title: Effect of JWH-250, JWH-073 and their interaction on "tetrad", sensorimotor, neurological and neurochemical responses in mice.
abstract: 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.
authors.affiliation: Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ossato
authors.affiliation: Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Canazza
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: De Luca
authors.affiliation: Department of Public Health and Community Medicine, University of Verona, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rimondo
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.affiliation: Department of Medical Sciences, University of Ferrara, Italy.
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.affiliation: Department of Neuroscience, Psychology, Medicine and Child Health (NEUROFARBA), University of Florence, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Serpelloni
authors.affiliation: Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, Italy; Center for Neuroscience and Istituto Nazionale di Neuroscienze, Italy. Electronic address: m.marti@unife.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Marti
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003511:Cyclohexanols / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D056228:Feedback, Sensory / Q000187:drug effects*; D020233:Gait Disorders, Neurologic / Q000139:chemically induced*; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009281:Naphthalenes / Q000494:pharmacology*; D009422:Nervous System Diseases / Q000139:chemically induced*; D017288:Pain Threshold / Q000187:drug effects; D012022:Reflex, Acoustic / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D014785:Vision, Ocular / Q000187:drug effects
chemical_list: C569194:1-(1- pentyl-1H-indol-3-yl)-2-(2-methoxyphenyl)ethanone; D000840:Anisoles; D003511:Cyclohexanols; D007211:Indoles; D009281:Naphthalenes; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C568258:JWH-073
keywords: JWH-018; JWH-073; JWH-250; Microdialysis; Δ(9)-THC