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.

Effects of the Nanoparticle-Based Vaccine, SEL-068, on Nicotine Discrimination in Squirrel Monkeys

“…The present results with SEL-068 are consistent with previous findings showing that earlier nicotine-targeting vaccines can effectively: (a) attenuate nicotine's discriminative-stimulus and reinforcing properties; (b) lessen nicotine's withdrawal effects; and (c) influence nicotine's pharmacokinetic properties (eg, Carrera et al, 2004;Lindblom et al, 2002;2005;LeSage et al, 2006;Raupach et al, 2012;Pentel and LeSage, 2014). However, such promising preclinical evidence has not yet led to the introduction of immunotherapy that can effectively reduce human tobacco consumption, maintain or enhance long-term smoking cessation, or prevent relapse.…”

“…However, the development of an effective vaccine against nicotine has been challenging. Several different formulations of first-generation nicotine-targeting vaccines-entailing protein conjugate immunogens linked to nicotine or conjugated to a carrier protein and mixed with an adjuvant-have failed in clinical trials, despite preclinical data showing that they can: (a) alter nicotine's pharmacokinetic properties; (b) interfere with nicotine's abuse-related neurochemical and behavioral actions; and (c) lessen nicotine withdrawal symptoms (Carrera et al, 2004;Lindblom et al, 2002Lindblom et al, , 2005de Villiers et al, 2002;LeSage et al, 2006;Hartmann-Boyce et al, 2012;Raupach et al, 2012;Pentel and LeSage, 2014). Yet, only modest increases in quit rates have been observed in smokers with high levels of antinicotine antibodies (eg, Hartmann-Boyce et al, 2012).…”

Rodent Models of Nicotine Withdrawal Syndrome

“…During withdrawal from continuous nicotine infusion, rats displayed reduced activity levels and reduced DA content in the striatum and NAcc as well as reduced D2 DA receptors in the NAcc (Fung et al 1996). A particularly consistent finding is lowered DA output in the NAcc during nicotine withdrawal in rodent models, with a time course roughly consistent with various behavioral withdrawal signs (Carboni et al 2000;Hildebrand et al 1998;Lindblom et al 2005;Rada et al 2001;Rahman et al 2004). This decreased release is likely due to alterations at the origin of the mesolimbic DA pathway in the VTA, since mecamylamine injected directly into the VTA, but not the NAcc, of nicotine-dependent rats triggered both withdrawal signs and reduced NAcc DA output .…”

“…This suggests that an immunized smoker undergoing the discomforts of smoking cessation might not be able to find relief through renewed smoking, thus removing one cause of early relapse. Surprisingly, Lindblom et al (2005) found that actively immunized rats experienced a milder nicotine withdrawal syndrome, in terms of somatically expressed signs and alterations of dopamine release in the nucleus accumbens. One possible explanation for this is that nicotine antibodies cause a more gradual elimination of nicotine from the body (Keyler et al 1999).…”

The Natural History and Diagnosis of Nicotine Addiction

“…Evidence that the compulsion to use tobacco is a physiological phenomenon include its predictable periodicity, and changes in brain neurotransmitters, electroencephalogram patterns, and physiologic measures that can accompany nicotine withdrawal [87][88][89][90][91].…”