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Signal Transduction and Modulation

開催日 2014/9/13
時間 11:00 - 12:00
会場 Poster / Exhibition(Event Hall B)

MAM-2201, a Newly Emerged Abused Drug, Potently Suppresses Synaptic Transmission via CB1R, and Reduces Synaptically-Evoked Dendritic Ca2+ Transient in Cerebellar Neurons of Mice

  • P3-001
  • 入江 智彦 / Tomohiko Irie:1 花尻(木倉) 瑠理 / Ruri Kikura-Hanajiri:2 宇佐見 誠 / Makoto Usami:1 内山 奈穂子 / Nahoko Uchiyama:2 合田 幸広 / Yukihiro Goda:3 関野 祐子 / Yuko Sekino:1 :1
  • 1:国立医薬品食品衛生研薬理 / Div Pharmacology, National Institute of Health Sciences 2:国立医薬品食品衛生研生薬 / Div Pharmacognosy, Phytochemistry, Narcotics, National Institute of Health Sciences 3:国立医薬品食品衛生研薬品 / Div Drugs, Narcotics, National Institute of Health Sciences 

Endocannabinoid signaling enables neurons to inhibit synaptic transmission retrogradely via presynaptic cannabinoid receptor type 1 (CB1R). The endocannabinoid signaling has been extensively investigated in the cerebellum. Therefore, the cerebellum is considered to be the ideal neuronal circuit to study the pharmacological effects of cannabinoid-related compounds on the brain. In the cerebellum, Purkinje cells (PCs) are principal neurons, and receive two glutamatergic excitatory inputs: climbing fiber (CF) and parallel fiber (PF). PCs also receive GABAergic inhibitory inputs from molecular layer interneurons. Synthetic cannabinoid receptor agonists inhibit these three types of synapses by activation of presynaptic CB1R. Recently, MAM-2201 is a newly emerged synthetic cannabinoid as an abused drug. MAM-2201 causes a psychotic state and serious health damage in human, implying MAM-2201 has potent psychoactivity and intoxication. Nevertheless, pharmacological effects of MAM-2201 on the brain have not been elucidated yet.
In this study, we investigated the effects of MAM-2201 on synaptic transmission onto PCs using acute cerebellar slice preparations of mice. Whole-cell patch-clamp recordings revealed that MAM-2201 showed stronger inhibition on PF-PC synapses via CB1R activation than JWH-018, a widely abused synthetic cannabinoid. MAM-2201 also suppressed presynaptically GABAergic transmission from the interneurons concentration-dependently. Furthermore, MAM-2201-induced presynaptic suppression of CF-PC synapses led to reduction of activity of CF-evoked complex spikes and dendritic Ca2+ transient. These results suggest that abuse of MAM-2201 inhibits transmitter release in various regions of the brain, and that the inhibition causes adverse effects including motor dysfunction.

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