RT Journal Article
T1 Increasing kynurenine brain levels reduces ethanol consumption in mice by inhibiting dopamine release in nucleus accumbens
A1 Giménez Gómez, Pablo
A1 Pérez Hernández, Mercedes
A1 Vidal Casado, Rebeca
A1 Gutiérrez López, María Dolores
A1 Vidal Casado, Rebeca
A1 Abuin Martínez, Cristina
A1 O'Shea Gaya, María Esther
A1 Colado Megías, María Isabel
AB Recent research suggests that ethanol (EtOH) consumption behaviour can be regulated by modifying the kynurenine (KYN) pathway, although the mechanisms involved have not yet been well elucidated. To further explore the implication of the kynurenine pathway in EtOH consumption we inhibited kynurenine 3-monooxygenase (KMO) activity with Ro 61-8048 (100 mg/kg, i.p.), which shifts the KYN metabolic pathway towards kynurenic acid (KYNA) production. KMO inhibition decreases voluntary binge EtOH consumption and EtOH preference in mice subjected to "drinking in the dark" (DID) and "two-bottle choice" paradigms, respectively. This effect seems to be a consequence of increased KYN concentration, since systemic KYN administration (100 mg/kg, i.p.) similarly deters binge EtOH consumption in the DID model. Despite KYN and KYNA being well-established ligands of the aryl hydrocarbon receptor (AhR), administration of AhR antagonists (TMF 5 mg/kg and CH-223191 20 mg/kg, i.p.) and of an agonist (TCDD 50 μg/kg, intragastric) demonstrates that signalling through this receptor is not involved in EtOH consumption behaviour. Ro 61-8048 did not alter plasma acetaldehyde concentration, but prevented EtOH-induced dopamine release in the nucleus accumbens shell. These results point to a critical involvement of the reward circuitry in the reduction of EtOH consumption induced by KYN and KYNA increments. PNU-120596 (3 mg/kg, i.p.), a positive allosteric modulator of α7-nicotinic acetylcholine receptors, partially prevented the Ro 61-8048-induced decrease in EtOH consumption. Overall, our results highlight the usefulness of manipulating the KYN pathway as a pharmacological tool for modifying EtOH consumption and point to a possible modulator of alcohol drinking behaviour.
PB Elsevier
SN 0028-3908
YR 2018
FD 2018-06-01
LK https://hdl.handle.net/20.500.14352/112138
UL https://hdl.handle.net/20.500.14352/112138
LA eng
NO Giménez-Gómez P, Pérez-Hernández M, Gutiérrez-López MD, Vidal R, Abuin-Martínez C, O'Shea E, Colado MI. Increasing kynurenine brain levels reduces ethanol consumption in mice by inhibiting dopamine release in nucleus accumbens. Neuropharmacology. 2018 Jun;135:581-591. doi: 10.1016/j.neuropharm.2018.04.016. Epub 2018 Apr 18. PMID: 29705534.
NO UCM 910258
NO Ministerio de Economía y Competitividad (España)
NO Ministerio de Sanidad, Servicios Sociales e Igualdad (España)
NO Instituto de Salud Carlos III (España)
NO Comunidad Autónoma de Madrid
NO Universidad Complutense de Madrid
DS Docta Complutense
RD 5 abr 2025