“DIFFERENTIAL ADAPTIVE PROPERTIES OF MESOLIMBIC AND MESOCORTICAL DOPAMINE TRANSMISSION TO TASTE STIMULI, NEUROINFLAMMATORY EFFECTS AND BEHAVIORAL CORRELATES AFTER REPEATED EXPOSURE TO THE SYNTHETIC CANNABINOID JWH-018”

Since 2004, herbal mixtures broadly known as Spice/K2, containing synthetic cannabinoids (SC) such as JWH-018, have been marketed as a legal marijuana surrogate. Previous studies of our group showed that JWH-018 has CB1-receptor dependent reinforcing properties and increases dopamine (DA) transmission selectively in the shell of the nucleus accumbens (NAc) at the dose of 0.25 mg/kg i.p. (De Luca et al., 2015). Other studies showed that taste stimuli increase extracellular DA in the NAc and in the medial prefrontal cortex (mPFC) of rats; this effect shows single-trial habituation in NAc shell but not in core or in mPFC (Bassareo et al., 2002). However, the selective disruption of mPFC by 6-OHDA lesions, abolishes habituation of DA responsiveness to taste stimuli in NAc shell (Bimpisidis et al., 2013). Such findings support the hypothesis of an inhibitory influence of mPFC on NAc DA, suggesting a top-down control of NAc DA by mPFC and its putative role in the loss of control of the motivational value of stimuli and in impulsivity (De Luca, 2014). In order to test if the repeated administration of JWH-018 is able to modulate the activity of DA terminal areas and is associated to changes in the responsiveness to motivational taste stimuli, adult male Sprague Dawley (SD) rats were administered once a day for 14 consecutive days with JWH-018 (0.25 mg/kg i.p.) or with vehicle. During the last day of administration, DA was quantified by in vivo brain microdialysis in the NAc and in the mPFC. JWH-018 repeated exposure decreases the sensitivity of NAc shell DA to the last JWH-018 administration. After a week of washout, DA was quantified in NAc shell, NAc core and mPFC of rats either naive or pre-exposed to chocolate (1 ml/5 min i.o.). JWH-018 administration decreases the sensitivity of NAc shell DA in naive rats, abolished habituation of DA responsiveness to repeated chocolate exposure in the NAc shell while induced it in the mPFC, suggesting a possible loss of control of the motivational value of stimuli. In the NAc core, JWH-018 treatment potentiated, delayed and prolonged the stimulatory DA response to taste stimuli of animals pre-exposed to chocolate. Parallel studies showed that repeated JWH-018 exposure reduces either spontaneous activity or number of VTA DA neurons, together with an increase of obsessive-compulsive/anxious behavior, attentional deficits, and signs of withdrawal. These data show that JWH-018 is able to change the activity of DA neurons and to induce differential adaptive changes of the responsiveness of DA transmission to taste stimuli in DA terminal areas, similarly to previous results obtained in mPFC 6-OHDA lesioned rats. Interestingly, these neurochemical and behavioral observation are associated with a neuroinflammatory phenotype, as indicated by IBA-1 immunoreactivity and reactive astrogliosis (GFAP) in DA brain areas. Therefore, JWH-018 induces behavioral effects and changes of glial cells (astrocytes and microglia), which might be related to the central effects observed after repeated JWH-018 administration. Taken together these results suggest that JWH-018 repeated treatment may reflect a model of addiction, and this study could be useful to understand if dysfunctions of cortical-limbic-striatal DA circuit, as well as glial cells alterations, can lead or are related to specific detrimental effects of recurring use of Spice/K2 drugs.