2026-04-14T03:13:07Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/579922025-12-21T18:06:18Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Alegre Zurano, Laia author García Baos, Alba author Castro-Zavala, Adriana author Medrano, Mireia author Gallego-Landin, Ines author Valverde Granados, Olga author 2023-09-29T07:33:29Z 2023-09-29T07:33:29Z 2023 The endocannabinoid system is prominently implicated in the control of cocaine reinforcement due to its relevant role in synaptic plasticity and neurotransmitter modulation in the mesocorticolimbic system. The inhibition of fatty acid amide hydrolase (FAAH), and the resulting increase in anandamide and other N-acylethanolamines, represents a promising strategy for reducing drug seeking. In the present study, we aimed to assess the effects of the FAAH inhibitor URB597 (1 mg/kg) on crucial features of cocaine addictive-like behaviour in mice. Therefore, we tested the effects of URB597 on acquisition of cocaine (0.6 mg/kg/inf) self-administration, compulsive-like cocaine intake and cue-induced drug-seeking behaviour during withdrawal. URB597 reduced cocaine intake under conditioned punishment while having no impact on acquisition. This result was associated to increased cannabinoid receptor 1 gene expression in the ventral striatum and medium spiny neurons activation in the nucleus accumbens shell. Moreover, URB597 mitigated cue-induced drug-seeking behaviour during prolonged abstinence and prevented the withdrawal-induced increase in FAAH gene expression in the ventral striatum. In this case, URB597 decreased activation of medium spiny neurons in the nucleus accumbens core. Our findings evidence the prominent role of endocannabinoids in the development of cocaine addictive-like behaviours and support the potential of FAAH inhibition as a therapeutical target for the treatment of cocaine addiction. This work was supported by the Ministerio de Ciencia e Innovación (#PID2019-104077RB-100 and PID2022-136962OB-100 MCIN/AEI/10.13039/501100011033), Ministerio de Sanidad (Plan Nacional sobre Drogas #2018/007, and EXP2022/008695 - funds from the Recovery, Transformation and Resilience Mechanism (PRTR) of the European Union. Funded by the European Union – NextGenerationEU) and by the Generalitat de Catalunya, AGAUR (#2021SGR00485). L.A-Z received a FPI grant (BES-2017-080066) associated to #SAF2016–75966-R grant to O.V. from Ministerio de Economia y Competitividad. A.G-B received a FI-AGAUR grant from the Generalitat de Catalunya (2019FI_B0081). I.G-L. obtained a grant from the Ministerio de Ciencia e Innovación (PRE2020-091923). The Department of Medicine and Health Sciences (UPF) is a “Unidad de Excelencia María de Maeztu” funded by the AEI (#CEX2018-000792-M). O.V. is recipient of an ICREA Academia Award (Institució Catalana de Recerca i Estudis Avançats, Generalitat de Catalunya). Abstinence Cocaine Conditioned punishment FAAH inhibition Self-administration URB597 The FAAH inhibitor URB597 reduces cocaine intake during conditioned punishment and mitigates cocaine seeking during withdrawal