title: Active immunisation against nicotine blocks the reward facilitating effects of nicotine and partially prevents nicotine withdrawal in the rat as measured by dopamine output in the nucleus accumbens, brain reward thresholds and somatic signs.
abstract: We recently showed that active immunisation with the nicotine immunoconjugate IP18-KLH reduces the nicotine-induced increase in dopamine (DA) output in the nucleus accumbens (NAC) and prevents reinstatement of nicotine-seeking behaviour in rats. These effects are mediated by altered distribution of nicotine, resulting in reduced amounts of nicotine reaching the brain, thereby interfering with the rewarding properties of the drug. The present study was designed to explore the effect of immunisation against nicotine on mecamylamine-precipitated nicotine withdrawal as assessed by the reduction in DA output in the NAC in rats. Measuring brain reward thresholds and somatic signs of nicotine withdrawal, the effects of immunisation were also tested during chronic nicotine treatment and after its withdrawal. Finally, we examined the effect of immunisation on challenge injections of nicotine on brain reward thresholds after the increases in somatic signs and reward thresholds associated with nicotine withdrawal had dissipated. The results show that immunisation with IP18-KLH prevented the decrease in DA output in the NAC associated with mecamylamine-precipitated nicotine withdrawal. Moreover, immunisation against nicotine did not precipitate a withdrawal syndrome, as measured by brain reward thresholds and somatic signs, in rats chronically exposed to nicotine. Furthermore, the withdrawal syndrome elicited after cessation of chronic nicotine administration was attenuated in immunised rats compared to that of mock-immunised rats. Finally, the lowering in reward thresholds after nicotine challenge injections was attenuated in both naïve and previously nicotine-exposed immunised rats. In conclusion, the present results show that immunisation with IP18-KLH did not precipitate nicotine withdrawal in rats. Thus, immunisation with IP18-KLH may not elicit nicotine withdrawal in smokers either. Furthermore, since the withdrawal syndrome in rats was attenuated by immunisation, the nicotine withdrawal in smokers should not be worsened but may even be ameliorated during a quit attempt.
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Nanna Svartz väg 2, 171 77, Stockholm, Sweden.
authors.forename: Nina
authors.initials: N
authors.lastname: Lindblom
authors.forename: Sabina H L
authors.initials: SH
authors.lastname: de Villiers
authors.forename: Svetlana
authors.initials: S
authors.lastname: Semenova
authors.forename: Genadiy
authors.initials: G
authors.lastname: Kalayanov
authors.forename: Sandra
authors.initials: S
authors.lastname: Gordon
authors.forename: Björn
authors.initials: B
authors.lastname: Schilström
authors.forename: Anette M
authors.initials: AM
authors.lastname: Johansson
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
authors.forename: Torgny H
authors.initials: TH
authors.lastname: Svensson
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism; D008297:Male; D008464:Mecamylamine / Q000627:therapeutic use*; D017551:Microdialysis; D009538:Nicotine / Q000097:blood / Q000633:toxicity*; D018733:Nicotinic Antagonists / Q000627:therapeutic use*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000276:immunology* / Q000517:prevention & control
chemical_list: D018733:Nicotinic Antagonists; D008464:Mecamylamine; D009538:Nicotine; D004298:Dopamine