Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release.
Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa, has therapeutic potential for certain psychiatric and neurological disorders. Studies in laboratory animals and limited human trials indicate that CBD has anticonvulsant and neuroprotective properties. Its effects against cocaine neurotoxicity, however, have remained unclear. Thus, the present study tested the hypothesis that CBD protects against cocaine-induced seizures and investigated the underlying mechanisms. CBD (30 mg/kg) pre-treatment increased the latency and reduced the duration of cocaine (75 mg/kg)-induced seizures in mice. The CB1 receptor antagonist, AM251 (1 and 3mg/kg), and the CB2 receptor antagonist, AM630 (2 and 4 mg/kg), failed to reverse this protective effect, suggesting that alternative mechanisms are involved. Synaptosome studies with the hippocampus of drug-treated animals revealed that cocaine increases glutamate release, whereas CBD induces the opposite effect. Finally, the protective effect of this cannabinoid against cocaine-induced seizure was reversed by rapamycin (1 and 5mg/kg), an inhibitor of the mammalian target of rapamycin (mTOR) intracellular pathway. In conclusion, CBD protects against seizures in a model of cocaine intoxication. These effects possibly occur through activation of mTOR with subsequent reduction in glutamate release. CBD should be further investigated as a strategy for alleviating psychostimulant toxicity.
Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
Pedro H
PH
Gobira
Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
Luciano R
LR
Vilela
Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
Bruno D C
BD
Gonçalves
Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
Rebeca P M
RP
Santos
Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
Antonio C
AC
de Oliveira
Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
Luciene B
LB
Vieira
Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
Daniele C
DC
Aguiar
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.
José A
JA
Crippa
Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil. Electronic address: fabriciomoreira@icb.ufmg.br.
Fabricio A
FA
Moreira
D000779:Anesthetics, Local / Q000633:toxicity; D000818:Animals; D000932:Antiemetics / Q000627:therapeutic use*; D002185:Cannabidiol / Q000627:therapeutic use*; D003042:Cocaine / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D000779:Anesthetics, Local; D000932:Antiemetics; D007166:Immunosuppressive Agents; D007211:Indoles; D002185:Cannabidiol; D018698:Glutamic Acid; D058570:TOR Serine-Threonine Kinases; D003042:Cocaine; C094023:iodopravadoline; D020123:Sirolimus
Cannabidiol; Cocaine; Glutamate; Neurotoxicity; Seizure; mTOR