Background and purpose
The kynurenine pathway has been proposed as a target for modulating drug abuse. We previously demonstrated that inhibition of kynurenine 3-monooxygenase (KMO), using Ro 61-8048, reduces ethanol consumption in a binge drinking model. Here, we investigate the effect of the kynurenine pathway modulation in ethanol-dependent mice. Experimental approach: Adult male and female mice were subjected to a Chronic Intermittent Ethanol (CIE) paradigm. On the last day of CIE, mice were treated with Ro 61-8048, Ro 61-8048 + PNU-120596, a positive allosteric modulator of α7nAChR, and Ro 61-8048 + L-leucine or probenecid, which blocks the influx or efflux of kynurenine from the brain, respectively. Ethanol, water consumption and preference were measured and kynurenine levels in plasma and limbic forebrain were determined. Key
Purpose
The kynurenine pathway has been proposed as a target for modulating drug abuse. We previously demonstrated that inhibition of kynurenine 3-monooxygenase (KMO), using Ro 61-8048, reduces ethanol consumption in a binge drinking model. Here, we investigate the effect of the kynurenine pathway modulation in ethanol-dependent mice. Experimental approach: Adult male and female mice were subjected to a Chronic Intermittent Ethanol (CIE) paradigm. On the last day of CIE, mice were treated with Ro 61-8048, Ro 61-8048 + PNU-120596, a positive allosteric modulator of α7nAChR, and Ro 61-8048 + L-leucine or probenecid, which blocks the influx or efflux of kynurenine from the brain, respectively. Ethanol, water consumption and preference were measured and kynurenine levels in plasma and limbic forebrain were determined. Key
Results
Ro 61-8048 decreases consumption and preference for ethanol in both sexes exposed to the CIE model, an effect that was prevented by PNU-120596. The Ro 61-8048-induced decrease in ethanol consumption depends on the influx of kynurenine into the brain.