REPEATED EXPOSURE TO JWH-018 INDUCES ADAPTIVE CHANGES IN THE MESOLIMBIC AND MESOCORTICAL DOPAMINE PATHWAYS, GLIAL CELLS ALTERATION AND BEHAVIOURAL CORRELATES

• Published in: British journal of pharmacology
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England 10-04-2021
• Subjects: glial cells; Addiction; novel psychoactive substances; habituation; taste; dopamine; synthetic cannabinoids
• ISSN: 1476-5381

Spice/K2 herbal mixtures, containing synthetic cannabinoids such as JWH-018, have been marketed as marijuana surrogates since 2004. We demonstrated that JWH-018 has cannabinoid CB1 receptor-dependent reinforcing properties and acutely increases dopamine transmission selectively in the NAc shell. Here we tested the hypothesis that repeated administration of JWH-018 (i) modulates behaviour, (ii) affects dopamine transmission and its responsiveness to motivational stimuli, and (iii) is associated with a neuroinflammatory phenotype.
Rats were administered with JWH-018 once a day for 14 consecutive days, then we performed behavioural, electrophysiological, and neurochemical evaluation at multiple time points after drug discontinuation.
Our data demonstrated that repeated JWH-018 exposure (i) induces anxious and aversive behaviours, transitory attentional deficits and withdrawal signs, (ii) decreases spontaneous activity and number of dopamine neurons in the VTA and (iii) reduces the stimulation of dopamine 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 the first chocolate exposure; conversely, after the 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 CB1Rs (mPFC, NAc shell and core).
These results suggest that repeated JWH-018 exposure may reflect a useful model to clarify the detrimental effects of recurring use of Spice/K2 drugs.