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

Abstract

In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-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 re-exposure 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 currently no medications approved for treatment of marijuana dependence. Modulation of KYNA provides a novel pharmacological strategy for achieving abstinence from marijuana and preventing relapse.

Social cognitive predictors of treatment outcome in cannabis dependence

“…Cannabis dependence is associated with a wide variety of adverse physical and mental health consequences (Hall and Degenhardt, 2009;Hall and Pacula, 2003). No medications have been approved for the treatment of cannabis dependence (Justinova et al, 2013). Psychological therapies are the first line of treatment (Davis et al, 2015;Litt et al, 2008).…”

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease

“…Evidence of the KP's involvement largely comes from animal models and humans, but few studies have been conducted with optimized molecules with suitable properties for longterm dosing, a necessary step to evaluate the contribution of specific enzymes to disease progression (Justinova et al, 2013;Kozak et al, 2014).…”

Cannabinoid-Nicotine Interactions

“…Reliable self-administration behavior has now been demonstrated in laboratory animals for almost all drugs abused by humans, including psychostimulants, opiates, ethanol, nicotine [8,[164][165][166][167]. However, THC has only been showed to be persistently self-administered by squirrel monkeys [168][169][170][171][172][173]. However, a rodent model of intravenous cannabinoid self-administration can be achieved by training rats to self-administer synthetic CB 1 /CB 2 receptor agonist WIN 55,212-2 [173][174][175][176].…”

“…However, THC has only been showed to be persistently self-administered by squirrel monkeys [168][169][170][171][172][173]. However, a rodent model of intravenous cannabinoid self-administration can be achieved by training rats to self-administer synthetic CB 1 /CB 2 receptor agonist WIN 55,212-2 [173][174][175][176].…”

“…However, a safer way to manipulate this system might be through allosteric modulation instead of direct antagonism. It was recently discovered that enhancing brain levels of kynurenic acid, an endogenous allosteric modulator of α7nAChR, is highly effective at blocking the addiction-related effects of cannabinoid agonists [173]. Enhancing levels of kynurenic acid: (1) attenuated the ability of THC and WIN 55,212-2 to increase extracellular dopamine levels in reward related areas in rats; (2) decreased WIN 55,212-2 self-administration in rats; (3) decreased THC self-administration in squirrel monkeys; (4) prevented drug-induced reinstatement of cannabinoid-seeking behavior in rats and monkeys; and (5) blocked reinstatement induced by re-exposure to THC-associated cues in monkeys, showing that it decreased not only the direct effects of THC, but also the conditioned effects of THC-associated stimuli.…”