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Repeated exposure to JWH‐018 induces adaptive changes in the mesolimbic and mesocortical dopaminergic pathways, glial cells alterations, and behavioural correlates
Author(s) -
Pintori Nicholas,
Castelli Maria Paola,
Miliano Cristina,
Simola Nicola,
Fadda Paola,
Fattore Liana,
Scherma Maria,
Ennas Maria Grazia,
Mostallino Rafaela,
Flore Giovanna,
De Felice Marta,
Sagheddu Claudia,
Pistis Marco,
Di Chiara Gaetano,
De Luca Maria Antonietta
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15494
Subject(s) - dopaminergic , dopamine , neurochemical , neuroscience , astrogliosis , mesolimbic pathway , pharmacology , nucleus accumbens , psychology , ventral tegmental area , medicine , central nervous system
Background 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 CB 1 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 CB 1 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.