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Sex differences in the reward deficit and somatic signs associated with precipitated nicotine withdrawal in rats.

ABSTRACT: Female smokers are more likely to relapse than male smokers, but little is known about sex differences in nicotine withdrawal. Therefore, male and female rats were prepared with minipumps that contained nicotine or saline and sex differences in precipitated and spontaneous nicotine withdrawal were investigated. The intracranial self-stimulation (ICSS) procedure was used to assess mood states. Elevations in brain reward thresholds reflect a deficit in reward function. Anxiety-like behavior was investigated after the acute nicotine withdrawal phase in a large open field and the elevated plus maze test. The nicotinic receptor antagonist mecamylamine elevated the brain reward thresholds of the nicotine-treated rats but did not affect those of the saline-treated control rats. A low dose of mecamylamine elevated the brain reward thresholds of the nicotine-treated male rats but not those of the females. Mecamylamine also precipitated more somatic withdrawal signs in the nicotine-treated male than female rats. Minipump removal elevated the brain reward thresholds of the nicotine-treated rats for about 36?h but did not affect those of the saline-treated rats. There was no sex difference in the reward deficit during spontaneous nicotine withdrawal. In addition, the nicotine-treated male and female rats did not display increased anxiety-like behavior three to four days after minipump removal. In conclusion, these studies suggest that relatively low doses of a nicotinic receptor antagonist induce a greater reward deficit and more somatic withdrawal signs in male than female rats, but there is no sex difference in the reward deficit during spontaneous withdrawal.

SUBMITTER: Tan S

PROVIDER: S-EPMC6842125 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Sex differences in the reward deficit and somatic signs associated with precipitated nicotine withdrawal in rats.

Tan Sijie S Xue Song S Behnood-Rod Azin A Chellian Ranjithkumar R Wilson Ryann R Knight Parker P Panunzio Stefany S Lyons Hannah H Febo Marcelo M Bruijnzeel Adriaan W AW

Neuropharmacology 20190902

Female smokers are more likely to relapse than male smokers, but little is known about sex differences in nicotine withdrawal. Therefore, male and female rats were prepared with minipumps that contained nicotine or saline and sex differences in precipitated and spontaneous nicotine withdrawal were investigated. The intracranial self-stimulation (ICSS) procedure was used to assess mood states. Elevations in brain reward thresholds reflect a deficit in reward function. Anxiety-like behavior was in ...[more]

PMID: 31487496

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Project description:Cannabis is the most frequently used federally illicit substance in the United States. However, there are currently no FDA-approved pharmacotherapies to mitigate the withdrawal symptoms associated with cessation in heavy users. A promising, readily available, non-cannabinoid therapy are the gabapentinoids. Although currently approved for epilepsy and neuropathic pain, gabapentinoids are increasingly used for their "off-label" efficacy in treating various psychiatric conditions and substance abuse. Gabapentin (GBP) synergizes with cannabinoid agonism in neuropathic pain models, substitutes for Δ9-tetrahydrocannabinol (THC) in drug discrimination procedures, and reduced withdrawal symptoms in an outpatient clinical trial. However, there are limited data on the biological plausibility of the therapeutic action of gabapentinoids in cannabinoid withdrawal in preclinical models. The purpose of the current study was to determine the efficacy of GBP on attenuating THC withdrawal in mice, using an array of tests targeting withdrawal-induced and withdrawal-suppressed behaviors. Separate cohorts of male and female mice were administered THC (10 mg/kg, s.c.) or vehicle for 5.5 days, and withdrawal was precipitated by the CB1 antagonist rimonabant (2 or 3 mg/kg, i.p.) on the sixth day. GBP (≥10 mg/kg) reduced somatic signs of withdrawal (i.e., paw tremors and head twitches), but had no effect in locomotor activity or conditioned place preference. GBP (50 mg/kg) also restored withdrawal-suppressed responding on a progressive ratio reinforcement schedule. However, GBP (50 mg/kg) had no effect in withdrawal-suppressed marble burying or tail suspension struggling and did not normalize the stress response induced by THC withdrawal, as indicated by plasma corticosterone. These data suggest gabapentin may be effective at treating cannabinoid withdrawal symptoms including somatic and affective symptoms but may act independently of endocrine stress activation.

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.

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Sex differences in the reward deficit and somatic signs associated with precipitated nicotine withdrawal in rats.

Publications

Sex differences in the reward deficit and somatic signs associated with precipitated nicotine withdrawal in rats.

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