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.
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References
Benowitz NL, Jacob P (1984) Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther 35:499–504
Caillé S, Rodriguez–Arias M, Minarro J, Espejo EF, Cador M, Stinus L (2003) Changes in dopaminergic neurotransmission do not alter somatic or motivational opiate withdrawal-induced symptoms in rats. Behav Neurosci 117:995–1005
de Villiers SH, Lindblom N, Kalayanov G, Gordon S, Malmerfelt A, Johansson AM, Svensson TH (2002) Active immunization against nicotine suppresses nicotine-induced dopamine release in the rat nucleus accumbens shell. Respiration 69:247–253
de Villiers SH, Lindblom N, Kalayanov G, Gordon S, Johansson AM, Svensson TH (2004) Active immunization against nicotine alters the distribution of nicotine but not the metabolism to cotinine in the rat. Naunyn Schmiedebergs Arch Pharmacol 370:299–304
Epping–Jordan MP, Watkins SS, Koob GF, Markou A (1998) Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76–79
Geng Y, Savage SM, Johnson LJ, Seagrave J, Sopori ML (1995) Effects of nicotine on the immune response. I. Chronic exposure to nicotine impairs antigen receptor-mediated signal transduction in lymphocytes. Toxicol Appl Pharmacol 135:268–278
Glick SD, Weaver LM, Meibach RC (1980) Lateralization of reward in rats: differences in reinforcing thresholds. Science 207:1093–1095
Harrison AA, Liem YT, Markou A (2001) Fluoxetine combined with a serotonin–1A receptor antagonist reversed reward deficits observed during nicotine and amphetamine withdrawal in rats. Neuropsychopharmacology 25:55–71
Hieda Y, Keyler DE, Ennifar S, Fattom A, Pentel PR (2000) Vaccination against nicotine during continued nicotine administration in rats: immunogenicity of the vaccine and effects on nicotine distribution to brain. Int J Immunopharmacol 22:809–819
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) 129:348–356
Hildebrand BE, Panagis G, Svensson TH, Nomikos GG (1999) Behavioral and biochemical manifestations of mecamylamineprecipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area. Neuropsychopharmacology 21:560–574
Hughes JR, Gust SW, Skoog K, Keenan RM, Fenwick JW (1991) Symptoms of tobacco withdrawal. A replication and extension. Arch Gen Psychiatry 48:52–59
Isola R, Vogelsberg V, Wemlinger TA, Neff NH, Hadjiconstantinou M (1999) Nicotine abstinence in the mouse. Brain Res 850:189–196
Kenny PJ, Markou A (2001) Neurobiology of the nicotine withdrawal syndrome. Pharmacol Biochem Behav 70:531–549
Kornetsky C, Esposito, RU (1979) Euphorigenic drugs: effects on the reward pathways of the brain. Fed Proc 38:2473–2476
Lindblom N, de Villiers SH, Kalayanov G, Gordon S, Johansson AM, Svensson TH (2002) Active immunization against nicotine prevents reinstatement of nicotine-seeking behavior in rats. Respiration 69:254–260
Liu ZH, Jin WQ (2004) Decrease of ventral tegmental area dopamine neuronal activity in nicotine withdrawal rats. Neuroreport 15:1479–1481
Malin DH, Lake JR, Newlin–Maultsby P, Roberts LK, Lanier JG, Carter VA, Cunningham JS, Wilson OB (1992) Rodent model of nicotine abstinence syndrome. Pharmacol Biochem Behav 43:779–784
Malin DH, Lake JR, Lin A, Saldaña M, Balch L, Irvin ML, Chandrasekara H, Alvarado CL, Hieda Y, Keyler DE, Pentel PR, Ennifar S, Basham LE, Naso R, Fattom A (2001) Passive immunization against nicotine prevents nicotine alleviation of nicotine abstinence syndrome. Pharmacol Biochem Behav 68:87–92
Markou A, Frank RA (1987) The effect of operant and electrode placement on self-stimulation train duration response functions. Physiol Behav 41:303–308
Markou A, Koob GF (1992) Construct validity of a self-stimulation threshold paradigm: effects of reward and performance manipulations. Physiol Behav 51:111–119
Markou A, Koob GF (1993) Intracranial self-stimulation thresholds as a measure of reward. In: Sahgal A (ed) Behavioral Neuroscience, A Practical Approach. Oxford University Press, New York, pp 93–115
Markou A, Harrison AA, Chevrette J, Hoyer D (2005) Paroxetine combined with a 5–HT(1A) receptor antagonist reversed reward deficits observed during amphetamine withdrawal in rats. Psychopharmacology (Berl) 178:133–142
McAllister–Sistilli CG, Caggiula AR, Knopf S, Rose CA, Miller AL, Donny EC (1998) The effects of nicotine on the immune system. Psychoneuroendocrinology 23:175–187
Paterson NE, Myers C, Markou A (2000) Effects of repeated withdrawal from continuous amphetamine administration on brain reward function in rats. Psychopharmacology (Berl) 152:440–446
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic press, Sydney
Pellegrino LJ, Pellegrino AS, Cushman AJ (1979) A Stereotaxic Atlas of the Rat Brain. Plenum Press, New York
Pentel PR, Malin DH, Ennifar S, Hieda Y, Keyler DE, Lake JR, Milstein JR, Basham LE, Coy RT, Moon JW, Naso R, Fattom A (2000) A nicotine conjugate vaccine reduces nicotine distribution to brain and attenuates its behavioral and cardiovascular effects in rats. Pharmacol Biochem Behav 65:191–198
Rasmussen K, Czachura JF (1995) Nicotine withdrawal leads to increased firing rates of midbrain dopamine neurons. Neuroreport 7:329–332
Satoskar SD, Keyler DE, LeSage MG, Raphael DE, Ross CA, Pentel PR (2003) Tissue-dependent effects of immunization with a nicotine conjugate vaccine on the distribution of nicotine in rats. Int Immunopharmacol 3:957–970
Shiffman S (1982) Relapse following smoking cessation: a situational analysis. J Consult Clin Psychol 50:71–86
Shiffman SM, Jarvik ME (1976) Smoking withdrawal symptoms in two weeks of abstinence. Psychopharmacology (Berl) 50:35–39
Skjei KL, Markou A (2003) Effects of repeated withdrawal episodes, nicotine dose, and duration of nicotine exposure on the severity and duration of nicotine withdrawal in rats. Psychopharmacology (Berl) 168:280–292
Stellar J, Stellar E (1985) The neurobiology of motivation and reward. Springer, New York
Stinus L, Le Moal M, Koob GF (1990) Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal. Neuroscience 37:767–773
Watkins SS, Koob GF, Markou A (2000a) Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nicotine & Tobacco Research 2:19–37
Watkins SS, Stinus L, Koob GF, Markou A (2000b) Reward and somatic changes during precipitated nicotine withdrawal in rats: centrally and peripherally mediated effects. J Pharmacol Exp Ther 292:1053–1064
West R, Grunberg NE (1991) Implications of tobacco use as an addiction. Br J Addict 86:485–488
Acknowledgements
This work was supported by the Swedish Research Council grant no. 4747 to Torgny H. Svensson, the Tobacco–Related Disease Research Program (TRDRP) of the State of California 12RT–0231 grant to Athina Markou and Independent Pharmaceutica AB. We wish to thank Mrs. Ann–Chatrine Samuelsson, Mrs. Jessica Benedict and Mrs. Anna Malmerfelt for their excellent technical assistance during this study. This is publication #17553–NP of The Scripps Research Institute.
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Lindblom, N., de Villiers, S.H.L., Semenova, S. et al. 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. Naunyn Schmied Arch Pharmacol 372, 182–194 (2005). https://doi.org/10.1007/s00210-005-0019-0
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DOI: https://doi.org/10.1007/s00210-005-0019-0