Neurobiological Sequelae of the Passive or Voluntary Administration of the Synthetic Cannabinoid Receptor Agonist JWH-018

Abstract

The use of synthetic cannabinoids receptor agonists (SCRAs) is growing among adults and adolescents, posing major medical and psychiatric risks. JWH-018 represents the reference compound of SCRA-containing products. Our studies were performed to evaluate the enduring consequences of repeated JWH-018 exposure by both passive administration (0.25 mg/kg ip qd, 14 days) in adult rats, and by intravenous self-administration (lever pressing, Fixed Ratio 1–3; 7.5 µg/kg/inf) in adolescent mice. Main results, obtained 24 hours and 7 days after drug discontinuation, showed that repeated JWH-018 exposure in adult rats: (i) induced anxious/aversive behaviors; (ii) decreased spontaneous activity and number of dopamine neurons in the VTA; and (iii) 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. Moreover, passive JWH-018 induced: (iv) astrogliosis (mPFC, NAc shell/core, VTA), microgliosis (NAc shell/core), and downregulation of CB1 receptors (mPFC, NAc shell/core). Other studies showed that adolescent JWH-018 IVSA induced at adulthood: (i) repetitive/compulsive-like behaviors; (ii) microgliosis (CPu, NAc) and astrocytopathy (CPu), as revealed by a decreased GFAP expression; (iii) increased of the chemokines MPC1 (striatum) and RANTES (cortex), and a decrease of the cytokines IL2 and IL13 (cortex). Taken together, these data suggest that the long-lasting behavioral and neurochemical effects of JWH-018 exposures may not differ substantially as a function of passive or voluntary administration except for some specific aspects of the brain immune response, that deserve further clarification.