Effect of JWH-250, JWH-073 and their interaction on “tetrad”, sensorimotor, neurological and neurochemical responses in mice

JWH-250 and JWH-073 are two synthetic cannabinoid agonists with nanomolar affinity at CB1 and CB2 receptors. They are illegally marketed within “herbal blend” for theirs psychoactive effects greater than those produced by Cannabis. Recently, we analyzed an “herbal” preparation containing a mixture o...

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Published in:Progress in neuro-psychopharmacology & biological psychiatry 2016-06, Vol.67, p.31-50
Main Authors: Ossato, Andrea, Canazza, Isabella, Trapella, Claudio, Vincenzi, Fabrizio, De Luca, Maria Antonietta, Rimondo, Claudia, Varani, Katia, Borea, Pier Andrea, Serpelloni, Giovanni, Marti, Matteo
Format: Article
Language:English
Subjects:
Animals
Anisoles - pharmacology
Brain - cytology
Brain - drug effects
Brain - metabolism
Cells, Cultured
Cyclohexanols - pharmacokinetics
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Synergism
Feedback, Sensory - drug effects
Gait Disorders, Neurologic - chemically induced
Humans
Hypothermia - chemically induced
Indoles - pharmacology
JWH-018
JWH-073
JWH-250
Male
Mice
Mice, Inbred ICR
Microdialysis
Naphthalenes - pharmacology
Nervous System Diseases - chemically induced
Pain Threshold - drug effects
Reflex, Acoustic - drug effects
Spleen - cytology
Vision, Ocular - drug effects
Δ9-THC
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Summary:JWH-250 and JWH-073 are two synthetic cannabinoid agonists with nanomolar affinity at CB1 and CB2 receptors. They are illegally marketed within “herbal blend” for theirs psychoactive effects greater than those produced by Cannabis. Recently, we analyzed an “herbal” preparation containing a mixture of both JWH-250 and JWH-073. The present study was aimed at investigating the in vitro and in vivo pharmacological activity of JWH-250 and JWH-073 in male CD-1 mice. In vitro competition binding experiments performed on mouse and human CB1 and CB2 receptors revealed a nanomolar affinity and potency of the JWH-250 and JWH-073. In vivo studies showed that JWH-250 and JWH-073, administered separately, induced a marked hypothermia, increased pain threshold to both noxious mechanical and thermal stimuli, caused catalepsy, reduced motor activity, impaired sensorimotor responses (visual, acoustic and tactile), caused seizures, myoclonia, hyperreflexia and promote aggressiveness in mice. Moreover, microdialysis study in freely moving mice showed that systemic administration of JWH-250 and JWH-073 stimulated dopamine release in the nucleus accumbens in a dose-dependent manner. Behavioral, neurological and neurochemical effects were fully prevented by the selective CB1 receptor antagonist/inverse agonist AM 251. Co-administration of ineffective doses of JWH-250 and JWH-073 impaired visual sensorimotor responses, improved mechanical pain threshold and stimulated mesolimbic DA transmission in mice, living unchanged all other behavioral and physiological parameters. For the first time the present study demonstrates the overall pharmacological effects induced by the administration of JWH-250 and JWH-073 in mice and it reveals their potentially synergistic action suggesting that co-administration of different synthetic cannabinoids may potentiate the detrimental effects of individual compounds increasing their dangerousness and abuse potential. •JWH-250 and JWH-073 impaired sensorimotor responses in mice.•JWH-250 and JWH-073 facilitated extracellular DA release in the NAc shell.•Effects of JWH-250 and JWH-073 depend on CB1 receptor stimulation.•JWH-250 and JWH-073 potential synergistically impaired visual response.•Combination of JWH-250 and JWH-073 potential synergistically stimulated DA release.
ISSN:0278-5846
1878-4216
DOI:10.1016/j.pnpbp.2016.01.007