MAM-2201, a synthetic cannabinoid drug of abuse, suppresses the synaptic input to cerebellar Purkinje cells via activation of presynaptic CB1 receptors.
Herbal products containing synthetic cannabinoids-initially sold as legal alternatives to marijuana-have become major drugs of abuse. Among the synthetic cannabinoids, [1-(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl)-methanone (MAM-2201) has been recently detected in herbal products and has psychoactive and intoxicating effects in humans, suggesting that MAM-2201 alters brain function. Nevertheless, the pharmacological actions of MAM-2201 on cannabinoid receptor type 1 (CB1R) and neuronal functions have not been elucidated. We found that MAM-2201 acted as an agonist of human CB1Rs expressed in AtT-20 cells. In whole-cell patch-clamp recordings made from Purkinje cells (PCs) in slice preparations of the mouse cerebellum, we also found that MAM-2201 inhibited glutamate release at parallel fiber-PC synapses via activation of presynaptic CB1Rs. MAM-2201 inhibited neurotransmitter release with an inhibitory concentration 50% of 0.36 μM. MAM-2201 caused greater inhibition of neurotransmitter release than Δ(9)-tetrahydrocannabinol within the range of 0.1-30 μM and JWH-018, one of the most popular and potent synthetic cannabinoids detected in the herbal products, within the range of 0.03-3 μM. MAM-2201 caused a concentration-dependent suppression of GABA release onto PCs. Furthermore, MAM-2201 induced suppression of glutamate release at climbing fiber-PC synapses, leading to reduced dendritic Ca(2+) transients in PCs. These results suggest that MAM-2201 is likely to suppress neurotransmitter release at CB1R-expressing synapses in humans. The reduction of neurotransmitter release from CB1R-containing synapses could contribute to some of the symptoms of synthetic cannabinoid intoxication including impairments in cerebellum-dependent motor coordination and motor learning.
Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan. Electronic address: irie@nihs.go.jp.
Tomohiko
T
Irie
Division of Pharmacognosy, Phytochemistry, and Narcotics, National Institute of Health Sciences, Tokyo, Japan.
Ruri
R
Kikura-Hanajiri
Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
Makoto
M
Usami
Division of Pharmacognosy, Phytochemistry, and Narcotics, National Institute of Health Sciences, Tokyo, Japan.
Nahoko
N
Uchiyama
Division of Drugs, National Institute of Health Sciences, Tokyo, Japan.
Yukihiro
Y
Goda
Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan. Electronic address: yukos@nihs.go.jp.
Yuko
Y
Sekino
D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D013287:Illicit Drugs / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011619:Psychotropic Drugs / Q000737:chemistry / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects* / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D017661:Receptors, Presynaptic / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C000594853:1-(5-fluoropentyl)-3-(4-methyl-1-naphthoyl)indole; D013287:Illicit Drugs; D007211:Indoles; D009281:Naphthalenes; D011619:Psychotropic Drugs; D043884:Receptor, Cannabinoid, CB1; D017661:Receptors, Presynaptic; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D013759:Dronabinol; C552597:1-pentyl-3-(1-naphthoyl)indole; D002118:Calcium
Cannabinoid receptor type 1; Cerebellum; MAM-2201; Neurotransmitter release; Purkinje cell; Synthetic cannabinoids