Institutionen för fysiologi och farmakologi / Department of Physiology and Pharmacology
Abstract
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