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Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal.

ABSTRACT: Cigarette smoking is the leading cause of preventable disease and death in the United States, with more persons dying from nicotine addiction than any other preventable cause of death. Even though smoking cessation incurs multiple health benefits, the abstinence rate remains low with current medications. Here we show that the AMP-activated protein kinase (AMPK) pathway in the hippocampus is activated following chronic nicotine use, an effect that is rapidly reversed by nicotine withdrawal. Increasing pAMPK levels and, consequently, downstream AMPK signaling pharmacologically attenuate anxiety-like behavior following nicotine withdrawal. We show that metformin, a known AMPK activator in the periphery, reduces withdrawal symptoms through a mechanism dependent on the presence of the AMPKα subunits within the hippocampus. This study provides evidence of a direct effect of AMPK modulation on nicotine withdrawal symptoms and suggests central AMPK activation as a therapeutic target for smoking cessation.

SUBMITTER: Brynildsen JK

PROVIDER: S-EPMC5910809 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal.

Brynildsen Julia K JK Lee Bridgin G BG Perron Isaac J IJ Jin Sunghee S Kim Sangwon F SF Blendy Julie A JA

Proceedings of the National Academy of Sciences of the United States of America 20180402 16

Cigarette smoking is the leading cause of preventable disease and death in the United States, with more persons dying from nicotine addiction than any other preventable cause of death. Even though smoking cessation incurs multiple health benefits, the abstinence rate remains low with current medications. Here we show that the AMP-activated protein kinase (AMPK) pathway in the hippocampus is activated following chronic nicotine use, an effect that is rapidly reversed by nicotine withdrawal. Incre ...[more]

PMID: 29610348

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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:ImportanceBuprenorphine treatment of opioid use disorder (OUD) is safe and effective, but opioid withdrawal during treatment initiation is associated with poor retention in care. As fentanyl has replaced heroin in the drug supply, case reports and surveys have indicated increased concern for buprenorphine-precipitated withdrawal (PW); however, some observational studies have found a low incidence of PW.ObjectiveTo estimate buprenorphine PW incidence and assess factors associated with PW among emergency department (ED) or hospitalized patients.Design, setting, and participantsThis retrospective cohort study at 3 academic hospitals in Philadelphia, Pennsylvania, included adults with OUD who underwent traditional or high-dose buprenorphine initiation between January 1, 2020, and December 31, 2021. Exclusion criteria included low-dose buprenorphine initiation and missing documentation of opioid withdrawal severity within 4 hours of receiving buprenorphine.ExposureBuprenorphine initiation with an initial dose of at least 2 mg of sublingual buprenorphine after a Clinical Opiate Withdrawal Scale (COWS) score of 8 or higher. Additional exposures included 4 predefined factors potentially associated with PW: severity of opioid withdrawal before buprenorphine (COWS score of 8-12 vs ≥13), initial buprenorphine dose (2 vs 4 or ≥8 mg), body mass index (BMI) (<25 vs 25 to <30 or ≥30; calculated as weight in kilograms divided by height in meters squared), and urine fentanyl concentration (0 to <20 vs 20 to <200 or ≥200 ng/mL).Main outcome and measuresThe main outcome was PW incidence, defined as a 5-point or greater increase in COWS score from immediately before to within 4 hours after buprenorphine initiation. Logistic regression was used to estimate the odds of PW associated with the 4 aforementioned predefined factors.ResultsThe cohort included 226 patients (150 [66.4%] male; mean [SD] age, 38.6 [10.8] years). Overall, 26 patients (11.5%) met criteria for PW. Among patients with PW, median change in COWS score was 9 points (IQR, 6-13 points). Of 123 patients with confirmed fentanyl use, 20 (16.3%) had PW. In unadjusted and adjusted models, BMI of 30 or greater compared with less than 25 (adjusted odds ratio [AOR], 5.12; 95% CI, 1.31-19.92) and urine fentanyl concentration of 200 ng/mL or greater compared with less than 20 ng/mL (AOR, 8.37; 95% CI, 1.60-43.89) were associated with PW.Conclusions and relevanceIn this retrospective cohort study, 11.5% of patients developed PW after buprenorphine initiation in ED or hospital settings. Future studies should confirm the rate of PW and assess whether bioaccumulated fentanyl is a risk factor for PW.

Project description:Background and purposeEvidence suggests that exercise decreases nicotine withdrawal symptoms in humans; however, the mechanisms mediating this effect are unclear. We investigated, in a mouse model, the effect of exercise intensity during chronic nicotine exposure on nicotine withdrawal severity, binding of α4β2*, α7 nicotinic acetylcholine (nAChR), μ-opioid (μ receptors) and D2 dopamine receptors and on brain-derived neurotrophic factor (BDNF) and plasma corticosterone levels.Experimental approachMale C57Bl/6J mice treated with nicotine (minipump, 24 mg·kg-1 ·day-1 ) or saline for 14 days underwent one of three concurrent exercise regimes: 24, 2 or 0 h·day-1 voluntary wheel running. Mecamylamine-precipitated withdrawal symptoms were assessed on day 14. Quantitative autoradiography of α4β2*, α7 nAChRs, μ receptors and D2 receptor binding was performed in brain sections of these mice. Plasma corticosterone and brain BDNF levels were also measured.Key resultsNicotine-treated mice undertaking 2 or 24 h·day-1 wheel running displayed a significant reduction in withdrawal symptom severity compared with the sedentary group. Wheel running induced a significant up-regulation of α7 nAChR binding in the CA2/3 area of the hippocampus of nicotine-treated mice. Neither exercise nor nicotine treatment affected μ or D2 receptor binding or BDNF levels. Nicotine withdrawal increased plasma corticosterone levels and α4β2* nAChR binding, irrespective of exercise regimen.Conclusions and implicationsWe demonstrated for the first time a profound effect of exercise on α7 nAChRs in nicotine-dependent animals, irrespective of exercise intensity. These findings shed light onto the mechanism underlining the protective effect of exercise on the development of nicotine dependence.Linked articlesThis article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.

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Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal.

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Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal.

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