaction. Systemic administration of the nAChR antagonist mecamylamine significantly reduced DA output in the NAC selectively in the nicotine-treated group. The somatic withdrawal signs and the reduction in NAC DA appeared not to be specifically or causally related. Also, intrategmental injection of mecamylamine elicited a reduction in accumbal DA output, somatic withdrawal signs as well as hypolocomotion, whereas intraaccumbal administration of mecamylamine failed to elicit any changes in NAC DA output or in somatic signs. Similarly, intrategmental application of an a7 nAChR antagonist resulted in a decreased NAC DA output and a reduction in locomotor activity. Finally, nicotine withdrawal precipitated by a systemic injection of mecamylamine both attenuated DA output and activated c-fos in the CNA.

These results demonstrate a significant contribution of peripheral nAChRs to the nicotine withdrawal reaction and predict that drugs stimulating selectively peripheral nAChRs may have some usefulness in smoking cessation. The withdrawal-induced reduction in NAC DA, if it occurs also in man, may have bearing on clinical symptoms such as depression and dysphoria that are often encountered in association with smoking cessation. In addition, the clinical efficacy of bupropion in smoking cessation programmes may largely be due to its ability to restore a compromised mesolimbic DA function. Specifically, nAChRs at the level of the VTA rather than in the NAC seem to contribute to the behavioral and biochemical consequences of nicotine withdrawal precipitated with systemic mecamylamine, and a role for a7 nAChRs within the VTA is indicated in this regard. The withdrawal-induced selective activation of c-fos in the CNA may have bearing on anxiety and distress, symptoms that in animals can be elicited from this brain region and frequently occur in nicotine abstinent humans.

List of scientific papers

I. Hildebrand BE, Nomikos GG, Bondjers C, Nisell M, Svensson TH (1997). Behavioral manifestations of the nicotine abstinence syndrome in the rat: peripheral versus central mechanisms. Psychopharmacology (Berl). 129(4): 348-356.
https://pubmed.ncbi.nlm.nih.gov/97239743

II. Hildebrand BE, Nomikos GG, Hertel P, Schilström 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.
https://pubmed.ncbi.nlm.nih.gov/98140952

III. Hildebrand BE, Panagis G, Svensson TH, Nomikos GG (1999). Behavioral and biochemical manifestations of mecamylamine-precipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area. Neuropsychopharmacology. 21(4): 560-574.
https://pubmed.ncbi.nlm.nih.gov/99411454

IV. Nomikos GG, Hildebrand BE, Panagis G, Svensson TH (1999). Nicotine withdrawal in the rat: role of alpha7 nicotinic receptors in the ventral tegmental area. Neuroreport. 10(4): 697-702.
https://pubmed.ncbi.nlm.nih.gov/99223232

V. Hildebrand BE, Svensson TH (1999). Intraaccumbal mecamylamine infusion does not affect dopamine output in the nucleus accumbens of chronically nicotine-treated rats. [Submitted]

VI. 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 mecamylamine-precipitated nicotine withdrawal syndrome. Synapse. 35(1): 15-25.
https://pubmed.ncbi.nlm.nih.gov/20047126