Reducing Cannabinoid Abuse and Preventing Relapse by Enhancing Endogenous Brain Levels of Kynurenic Acid

Nat Neurosci. 2013 Nov;16(11):1652-61. doi: 10.1038/nn.3540. Epub 2013 Oct 13.

Abstract

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / administration & dosage
  • Animals
  • Benzoxazines / administration & dosage
  • Brain / metabolism*
  • Cannabinoid Receptor Agonists / pharmacology
  • Conditioning, Operant / drug effects
  • Cues
  • Discrimination, Psychological / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Dronabinol / pharmacology
  • Drug-Seeking Behavior / drug effects
  • Kynurenic Acid / metabolism*
  • Male
  • Memory, Short-Term / drug effects
  • Morpholines / administration & dosage
  • Naphthalenes / administration & dosage
  • Rats
  • Rats, Long-Evans
  • Rats, Sprague-Dawley
  • Reinforcement, Psychology
  • Saimiri
  • Secondary Prevention
  • Self Administration
  • Substance-Related Disorders* / drug therapy
  • Substance-Related Disorders* / metabolism
  • Substance-Related Disorders* / pathology
  • Sulfonamides / pharmacology
  • Thiazoles / pharmacology
  • Time Factors
  • Wakefulness

Substances

  • Analgesics
  • Benzoxazines
  • Cannabinoid Receptor Agonists
  • Morpholines
  • Naphthalenes
  • Ro 61-8048
  • Sulfonamides
  • Thiazoles
  • Win 55212-2
  • Dronabinol
  • Kynurenic Acid