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Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.

ABSTRACT: In the reward circuitry of the brain, ?-7-nicotinic acetylcholine receptors (?7nAChRs) modulate effects of ?(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of ?7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of ?7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse.

SUBMITTER: Justinova Z

PROVIDER: S-EPMC3835353 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.

Justinova Zuzana Z Mascia Paola P Wu Hui-Qiu HQ Secci Maria E ME Redhi Godfrey H GH Panlilio Leigh V LV Scherma Maria M Barnes Chanel C Parashos Alexandra A Zara Tamara T Fratta Walter W Solinas Marcello M Pistis Marco M Bergman Jack J Kangas Brian D BD Ferré Sergi S Tanda Gianluigi G Schwarcz Robert R Goldberg Steven R SR

Nature neuroscience 20131013 11

In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration m ...[more]

PMID: 24121737

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Project description:ImportanceMost women who quit smoking during pregnancy will relapse postpartum. Previous efforts to prevent postpartum relapse have been unsuccessful at increasing rates of sustained abstinence.ObjectiveTo evaluate the relative efficacy of 2 different approaches to prevent postpartum smoking relapse.Design, setting, and participantsPregnant women who recently had quit smoking were recruited before the end of pregnancy. Intervention sessions were conducted through a combination of telephone calls and in-person visits beginning at delivery and continuing through 24 weeks postpartum. Participants completed assessments at the prenatal baseline and at 12, 24, and 52 weeks postpartum. Participants were recruited between March 2008 and December 2012. The dates of the analysis were April 2014 to February 2015.InterventionsWomen received postpartum-adapted, behavioral smoking relapse prevention intervention and were randomly assigned to an enhanced cognitive behavioral intervention that included additional specialized strategies and content focused on women's postpartum concerns about mood, stress, and weight (Strategies to Avoid Returning to Smoking [STARTS]) or a supportive, time and attention-controlled comparison (SUPPORT). Intervention began before delivery and continued through 24 weeks postpartum.Main outcomes and measuresThe primary outcome was biochemically confirmed sustained tobacco abstinence at 52 weeks postpartum. Secondary outcomes were self-reported mood, levels of perceived stress, and degree of concern about smoking-related weight gain.ResultsThe study cohort comprised 300 participants (150 randomly assigned to each group). Their mean (SD) age was 24.99 (5.65) years. Overall, 38.0% (114 of 300), 33.7% (101 of 300), and 24.0% (72 of 300) of the sample maintained abstinence at 12, 24, and 52 weeks' postpartum, respectively. There were no differences between the intervention groups in abstinence or time to relapse. Self-reported depressive symptoms and perceived stress significantly improved over time, and improvements were similar for both intervention groups. Women with more depressive symptoms and higher levels of perceived stress were more likely to relapse (hazard ratio, 1.02; 95% CI, 1.00-1.04; P = .04 for depressive symptoms and hazard ratio, 1.04; 95% CI, 1.01-1.07; P = .003 for stress).Conclusions and relevanceAn intervention designed to address women's concerns about mood, stress, and weight did not differentially improve rates of sustained tobacco abstinence postpartum compared with a time and attention-controlled comparison. Women in STARTS and SUPPORT reported postpartum improvements in mood and stress, and the experience of fewer depressive symptoms and less perceived stress was related to sustained abstinence. Given that most pregnant quitters will relapse within 1 year postpartum and that postpartum smoking has negative health consequences for women and children, effective interventions that target postpartum mood and stress are needed.Trial registrationclinicaltrials.gov Identifier: NCT00757068.

Dataset Information

Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.

Publications

Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.

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