Behavioral and biochemical manifestations of mecamylamine-precipitated nicotine withdrawal in the rat: Role of nicotinic receptors in the ventral tegmental area

Eli Lilly, Indianapolis, Indiana, United States
Neuropsychopharmacology (Impact Factor: 7.83). 11/1999; 21(4):560-74. DOI: 10.1016/S0893-133X(99)00055-X
Source: PubMed

ABSTRACT Brain mesolimbic dopamine (DA) neurons are considered critical for the dependence-producing action of nicotine, and its stimulatory effect on behavior and DA neurotransmission appears largely mediated via nicotinic receptors (nAChRs) in the ventral tegmental area (VTA). The nAChR antagonist mecamylamine administered systemically in chronically nicotine-treated rats elicits a behavioral withdrawal syndrome concomitant with a reduced DA output in the nucleus accumbens (NAC). Here, we investigated the behavioral and biochemical consequences of intrategmental administration of mecamylamine in rats chronically infused with nicotine by means of minipumps for 14 days (9 mg/kg/day). Bilateral, intrategmental mecamylamine injections (1, 3 or 9 micrograms/0.5 microliter/side) dose-dependently increased abstinence signs such as gasps, teeth chatter, and reduced locomotor activity in nicotine-treated, but not in control animals. Moreover, a unilateral intrategmental injection of 9 micrograms mecamylamine reduced DA output in the ipsilateral NAC of chronically nicotine-treated rats, but not in control animals. Consequently, nAChRs in the VTA may be involved not only in the stimulatory effects of acute nicotine administration, but also in the withdrawal reaction following cessation of chronic nicotine treatment.


Available from: George Panagis, May 30, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene, CHRNA5, increases vulnerability to tobacco addiction. Here, we investigated the role of α5* nAChRs in the effects of nicotine on brain reward systems. Effects of acute (0.03125-0.5 mg/kg SC) or chronic (24 mg/kg per day; osmotic minipump) nicotine and mecamylamine-precipitated withdrawal on intracranial self-stimulation (ICSS) thresholds were assessed in wild-type and α5 nAChR subunit knockout mice. Noxious effects of nicotine were further investigated using a conditioned taste aversion procedure. Lower nicotine doses (0.03125-0.125 mg/kg) decreased ICSS thresholds in wild-type and α5 knockout mice. At higher doses (0.25-0.5 mg/kg), threshold-lowering effects of nicotine were diminished in wild-type mice, whereas nicotine lowered thresholds across all doses tested in α5 knockout mice. Nicotine (1.5 mg/kg) conditioned a taste aversion to saccharine equally in both genotypes. Mecamylamine (5 mg/kg) elevated ICSS thresholds by a similar magnitude in wild-type and α5 knockout mice prepared with minipumps delivering nicotine. Unexpectedly, mecamylamine also elevated thresholds in saline-treated α5 knockout mice. α5* nAChRs are not involved in reward-enhancing effects of lower nicotine doses, the reward-inhibiting effects of nicotine withdrawal, or the general noxious effects of higher nicotine doses. Instead, α5* nAChRs regulate the reward-inhibiting effects nicotine doses that oppose the reward-facilitating effects of the drug. These data suggest that disruption of α5* nAChR signaling greatly expands the range of nicotine doses that facilitate brain reward activity, which may help explain the increased tobacco addiction vulnerability associated with CHRNA5 risk alleles.
    Psychopharmacology 08/2013; DOI:10.1007/s00213-013-3235-1 · 3.99 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Diseases associated with tobacco use constitute a major health problem worldwide. Upon cessation of tobacco use, an unpleasant withdrawal syndrome occurs in dependent individuals. Avoidance of the negative state produced by nicotine withdrawal represents a motivational component that promotes continued tobacco use and relapse after smoking cessation. With the modest success rate of currently available smoking cessation therapies, understanding mechanisms involved in the nicotine withdrawal syndrome are crucial for developing successful treatments. Animal models provide a useful tool for examining neuroadaptative mechanisms and factors influencing nicotine withdrawal, including sex, age, and genetic factors. Such research has also identified an important role for nicotinic receptor subtypes in different aspects of the nicotine withdrawal syndrome (e.g., physical vs. affective signs). In addition to nicotinic receptors, the opioid and endocannabinoid systems, various signal transduction pathways, neurotransmitters, and neuropeptides have been implicated in the nicotine withdrawal syndrome. Animal studies have informed human studies of genetic variants and potential targets for smoking cessation therapies. Overall, the available literature indicates that the nicotine withdrawal syndrome is complex, and involves a range of neurobiological mechanisms. As research in nicotine withdrawal progresses, new pharmacological options for smokers attempting to quit can be identified, and treatments with fewer side effects that are better tailored to the unique characteristics of patients may become available. Copyright © 2014. Published by Elsevier Ltd.
    Neuropharmacology 11/2014; DOI:10.1016/j.neuropharm.2014.11.009 · 4.82 Impact Factor