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: 7.05). 11/1999; 21(4):560-74. DOI: 10.1016/S0893-133X(99)00055-X
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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.

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    • "Therefore, it may be predicted that molecular adaptations that reside in the VTA or other areas involved in nicotine reward are likely to play a prominent role in the emergence of a state of negative reward during withdrawal from chronic nicotine treatment and the development of nicotine dependence. Indeed, it has been shown that disruption of nAChR signaling in the VTA can precipitate withdrawal in nicotine-dependent rodents (Bruijnzeel and Markou 2004; Hildebrand et al. 1999; Liu and Jin 2004); however, see Salas et al. 2009). A major caveat to the interpretation that α5* nAChRs are not involved in reward-inhibiting effects of nicotine withdrawal is the fact that we precipitated withdrawal using mecamylamine, and the effects of spontaneous nicotine withdrawal on ICSS thresholds were not assessed. "
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    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; 229(3). DOI:10.1007/s00213-013-3235-1 · 3.88 Impact Factor
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    • "Accordingly, the VTA has been directly implicated in the reinforcing (Besson et al. 2006; David et al. 2006; Ikemoto et al. 2006; Laviolette and van der Kooy 2004; Maskos et al. 2005) and rewarding (Laviolette and van der Kooy 2003a) properties of nicotine. Long-term or repeated administration of nicotine (Belluardo et al. 2000; Brown and Kolb 2001; Pich et al. 1997; Shim et al. 2001; Visanji et al. 2006) and nicotine withdrawal (Gäddnäs et al. 2002; Hildebrand et al. 1999; Rada et al. 2001) also induce neuroadaptations within the reward system. After chronic exposure to nicotine, high affinity nicotinic receptors could remain in a desensitised state in animals (Benwell et al, 1995) and human smokers (Brody et al, 2006), which could account for tolerance to nicotine's effect on dopamine activity (Benwell et al, 1995). "
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    ABSTRACT: Nicotine is the main addictive component of tobacco and modifies brain function via its action on neuronal acetylcholine nicotinic receptors (nAChRs). The mesolimbic dopamine (DA) system, where neurons of the ventral tegmental area (VTA) project to the nucleus accumbens (ACb), is considered a core site for the processing of nicotine's reinforcing properties. However, the precise subtypes of nAChRs that mediate the rewarding properties of nicotine and that contribute to the development of addiction remain to be identified. We investigated the role of the nAChRs containing the α7 nicotinic subunit (α7 nAChRs) in the reinforcing properties of nicotine within the VTA and in the nicotine-induced changes in ACb DA outflow in vivo. We performed intra-VTA self-administration and microdialysis experiments in genetically modified mice lacking the α7 nicotinic subunit or after pharmacological blockade of α7 nAChRs in wild-type mice. We show that the reinforcing properties of nicotine within the VTA are lower in the absence or after pharmacological blockade of α7 nAChRs. We also report that nicotine-induced increases in ACb DA extracellular levels last longer in the absence of these receptors, suggesting that α7 nAChRs regulate the action of nicotine on DA levels over time. The present results reveal new insights for the role of α7 nAChRs in modulating the action of nicotine within the mesolimbic circuit. These receptors appear to potentiate the reinforcing action of nicotine administered into the VTA while regulating its action over time on DA outflow in the ACb.
    Psychopharmacology 09/2011; 220(1):1-14. DOI:10.1007/s00213-011-2422-1 · 3.88 Impact Factor
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    • "Further interrogation of galanin or GALR expression in whole brain, hippocampus, striatum, amygdala, and prefrontal cortex did not yield any significant correlations with nicotine withdrawal signs, suggesting region-specific effects of galanin and GALR expression on nicotine somatic withdrawal . Indeed, rats chronically infused with nicotine and subsequently administered mecamylamine site-specifically into the VTA, provide evidence that both the VTA and NAc have a role in nicotine withdrawal (Hildebrand et al, 1999). Higher basal GALR1 expression in the NAc was observed in strains with more severe nicotine withdrawal signs while lower galanin levels in VMB occurred in those strains. "
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    ABSTRACT: The neuropeptide galanin and its receptors are expressed in brain regions implicated in drug dependence. Indeed, several lines of evidence support a role for galanin in modulating the effects of drugs of abuse, including morphine, cocaine, amphetamine, and alcohol. Despite these findings, the role of galanin and its receptors in the effects of nicotine is largely underexplored. Here, using mouse models of nicotine reward and withdrawal, we show that there is a significant correlation between mecamylamine-precipitated nicotine withdrawal somatic signs and basal galanin or galanin receptor 1 (GALR1) expression in mesolimbocortical dopamine regions across the BXD battery of recombinant inbred mouse lines. The non-peptide galanin receptor agonist, galnon, also blocks nicotine rewarding effects and reverses mecamylamine-precipitated nicotine withdrawal signs in ICR mice. Additionally, we conducted a meta-analysis using smoking information from six European-American and African-American data sets. In support of our animal data, results from the association study show that variants in the GALR1 gene are associated with a protective effect in nicotine dependence (ND). Taken together, our data suggest that galanin has a protective role against progression to ND, and these effects may be mediated through GALR1.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2011; 36(11):2339-48. DOI:10.1038/npp.2011.123 · 7.05 Impact Factor
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