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

Nature Neuroscience volume 16, pages 1652–1661 (2013)Cite this article

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Abstract

In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ9-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 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 α7nAChRs. 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.

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Figure 1: Effects of treatment with Ro 61-8048 on the extracellular concentration of kynurenic acid (KYNA) in NAc shell and VTA of freely moving rats.
Figure 2: Effects of elevated brain KYNA on THC-induced elevations of extracellular dopamine (that is, dopamine overflow) in NAc shell and VTA of freely moving rats.
Figure 3: Prevention of the neurochemical effects of Ro 61-8048 by two agonists at the allosteric potentiating site of the α7nAChR, galantamine and PNU120596.
Figure 4: Effects of treatment with Ro 61-8048 on abuse-related effects of the synthetic CB1 agonist WIN 55,212-2 in rats.
Figure 5: Effects of Ro 61-8048 on THC, food and cocaine self-administration in squirrel monkeys.
Figure 6: Reversal of behavioral effects of Ro 61-8048 by positive allosteric modulators of α7nAChRs.
Figure 7: Effects of Ro 61-8048 and THC on working memory in rats and squirrel monkeys.
Figure 8: Effects of Ro 61-8048 on discriminative-stimulus effects of THC in rats and squirrel monkeys.

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Acknowledgements

We thank E. Thorndike for excellent technical assistance during the rodent studies. We thank I. Baum, S. Stevens and P. White for excellent veterinary assistance during the primate studies. This study was supported in part by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health, Department of Health and Human Services, NIDA Residential Research Support Services Contract N01 DA59909 (principal investigator D. Kelly), by the Italian Ministry of University and Scientific Research, by DA023142 (J.B.) and DA035974 (B.D.K.) and by the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine. T.Z. was supported by a Grant from Regione Autonoma della Sardegna and by the European Social Fund, LR7 2007.

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Author notes

  1. Paola Mascia

    Present address: Present address: Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.,

  2. Zuzana Justinova and Paola Mascia: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Health and Human Services, Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA

    Zuzana Justinova, Paola Mascia, Maria E Secci, Godfrey H Redhi, Leigh V Panlilio, Chanel Barnes, Alexandra Parashos & Steven R Goldberg

  2. Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA

    Zuzana Justinova, Hui-Qiu Wu & Robert Schwarcz

  3. Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Italy

    Maria Scherma, Tamara Zara, Walter Fratta & Marco Pistis

  4. Inserm U1084, Experimental and Clinical Neurosciences Laboratory, Neurobiology and Neuropharmacology Addiction Group, Poitiers, France

    Marcello Solinas

  5. Université de Poitiers, Poitiers, France

    Marcello Solinas

  6. Neuroscience Institute, Consiglio Nazionale delle Ricerche, Cagliari, Italy

    Marco Pistis

  7. McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA

    Jack Bergman & Brian D Kangas

  8. Department of Health and Human Services, Integrative Neurobiology Section, Molecular Targets & Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA

    Sergi Ferré

  9. Department of Health and Human Services, Psychobiology Section, Molecular Targets & Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA

    Gianluigi Tanda

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Contributions

Z.J. was involved in the design of the study, supervised and analyzed the primate self-administration and reinstatement experiments and rodent drug discrimination experiments, and wrote the first draft of the manuscript. P.M. was involved in design of the study, conducted microdialysis experiments including collection of all samples, performed dopamine assay, analyzed microdialysis data and helped prepare the final draft of the manuscript. H.-Q.W. analyzed KYNA levels in microdialysis samples. M.E.S. conducted and analyzed microdialysis experiments with local KYNA infusion and PNU120596. G.H.R. conducted the primate self-administration and reinstatement experiments. L.V.P designed and analyzed the experiments with delayed nonmatching to position and was involved in discussions of the data. C.B. conducted rodent drug discrimination experiments and was involved in discussions of the data. T.Z. conducted the rat self-administration and microdialysis experiments with WIN 55,212-2. M. Scherma supervised the rat self-administration and microdialysis experiments with WIN 55,212-2, analyzed the data and was involved in the discussions of the data. W.F. was involved in the discussions of the data. A.P. assisted in conducting the microdialysis experiments with THC. J.B. and B.D.K. designed, conducted and analyzed the data from the primate discrimination and memory experiments. S.F., M. Solinas, M.P. and G.T. were involved in the design of the study and discussions of the data. R.S. and S.R.G. conceived, designed and supervised the study and edited the manuscript.

Corresponding author

Correspondence to Steven R Goldberg.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Ro 61-8048 reverses the depressant effects of THC on food self-administration in monkeys.

THC (0.56 mg/kg, i.v., immediately before the session) significantly decreased the number of food pellets self-administered over one-h sessions (a) and also decreased overall response rates (b) by squirrel monkeys under a fixed-ratio ten (FR10) schedule. Ro 61-8048 (20 mg/kg i.m., 40 min before session) did not significantly affect food-reinforced behavior, but reversed the effects of THC. The number of food pellets per session (a) and overall response rates in the presence of the green light signaling food availability (b) are shown. Each bar represents the mean ± s.e.m (n = 3). **P<0.01, post-hoc vs. vehicles condition; # P<0.05, ## P<0.01, post-hoc vs. vehicle + THC 0.56 condition, Bonferroni test.

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Justinova, Z., Mascia, P., Wu, HQ. et al. Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid. Nat Neurosci 16, 1652–1661 (2013). https://doi.org/10.1038/nn.3540

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