'Spice' is a smokable herbal mixture marketed under many brand names as herbal alternatives to Cannabis. Spice users report experiences similar to those produced by Cannabis and regular users may develop addiction and experience withdrawal and symptoms. Spice contains dried, shredded plant material and chemical additives that could be responsible for its psychoactive cannabis-like effects. We analyzed by GC-IT/MS the composition of four different specimens of Spice drugs (Artic Synergy, Silver, Gold, Diamond). In all the samples tested we found the presence of JWH-018 (1-pentyl-3-(1-naphthoyl) indole), a potent CB1 and CB2 synthetic agonist. Then, we investigated the rewarding properties of JWH-018 by in vivo microdialysis and intravenous self-administration behavior (SA) in separate groups of male Sprague-Dawley rats. In microdialysis studies, we observed that JWH-018, at the dose of 0.25 mg/kg ip, preferentially stimulates extracellular dopamine (DA) release in the nucleus accumbens (NAc) shell with respect to core and prefrontal cortex while no sub-regional differences were observed in the DA output after lower and higher doses tested (0.125 and 0.5 mg/kg ip). The administration of the CB1 receptor inverse agonist/antagonist rimonabant (1 mg/kg ip 30 min before JWH-018) blocked the NAc shell DA increase for 1 h after JWH-018 injection. In SA studies, rats implanted with a jugular catheter were trained to self-administer JWH-018 (10 and 20 µg/kg/inf iv) in single daily 1h session for 11 weeks, under an initial Fixed Ratio (FR) 1 schedule, than increased to FR3. Active nose-poking significantly increased over inactive ones from the 21st SA session (20 µg/kg/inf iv, FR3, acquisition phase) and the reinforcing effect was blocked by rimonabant (1 mg/kg ip, 30 min before SA session). However, when vehicle was substituted for JWH-018 (37th SA session, extinction phase), a low reduction of SA behavior was observed. But, the replacement of vehicle with JWH-018, significantly increased the rate responding and the number of injections (reacquisition phase). These results suggest that the JWH-018 shares with the psychoactive compound in Cannabis (THC) and with other drugs of abuse the property of stimulating preferentially NAc shell DA and of being self-administered by rats. Moreover, JWH-018 is more potent than THC and our results suggest an important role of active metabolites. Metabolites quantification in plasma by GC/MS and behavioral (motor activity, nociception, body temperature, aggressiveness and short and long term memory) studies will be completed in rats and mice to fully evaluate the neurobiological effects of JWH-018 and its active metabolites.
Behavioral and neurochemical rewarding properties of a cannabinoid compound of Spice drugs: jwh-018
DE LUCA, MARIA ANTONIETTA;CABONI, PIERLUIGI;VALENTINI, VALENTINA;
2012-01-01
Abstract
'Spice' is a smokable herbal mixture marketed under many brand names as herbal alternatives to Cannabis. Spice users report experiences similar to those produced by Cannabis and regular users may develop addiction and experience withdrawal and symptoms. Spice contains dried, shredded plant material and chemical additives that could be responsible for its psychoactive cannabis-like effects. We analyzed by GC-IT/MS the composition of four different specimens of Spice drugs (Artic Synergy, Silver, Gold, Diamond). In all the samples tested we found the presence of JWH-018 (1-pentyl-3-(1-naphthoyl) indole), a potent CB1 and CB2 synthetic agonist. Then, we investigated the rewarding properties of JWH-018 by in vivo microdialysis and intravenous self-administration behavior (SA) in separate groups of male Sprague-Dawley rats. In microdialysis studies, we observed that JWH-018, at the dose of 0.25 mg/kg ip, preferentially stimulates extracellular dopamine (DA) release in the nucleus accumbens (NAc) shell with respect to core and prefrontal cortex while no sub-regional differences were observed in the DA output after lower and higher doses tested (0.125 and 0.5 mg/kg ip). The administration of the CB1 receptor inverse agonist/antagonist rimonabant (1 mg/kg ip 30 min before JWH-018) blocked the NAc shell DA increase for 1 h after JWH-018 injection. In SA studies, rats implanted with a jugular catheter were trained to self-administer JWH-018 (10 and 20 µg/kg/inf iv) in single daily 1h session for 11 weeks, under an initial Fixed Ratio (FR) 1 schedule, than increased to FR3. Active nose-poking significantly increased over inactive ones from the 21st SA session (20 µg/kg/inf iv, FR3, acquisition phase) and the reinforcing effect was blocked by rimonabant (1 mg/kg ip, 30 min before SA session). However, when vehicle was substituted for JWH-018 (37th SA session, extinction phase), a low reduction of SA behavior was observed. But, the replacement of vehicle with JWH-018, significantly increased the rate responding and the number of injections (reacquisition phase). These results suggest that the JWH-018 shares with the psychoactive compound in Cannabis (THC) and with other drugs of abuse the property of stimulating preferentially NAc shell DA and of being self-administered by rats. Moreover, JWH-018 is more potent than THC and our results suggest an important role of active metabolites. Metabolites quantification in plasma by GC/MS and behavioral (motor activity, nociception, body temperature, aggressiveness and short and long term memory) studies will be completed in rats and mice to fully evaluate the neurobiological effects of JWH-018 and its active metabolites.
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