Repeated exposure to JWH-018 induces adaptive changes in the mesolimbic and mesocortical dopaminergic pathways, glial cells alterations, and behavioural correlates

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dc.contributor.authorPintori, Nicholasen
dc.contributor.authorCastelli, Maria Paolaen
dc.contributor.authorMiliano, Cristinaen
dc.contributor.authorSimola, Nicolaen
dc.contributor.authorFadda, Paolaen
dc.contributor.authorFattore, Lianaen
dc.contributor.authorScherma, Mariaen
dc.contributor.authorEnnas, Maria Graziaen
dc.contributor.authorMostallino, Rafaelaen
dc.contributor.authorFlore, Giovannaen
dc.contributor.authorDe Felice, Martaen
dc.contributor.authorSagheddu, Claudiaen
dc.contributor.authorPistis, Marcoen
dc.contributor.authorDi Chiara, Gaetanoen
dc.contributor.authorDe Luca, Maria Antoniettaen
dc.contributor.departmentSchool of Neuroscienceen
dc.date.accessioned2021-07-21T17:46:10Zen
dc.date.available2021-07-21T17:46:10Zen
dc.date.issued2021-04-10en
dc.description.abstractBackground and Purpose Spice/K2 herbal mixtures, containing synthetic cannabinoids such as JWH-018, have been marketed as marijuana surrogates since 2004. JWH-018 has cannabinoid CB1 receptor-dependent reinforcing properties and acutely increases dopaminergic transmission selectively in the NAc shell. Here, we tested the hypothesis that repeated administration of JWH-018 (i) modulates behaviour, (ii) affects dopaminergic transmission and its responsiveness to motivational stimuli, and (iii) is associated with a neuroinflammatory phenotype. Experimental Approach Rats were administered with JWH-018 once a day for 14 consecutive days. We then performed behavioural, electrophysiological, and neurochemical evaluation at multiple time points after drug discontinuation. Key Results Repeated JWH-018 exposure (i) induced anxious and aversive behaviours, transitory attentional deficits, and withdrawal signs; (ii) decreased spontaneous activity and number of dopamine neurons in the VTA; and (iii) reduced stimulation of dopaminergic transmission in the NAc shell while potentiating that in the NAc core, in response to acute JWH-018 challenge. Moreover, (iv) we observed a decreased dopamine sensitivity in the NAc shell and core, but not in the mPFC, to a first chocolate exposure; conversely, after a second exposure, dialysate dopamine fully increased in the NAc shell and core but not in the mPFC. Finally, selected dopamine brain areas showed (v) astrogliosis (mPFC, NAc shell and core, VTA), microgliosis (NAc shell and core), and downregulation of CB1 receptors (mPFC, NAc shell and core). Conclusion and Implications Repeated exposure to JWH-018 may provide a useful model to clarify the detrimental effects of recurring use of Spice/K2 drugs.en
dc.description.notesThis research has been funded by the Drug Policies Department, Presidency of the Council of Ministers, Italy, projects: "INSIDE-018" (PI: Prof. De Luca, University of Cagliari) and "Effects of NPS: development of a multicentre research for the information enhancement of the Early Warning System" (PI: Prof. Marti, University of Ferrara) to M.A.D.L., and RAS-FSC 2018 (Codice intervento: RC_CRP_034; CUP RASSR03071; project: "Multidisciplinary preclinical study on NPS and evaluation of their behavioral and neurophysiological effects related to age and sex") to M.A.D.L., N.S., and L.F. Prof. De Luca would gratefully like to thank the Dipartimento Salute Mentale e Dipendenze (DSMD)-zona Sud-ATS Sardegna within the Convenzione sanitaria in materia di studio e ricerca tossicologica con il DiSB (UniCa) in oggetto al "PROGRAMMA REGIONALE PER L'ASSISTENZA SANITARIA DELLE PERSONE TOSSICODIPENDENTI NEGLI ISTITUTI PENITENZIARI DELLA SARDEGNA" (Resolution of the Special Commissioner ATS n. 121 of 21-02-2020).en
dc.description.sponsorshipDrug Policies Department, Presidency of the Council of Ministers, Italy, project: "INSIDE-018"; Drug Policies Department, Presidency of the Council of Ministers, Italy, project: "Effects of NPS: development of a multicentre research for the information enhancement of the Early Warning System"; Drug Policies Department, Presidency of the Council of Ministers, Italy, project: RAS-FSC 2018 [RC_CRP_034, CUP RASSR03071]; Dipartimento Salute Mentale e Dipendenze (DSMD)-zona Sud-ATS Sardegna within the Convenzione sanitaria in materia di studio e ricerca tossicologica con il DiSB (UniCa) in oggetto al "PROGRAMMA REGIONALE PER L'ASSISTENZA SANITARIA DELLE PERSONE TOSSICODIPEN [121]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1111/bph.15494en
dc.identifier.eissn1476-5381en
dc.identifier.issn0007-1188en
dc.identifier.pmid33837969en
dc.identifier.urihttp://hdl.handle.net/10919/104246en
dc.language.isoenen
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectaddictionen
dc.subjectdopamineen
dc.subjectglial cellsen
dc.subjecthabituationen
dc.subjectnovel psychoactive substancesen
dc.subjectsynthetic cannabinoidsen
dc.subjecttasteen
dc.titleRepeated exposure to JWH-018 induces adaptive changes in the mesolimbic and mesocortical dopaminergic pathways, glial cells alterations, and behavioural correlatesen
dc.title.serialBritish Journal of Pharmacologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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