Article

Nicotine Withdrawal in Adolescent and Adult Rats

Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 07/2004; 1021(1):167-74. DOI: 10.1196/annals.1308.022
Source: PubMed

ABSTRACT

Previous research with animal models has demonstrated that adolescent rats display heightened sensitivity to the reinforcing and stimulant effects of nicotine relative to adult rats. Little work has focused on the response of adolescent rats to measures of nicotine withdrawal. To test the hypothesis that adolescent rats may be differentially sensitive to withdrawal relative to their adult counterparts, the present study was designed to compare precipitated withdrawal in adolescent and adult rats following chronic nicotine administration. Adult and adolescent rats were prepared with subcutaneous osmotic minipumps that delivered either saline or nicotine (9 mg/kg per day, salt; N =12 per group). All rats were challenged with the nicotinic receptor antagonist mecamylamine (1.5 mg/kg) on day 7 of chronic nicotine treatment. Twenty minutes after the injection, overt somatic signs of withdrawal (i.e., eye blinks, writhes, body shakes, teeth chatter, gasps, and ptosis) were recorded for 10 min. Adult rats were observed on postnatal day 73-77, and adolescent rats were tested on postnatal day 36-40. The results revealed a robust increase in mecamylamine-induced withdrawal signs in adult rats receiving chronic nicotine relative to adult rats receiving saline. In contrast, mecamylamine did not precipitate withdrawal signs in adolescent rats receiving chronic nicotine. These results indicate that there is decreased sensitivity to the somatic aspects of nicotine withdrawal in adolescent rats that may maximize the reinforcing effects of nicotine during adolescence by minimizing the aversive effects of abstinence.

Full-text

Available from: Athina Markou, May 21, 2015
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In: R.E. Dahl and L.P. Spear (Eds.), Adolescent Brain Development:
Vulnerabilities and Opportunities (series title: Annals of the New York
Academy of Sciences, vol. 1021), New York Academy of Sciences,
New York, 2004, pp. 167-174.
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Page 8
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    • "All changes observed in the NIC offspring in the NAc at the end of nicotine exposure (PN15) were reverted after a 5-day withdrawal period , at PN21 Usually, a rebound effect is expected after withdrawal (Porrino et al., 1983; Ekblom et al., 1993; Teixeira, 2009). These results could be explained, in part, by a lower sensitivity to nicotine withdrawal symptoms in young rats (O'Dell et al., 2004, 2007). At weaning, NIC offspring presented lower DAT content in the DS, which may indicate greater dopaminergic action in this region. "
    [Show abstract] [Hide abstract] ABSTRACT: Nicotine exposure causes the release of dopamine from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). We have previously shown that maternal exposure to nicotine during lactation causes hyperleptinemia in dams and pups, and leptin is known to decrease dopamine release from the VTA. Here we evaluated whether maternal exposure to nicotine during lactation causes changes in dopamine and leptin signaling pathways at the end of exposure and after 5days of withdrawal in the: VTA, NAc, arcuate nucleus (ARC) and dorsal striatum (DS). On postnatal day (PN) 2, lactating Wistar rats were implanted with minipumps releasing nicotine (NIC; 6mg/Kg/day, s.c.) or saline (C) for 14days. Offspring were tested in the elevated plus maze (EPM) and open field on PN14 or PN20, and euthanized on PN15 or PN21. Entries into the open arms and head dips in the EPM were reduced in NIC pups at P20. At weaning (PN21), NIC dams had: lower tyrosine hydroxylase (TH), higher OBRb and SOCS3 contents in VTA; lower TH, higher D1R, D2R and DAT contents in NAc; higher TH content in DS; and higher D2R and SOCS3 contents in ARC. On PN15, NIC offspring had higher D1R, D2R and lower DAT contents in NAc, while on PN21, they had lower DAT in DS, and lower pSTAT3 content in ARC. We evidenced that postnatal nicotine exposure induces relevant changes in the brain reward system of dams and pups, possibly associated with changes in leptinemia and increased offspring anxiety-like behavior. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · Pharmacology Biochemistry and Behavior
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    • "Comparing nicotine effects in adolescents vs. adults tested whether cognitive or receptor modulation could depend on adolescent neurodevelopmental changes implicated in schizophrenia , addiction, or the NVHL model (Chambers et al. 2003; Weinberger 1987). The effects of nicotine history on learning did differ somewhat by age in terms of a three-way interaction between block, age, and nicotine on ETR, suggesting nicotine withdrawal has different effects in adolescents (O'Dell et al. 2004). However, this effect was subtle as it was not observed as a two-way interaction of age and nicotine in either ETR or session time. "
    [Show abstract] [Hide abstract] ABSTRACT: Rational: Nicotine use in schizophrenia has traditionally been explained as ‘self-medication’ of cognitive and/or nicotinic acetylcholinergic receptor (nAChR) abnormalities. Objectives: We test this hypothesis in a neurodevelopmental rat model of schizophrenia that shows increased addiction behaviors including enhanced nicotine reinforcement and drug-seeking. Methods: Nicotine transdermal patch (5 mg/kg/day vs. placebo x 10 days in adolescence or adulthood) effects on subsequent radial-arm maze learning (15 sessions) and frontal-cortical-striatal nAChR densities (α4β2; [3H]-epibatidine binding) were examined in neonatal ventral hippocampal lesion (NVHL) and SHAM-operated rats. Results: NVHL cognitive deficits were not differentially affected by nicotine history compared to SHAMs. Nicotine history produced minimal cognitive effects while increasing food–reward consumption on the maze, compounding with NVHL-induced overconsumption. Acute nicotine (0.5 mg/kg) delivered before the final maze sessions produced modest improvements in maze performance in rats with nicotine patch histories only, but not differentially so in NVHLs. Consistent with in vivo neuroimaging of β2 nAChR binding in schizophrenia smokers vs. non-smokers and healthy controls, adult NVHLs showed 12% reductions in nAChR binding in MPFC (p<0.05) but not ventral striatum (<5% changes, p>.40), whereas nicotine history elevated nAChRs across both regions (>30%, p<0.001) without interacting with NVHLs. Adolescent vs. adult nicotine exposure did not alter nAChRs differentially. Conclusions: Although replicating nicotine-induced up-regulation of nAChRs in human smokers and demonstrating NVHL validity in terms of schizophrenia-associated nAChR density patterns, these findings do not support hypotheses explaining increased nicotine use in schizophrenia as reflecting illness specific effects of nicotine to therapeutically alter cognition or nAChR densities.
    Full-text · Article · Apr 2015 · Psychopharmacology
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    • "In addition to its reinforcing effects, the persistence of nicotine self-administration by humans is thought to be due, at least in part, to the occurrence of a withdrawal syndrome upon cessation (for reviews see; Benowitz, 2010; Henningfield et al., 1998; Hughes et al., 1994). This phenomenon has been measured in rodents using somatic signs (e.g., writhes, gasps, shakes, and tremor; Kota et al., 2007; Malin et al., 1992; O&apos;Dell et al., 2004), increased thresholds for intracranial selfstimulation (Epping-Jordan et al., 1998), and with the disruption of food-reinforced responding (Corrigall et al., 1989; LeSage et al., 2006; Rosecrans et al., 1989; Vann et al., 2006). In the present study nicotine was capable of restoring foodmaintained responding during spontaneous and precipitated nicotine withdrawal. "
    [Show abstract] [Hide abstract] ABSTRACT: Tobacco use is associated with lethal diseases in an estimated 440,000 persons in the United States each year (Centers for Disease Control and Prevention, 2005). Successful smoking quit-rates are estimated at 5%-8%, even though a quarter of those attempts included use of smoking-cessation aids (Messer et al., 2008; Henningfield et al., 2009). Current projections are that 16% of the U.S. population-35 million people-will still smoke in 2025, thus more effective smoking-cessation aids are urgently needed (Pollock et al., 2009). The minor tobacco alkaloids may be promising candidates, but further research is necessary (Hoffman & Evans, 2013). Accordingly, we systematically evaluated the minor tobacco alkaloids nornicotine, anabasine, and anatabine using assays of behavioral tolerability, nicotine withdrawal, nicotine discrimination, and nicotine self-administration in male rodents. At doses that were well tolerated, all 3 minor alkaloids dose-dependently engendered robust substitution for a nicotine discriminative stimulus in mice (0.32 mg/kg, IP), and anabasine attenuated nicotine withdrawal. When the ED50 dose of each alkaloid was administered in combination with nicotine, the discriminative stimulus effects of nicotine were not enhanced by any of the alkaloids, and anatabine blunted nicotine's effects. In drug self-administration studies, only nornicotine was self-administered by rats that self-administered nicotine intravenously; anabasine and anatabine had no reinforcing effects. Moreover, prior administration of each of the minor tobacco alkaloids dose-dependently decreased nicotine self-administration. Collectively these results suggest that the minor tobacco alkaloids may substitute for the subjective effects of nicotine and attenuate withdrawal and craving without the abuse liability of nicotine. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Full-text · Article · Feb 2014 · Experimental and Clinical Psychopharmacology
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