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Effects of ceftriaxone on conditioned nicotine reward in rats.

ABSTRACT: Nicotine is the addictive compound in tobacco products which exerts psychosomatic effects that contribute to abuse and to low rates of abstinence in treatment-seeking smokers. At present, the most successful smoking cessation aide helps one in four individuals quit smoking at 1 year postcessation. New adjunctive therapies are needed to improve status of smoking-related public health crises, and ?-lactam antibiotics are one class of potential therapies as they favorably augment extrasynaptic glutamate clearance. Our study used two-chamber place conditioning to assess effects of ceftriaxone (CTX) on persistence of conditioned nicotine reward. Rats were conditioned to associate nicotine (0.4?mg/kg, subcutaneous) with one context and vehicle with an alternative context. After initial post-test, rats received either daily ceftriaxone (200?mg/kg, intraperitoneal) or saline. All rats showed nicotine place preference during post-test 1. CTX-treated rats meeting extinction criterion by post-test 7 showed significantly reduced preference for the nicotine-paired context during post-test 2 compared with vehicle-treated rats. We interpret these data to support the further study of CTX as a smoking cessation aide. Our results suggest that CTX reduces persistence of conditioned nicotine reward and may be helpful for improving abstinence rates in a subset of treatment-seeking smokers.

SUBMITTER: Philogene-Khalid HL

PROVIDER: S-EPMC5538934 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Effects of ceftriaxone on conditioned nicotine reward in rats.

Philogene-Khalid Helene L HL Simmons Steven J SJ Muschamp John W JW Rawls Scott M SM

Behavioural pharmacology 20170901 6

Nicotine is the addictive compound in tobacco products which exerts psychosomatic effects that contribute to abuse and to low rates of abstinence in treatment-seeking smokers. At present, the most successful smoking cessation aide helps one in four individuals quit smoking at 1 year postcessation. New adjunctive therapies are needed to improve status of smoking-related public health crises, and β-lactam antibiotics are one class of potential therapies as they favorably augment extrasynaptic glut ...[more]

PMID: 28704277

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Project description:Reward-related disturbances after withdrawal from nicotine are hypothesized to contribute to relapse to tobacco smoking but mechanisms underlying and linking such processes remain largely unknown.To determine whether withdrawal from nicotine affects reward responsiveness (ie, the propensity to modulate behavior as a function of prior reinforcement experience) across species using translational behavioral assessments in humans and rats.Experimental studies used analogous reward responsiveness tasks in both humans and rats to examine whether reward responsiveness varied in (1) an ad libitum smoking condition compared with a 24-hour acute nicotine abstinence condition in 31 human smokers with (n?=?17) or without (n?=?14) a history of depression; (2) rats 24 hours after withdrawal from chronic nicotine (n?=?19) or saline (n?=?20); and (3) rats following acute nicotine exposure after withdrawal from either chronic nicotine or saline administration.Performance on a reward responsiveness task under nicotine and nonnicotine conditions.In both human smokers and nicotine-treated rats, reward responsiveness was significantly reduced after 24-hour withdrawal from nicotine (P?<?.05). In humans, withdrawal-induced deficits in reward responsiveness were greater in those with a history of depression. In rats previously exposed to chronic nicotine, acute nicotine reexposure long after withdrawal potentiated reward responsiveness (P?<?.05).These findings across species converge in suggesting that organisms have diminished ability to modulate behavior as a function of reward during withdrawal of nicotine. This blunting may contribute to relapse to tobacco smoking, particularly in depression-vulnerable individuals, to reinstate responsiveness to natural rewards and to experience potentiated nicotine-induced reward responsiveness. Moreover, demonstration of behavioral homology across humans and rodents provides a strong translational framework for the investigation and development of clinical treatments targeting reward responsiveness deficits during early withdrawal of nicotine.

Project description:IntroductionTobacco use improves mood states and smoking cessation leads to anhedonia, which contributes to relapse. Animal studies have shown that noncontingent nicotine administration enhances brain reward function and leads to dependence. However, little is known about the effects of nicotine self-administration on the state of the reward system.MethodsTo investigate the relationship between nicotine self-administration and reward function, rats were prepared with intracranial self-stimulation electrodes and intravenous catheters. The rats were trained on the intracranial self-stimulation procedure and allowed to self-administer 0.03 mg/kg/infusion of nicotine. All rats self-administered nicotine daily for 10 days (1 hour/day) and were then switched to an intermittent short access (ShA, 1 hour/day) or long access (LgA, 23 hour/day) schedule (2 days/week, 5 weeks).ResultsDuring the first 10 daily, 1-hour sessions, nicotine self-administration decreased the reward thresholds, which indicates that nicotine potentiates reward function. After switching to the intermittent LgA or ShA schedule, nicotine intake was lower in the ShA rats than the LgA rats. The LgA rats increased their nicotine intake over time and they gradually consumed a higher percentage of their nicotine during the light phase. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine induced a larger increase in reward thresholds (ie, anhedonia) in the LgA rats than the ShA rats. In the LgA rats, nAChR blockade with mecamylamine decreased nicotine intake for 2 hours and this was followed by a rebound increase in nicotine intake.ConclusionsA brief period of nicotine self-administration enhances reward function and a high level of nicotine intake leads to dependence.ImplicationsThese animal studies indicate that there is a strong relationship between the level of nicotine intake and brain reward function. A high level of nicotine intake was more rewarding than a low level of nicotine intake and nicotine dependence was observed after long, but not short, access to nicotine. This powerful combination of nicotine reward and withdrawal makes it difficult to quit smoking. Blockade of nAChRs temporarily decreased nicotine intake, but this was followed by a large rebound increase in nicotine intake. Therefore, nAChR blockade might not decrease the use of combustible cigarettes or electronic cigarettes.

Project description:INTRODUCTION:This study investigated the effects of nicotine/tobacco on neural activation during performance of a monetary incentive delay task. AIMS AND METHODS:Prior to each scan, nonsmokers received nicotine or placebo nasal spray, and smokers were smoking satiated or 24-hour withdrawn. During the scan, participants made timed responses to reward-related cues and received feedback. Parameter estimates from cue- and feedback-related activation in medial prefrontal regions and the nucleus accumbens were extracted and underwent within- and between-group analyses. Smokers' nicotine dependence severity was included as a continuous predictor variable for neural activation. RESULTS:Among smokers (n = 21), withdrawal decreased cue-related activation in the supplementary motor area and ventromedial prefrontal cortex, and the difference in activation (satiety > withdrawal) in these regions negatively correlated with nicotine dependence severity (Fagerström Test for Nicotine Dependence). Among nonsmokers (n = 22), nicotine increased the difference in nucleus accumbens activation between rewarded and nonrewarded feedback phases. Tobacco withdrawal and acute nicotine also had widespread effects on activation throughout the brain during the feedback phase. CONCLUSIONS:Acute nicotine in nonsmokers may have increased the salience of feedback information, but produced few effects on reward-related activation overall, perhaps reflecting nicotine's modest, indirect effects on reward processing. Conversely, tobacco withdrawal decreased activation compared with satiety, and this difference between conditions correlated with nicotine dependence severity. This suggests that as smokers become more dependent on nicotine, tobacco withdrawal has a more pronounced effect on reward processing. IMPLICATIONS:Relative to the acute effects of nicotine in nonsmokers, withdrawal from daily tobacco use had more significant effects on reward-related brain activation. This study suggests that the effects of tobacco withdrawal on reward-related brain function interact with subjects' level of nicotine dependence severity. These are potentially important sources of variability that could contribute to smoking cessation outcomes.

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Effects of ceftriaxone on conditioned nicotine reward in rats.

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Effects of ceftriaxone on conditioned nicotine reward in rats.

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