Relationships between benzodiazepine receptors, impairment of GABAergic transmission and convulsant activity of beta-CCM: a PET study in the baboon Papio papio.
Central type benzodiazepine receptors were studied in vivo by positron emission tomography in brain areas of 2 different groups of the baboon Papio papio: non-photosensitive (group 1) and those with an allylglycine-induced decrease in GABA-mediated inhibition (group 2). Further, a naturally photosensitive Papio papio (+3 level of photosensitive response) was compared to both groups. Regional brain binding of the specific benzodiazepine receptor ligand, [11C]Ro 15-1788, was not significantly different between groups 1 and 2. In addition, the data from the naturally photosensitive Papio papio did not seem to differ markedly from groups 1 and 2 either. Pharmacological effects of increasing doses of beta-CCM (0.05-3 mg/kg i.v.) and regional benzodiazepine receptor occupancy by the drug were simultaneously studied using electroencephalographic activity recording and positron emission tomography. A positive correlation was observed between the degree of photosensitivity of the baboon and sensitivity to the action of beta-CCM, with increasing convulsant efficacy of beta-CCM in going from group 1 to the naturally photosensitive baboon, then to group 2. Dose-related displacement curves of [11C]Ro 15-1788 binding by beta-CCM revealed that reduction in brain GABA concentration did not modify the inhibitory potency of beta-CCM on [11C]Ro 15-1788 binding in cerebral cortex. This suggests a lack of detectable in vivo allosteric effects of GABA on beta-CCM binding during beta-CCM-induced seizures. Thus, a given dose of beta-CCM displayed increasing pharmacological potency in going from baboons with the lowest photosensitivity to those with the highest, whereas benzodiazepine receptor occupancy by beta-CCM was similar in the cerebral cortex of the different baboons. Conversely, a given level of convulsant activity of beta-CCM was related to a different benzodiazepine receptor occupancy by the drug, depending on the photosensitivity of Papio papio. A given dose of a drug may, thus, have a different pharmacological potency when occupying the same number of receptors, depending on the physiopathological state of the subject.
Chavoix
C
C
Département de Biologie, Service Hospitalier Frédéric Joliot, C.E.A., Orsay, France.
Brouillet
E
E
Kunimoto
M
M
De la Sayette
V
V
Khalili-Varasteh
M
M
Hantraye
P
P
Dodd
R H
RH
Guibert
B
B
Prenant
C
C
Naquet
R
R
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002243:Carbolines / Q000378:metabolism / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology*; D005442:Flumazenil / Q000493:pharmacokinetics; D008297:Male; D010215:Papio; D011963:Receptors, GABA-A / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission; D014055:Tomography, Emission-Computed; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D002243:Carbolines; D003292:Convulsants; D011963:Receptors, GABA-A; C026072:1-methyl-beta-carboline-3-carboxylic acid; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid