Cigarette smoking is the single largest cause of preventable death and disease. Each year ~50% of smokers attempt to quit, but less than 5% are successful, despite using pharmacotherapy. Immunotherapy is being explored as a new approach to smoking cessation; several anti-nicotine vaccines are being developed, which reduce nicotine reinforcement. Anti-nicotine antibodies bind nicotine, preventing it from entering the brain and acting on nicotinic acetylcholine receptors (nAChRs). However, this approach also renders nicotine replacement therapy (NRT) ineffective. Cotinine, the major metabolite of nicotine, is a weak agonist at nAChRs, inducing striatal dopamine release; there is also evidence that it antagonises nicotine's actions. An anti-cotinine vaccine would reduce such antagonism by preventing cotinine from passing the blood-brain-barrier, and sequestering it in the bloodstream. This should enhance the efficacy of NRT and assist with a reduce-to-quit approach to smoking cessation. Here we characterise the immune response to anti-cotinine vaccination and study the impact of vaccination on measures of nicotine dependence. Anti-cotinine vaccination was found to be safe and immunogenic, with regular booster injections required to maintain antibody levels. Antibodies raised were specific for cotinine, retaining it in the blood. Upregulation of nAChRs by chronic nicotine administration was not increased after vaccination, and no effects on conditioned taste aversion were observed. However, increases in locomotor activity induced by repeated nicotine administration occurred earlier and were more pronounced in vaccinated rats. And in a model of nicotine withdrawal, abstinence scores were increased in vaccinated rats, due to the removal of cotinine-mediated antagonism of nicotine's actions. Antibody levels measured here were not as high as titres in studies of antinicotine vaccines; however, in view of the effects observed with comparatively low titres, vaccination against cotinine could offer a new approach to smoking cessation, provided higher titres of cotinine-specific antibodies can be achieved.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:441521 |
| Date | January 2007 |
| Creators | Oliver, Jennifer Lynne |
| Publisher | University of Bath |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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