Abstract
JWH-018 and AKB48 are two synthetic cannabinoids (SCBs) belonging to different structural classes and illegally marketed as incense, herbal preparations, or chemical supply for theirs psychoactive cannabis-like effects. Clinical reports from emergency room reported psychomotor agitation as one of the most frequent effects in people assuming SCBs. This study aimed to investigate the psychostimulant properties of JWH-018 and AKB48 in male CD-1 mice and to compare their behavioral and biochemical effects with those caused by cocaine and amphetamine. In vivo studies showed that JWH-018 and AKB48, as cocaine and amphetamine, facilitated spontaneous locomotion in mice. These effects were prevented by CB1 receptor blockade and dopamine (DA) D1/5 and D2/3 receptors inhibition. SPECT-CT studies on dopamine transporter (DAT) revealed that, as cocaine and amphetamine, JWH-018 and AKB48 decreased the [123I]-FP-CIT binding in the mouse striatum. Conversely, in vitro competition binding studies revealed that, unlike cocaine and amphetamine, JWH-018 and AKB48 did not bind to mouse or human DAT. Moreover, microdialysis studies showed that the systemic administration of JWH-018, AKB48, cocaine, and amphetamine stimulated DA release in the nucleus accumbens (NAc) shell of freely moving mice. Finally, unlike amphetamine and cocaine, JWH-018 and AKB48 did not induce any changes on spontaneous [3H]-DA efflux from murine striatal synaptosomes. The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release. These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health.
Highlights
According to the European Drug Report, 100 new abused substances have been detected for the first time in 2016 [1]
To mice treated with cocaine and amphetamine, JWH018- and AKB48-injected animals spent more time in the central zone [Figure 1D; significant effect of treatment (F4,560 = 70.37, p < 0.0001), time (F15,560 = 32.48, p < 0.0001), and time × treatment interaction (F60,560 = 12.24, p < 0.0001)] than in the peripheral area of the cage [Figure 1C; significant effect of treatment (F4,560 = 9.751, p < 0.0001), time (F15,560 = 13.33, p < 0.0001), and time × treatment interaction (F60,560 = 4.394, p < 0.0001)]
The facilitation of spontaneous locomotion induced by JWH-018 (0.3 mg/kg) and AKB48 (1 mg/kg) was prevented by a pretreatment with AM 251 [1 mg/kg i.p.; Figure 1E: significant effect of treatment (F3,56 = 13.74, p < 0.0001), time (F1,56 = 31.88, Figure 1 | Effect of the systemic administration of vehicle, amphetamine (10 mg/kg i.p.), cocaine (20 mg/kg i.p.), JWH-018 (0.3 mg/kg i.p.), and AKB48 (1 mg/kg i.p.) on the total distance traveled (A), on the immobility time (B), and on the total time spent in the peripheral and central area (C,D) of the mouse
Summary
According to the European Drug Report, 100 new abused substances have been detected for the first time in 2016 [1]. Recent literature reported that an incredibly huge number of synthetic cannabinoids (SCBs) has been detected and commonly abused in the US, Europe, and Australia as Marijuana substitutes [2]. They are not preferred over cannabis but recreationally used to circumvent legal, work- and cost-related obstacles. In CD-1 murine preparation, AKB48 and JWH018 displayed a similar affinity for CB1 receptors [Ki = 5.34 and 5.82 nM, respectively; [6]], while AKB48 showed a slightly higher affinity than JWH-018 [Ki = 9.53 and 3.24 nM, respectively; [6]] for human CB1 receptors Based on these findings, it seems likely that, compared to other SCBs, the two compounds might induce similar or higher in vivo effects
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