JWH-018 impairs sensorimotor functions in mice.

Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) is a synthetic cannabinoid agonist illegally marketed in "Spice" and "herbal blend" for its psychoactive effect greater than those produced by cannabis. In rodents JWH-018 reproduces typical effects of (-)-Δ(9)-THC or Dronabinol® (Δ(9)-THC) such as hypothermia, analgesia, hypolocomotion and akinesia, while its effects on sensorimotor functions are still unknown. Therefore, the aim of the present study is to investigate the effect of acute administration of JWH-018 (0.01-6mg/kg i.p.) on sensorimotor functions in male CD-1 mice and to compare its effects with those caused by the administration of Δ(9)-THC (0.01-6mg/kg i.p.). A specific battery of behavioral tests were adopted to investigate effects of cannabinoid agonists on sensorimotor functions (visual, auditory, tactile) and neurological changes (convulsion, myoclonia, hyperreflexia) while video-tracking analysis was used to study spontaneous locomotion. JWH-018 administration inhibited sensorimotor responses at lower doses (0.01-0.1mg/kg), reduced spontaneous locomotion at intermediate/high doses (1-6mg/kg) and induced convulsions, myoclonia and hyperreflexia at high doses (6mg/kg). Similarly, administration of Δ(9)-THC reduced sensorimotor responses in mice but it did not inhibit spontaneous locomotion and it did not induce neurological alterations. All behavioral effects and neurological alterations were prevented by the administration of the selective CB1 receptor antagonist/inverse agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (AM 251). For the first time these data demonstrate that JWH-018 impairs sensorimotor responses in mice. This aspect should be carefully evaluated to better understand the potential danger that JWH-018 may pose to public health, with particular reference to decreased performance in driving and hazardous works.

Novel halogenated derivates of JWH-018: Behavioral and binding studies in mice.

JWH-018 is a synthetic CB1 and CB2 agonist illegally marketed as products named "Spice" or "herbal blend" for its psychoactive effects which are much higher than those produced by cannabis. In the last year, the European Monitoring Centre for Drugs and Drug Addiction reported to the Italian National Early Warning System the seizure of plant material containing new halogenated derivatives of JWH-018 (JWH-018 Cl and JWH-018 Br). The present study aimed to investigate the in vitro and in vivo activity of these two new synthetic cannabinoids in mice. In vitro competition binding experiments performed on mouse and human CB1 receptors revealed a high affinity and potency of the halogenated compounds. Synthetic cannabinoids (0.01-6 mg/kg i.p.) impaired motor activity and induced catalepsy in mice and their effects were more severe with respect to those evoked by Δ(9)-THC. Moreover, they increased the mechanical and thermal pain threshold and induced a marked hypothermia. It is interesting to note that whereas high doses of JWH-018 cause seizures, myoclonia and hyperreflexia, the halogenated compounds, in particular JWH-018Br, were less effective. Behavioral and neurological changes were prevented by the selective CB1 receptor antagonist AM 251. These data demonstrate for the first time that JWH-018 Cl and JWH-018 Br act similarly to JWH-018 while inducing less convulsive episodes and myoclonias. These data support the hypothesis that the halogenated compounds may have been introduced onto market to produce similar intoxicating effects as JWH-018 while causing less side effects.