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Increasing kynurenine brain levels reduces ethanol consumption in mice by inhibiting dopamine release in nucleus accumbens

Giménez-Gómez, Pablo et al.

Neuropharmacology. Volume 135 (2018); pp 581-591 -- Elsevier Science Ltd

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  • Title:
    Increasing kynurenine brain levels reduces ethanol consumption in mice by inhibiting dopamine release in nucleus accumbens
  • Author: Giménez-Gómez, Pablo;
    Pérez-Hernández, Mercedes;
    Gutiérrez-López, María Dolores;
    Vidal, Rebeca;
    Abuin-Martínez, Cristina;
    O'Shea, Esther;
    Colado, María Isabel
  • Found In: Neuropharmacology. Volume 135 (2018); pp 581-591
  • Journal Title: Neuropharmacology
  • Subjects: Neuropsychopharmacologie--Périodiques; Autonomic Agents--Periodicals; Electronic journals; Neuropsychopharmacology--Periodicals; Neuropsychopharmacology; Periodicals; Ethanol (PubChem CID: 702)--Ro 61-8048 (PubChem CID: 5282337)--L-kynurenine (PubChem CID: 161166)--CH-223191 (PubChem CID: 3091786)--6, 2′, 4′-Trimethoxyflavone (PubChem CID: 688802)--TCDD (PubChem CID: 15625)--PNU-120596 (PubChem CID: 311434); Ethanol--Kynurenine--Kynurenic acid--KMO--Ro 61-8048--Binge drinking--Drinking in the dark; Dewey: 615.78
  • Rights: legaldeposit
  • Publication Details: Elsevier Science Ltd
  • Abstract: Abstract:

    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.

    Graphical abstract:

    Highlights:

    KMO inhibition, by Ro 61-8048, increases kynurenine and kynurenic acid concentration in both plasma and limbic forebrain and reduces voluntary binge ethanol consumption and preference in mice.

    Ro 61-8048 prevents ethanol-induced dopamine release in nucleus accumbens.

    AhR signalling is not involved in the reduction of ethanol consumption induced by KMO inhibition.

    Ro 61-8048 does not modify plasma acetaldehyde concentration.


  • Identifier: System Number: LDEAvdc_100065958404.0x000001; Journal ISSN: 0028-3908; 10.1016/j.neuropharm.2018.04.016
  • Publication Date: 2018
  • Physical Description: Electronic
  • Shelfmark(s): ELD Digital store

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