Yohimbine-induced seizures involve NMDA and GABAergic transmission.
The alpha 2-antagonist, yohimbine has been shown to dose-dependently induce clonic seizures in mice. The convulsant effects of yohimbine are not due to alpha 2-antagonism, as other alpha 2-antagonists, such as rauwolscine and idazoxan, did not produce seizures at doses up to 100 mg/kg. Since GABAmimetic and excitatory amino acid antagonist agents attenuate yohimbine-induced seizures, the respective contribution of these systems to the production of yohimbine seizures was investigated. The CD50 dose of yohimbine (dose required to produce clonic seizures in 50% of the mice) was determined to be 25.5 mg/kg (s.c.). The CD15 dose of N-methyl-DL-aspartic acid (NMDLA), bicuculline and methyl-6,7-dimethoxy-4 ethyl-beta carboline-3-carboxylate (DMCM) significantly potentiated the convulsant effects of yohimbine, such that the CD50 dose was decreased from 25.5 mg/kg to 1.6, 10.9 and 9.9 mg/kg, respectively. Furthermore, the potentiation in the presence of NMDLA was significantly greater than either bicuculline or DMCM. These results suggest that yohimbine-induced seizures are not only mediated through the impairment of GABAergic transmission but moreover, by a possible endogenous enhancement of excitatory amino acid transmission. In addition, the effects of GABAmimetic agents, competitive and non-competitive NMDA receptor antagonists and strychnine-insensitive glycine receptor antagonists were compared in the yohimbine-, bicuculline- and NMDLA-induced seizure assays.
Dunn
R W
RW
Hoechst-Roussel Pharmaceuticals Inc., Somerville, NJ 08876.
Corbett
R
R
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D003292:Convulsants / Q000633:toxicity*; D004146:Dioxanes / Q000494:pharmacology; D019329:Idazoxan; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000494:pharmacology / Q000502:physiology*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects*; D015016:Yohimbine / Q000633:toxicity*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D002243:Carbolines; D003292:Convulsants; D004146:Dioxanes; D011942:Receptors, Adrenergic, alpha; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D015016:Yohimbine; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D019329:Idazoxan; D001640:Bicuculline