In vivo benzodiazepine receptor occupancy by CL 218,872 visualized by positron emission tomography in the brain of the living baboon: modulation by GABAergic transmission and relation with anticonvulsant activity

Abstract

In vivo benzodiazepine receptor occupancy by increasing doses of CL 218,872 has been evaluated in the baboon Papio papio, using (11C) RO 15-1788 as specific radioligand and positron emission tomography as external detection system. Although BZR heterogeneity has been previously demonstrated in the brain of the living baboon using PET, we did not observe in our studies that CL 218,872 interacts preferentially with one of the BZR subtypes. The monophasic pattern of the dose dependent CL 218,872 displacement curve and the corresponding "in vivo Hill coefficient" near unity suggest that CL 218,872 binds in cerebral baboon cortex with a similar affinity with BZ1 as well as BZ2 subtypes. The anticonvulsant properties of CL 218,872 against bicuculline and allylglycine-induced seizures were correlated with benzodiazepine receptor occupancy by assessment of electroencephalographic activity during positron emission tomography studies. Our data confirmed in vivo the hypothesis of a partial agonist anticonvulsant activity of CL 218,872. At the same time, the use of a GABA-antagonist (bicuculline) or an inhibitor of the GABA synthesis (allylglycine) suggested the existence of an allosteric interaction between benzodiazepine receptors and GABA receptors.

Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABAA/α1 receptors

“…Because of the low intrinsic efficacy of CL 218,872 (e.g. Melchior et al 1984;de la Sayette et al 1991;Tang and Franklin 1991;Wafford et al 1993), this finding suggests that substitution for zolpidem at training doses of 3.0 mg/kg or greater requires high intrinsic efficacy in addition to selectivity at the GABA A /a 1 subtype.…”

In Vivo High Intrinsic Efficacy of Triazolam: A Positron Emission Tomography Study in Nonhuman Primates

“…Thus, this percentage is likely to be independent of our anesthetic procedure. As discussed previously (Brouillet et al, 1991), the percentage of the PTZ dose increase gives a good estimate of the graded anticonvulsant effect of the BZR ligands, as a result of an allosteric regulation of the GABA, receptor complex.…”

“…This PET device allowed reconstruction of seven slices with spatial and axial resolutions of 5.7 and 9 mm, respectively (Trebossen and Mazoyer, 1991). The animals were prepared for the PET experiments as previously described (Brouillet et al, 1991). After subcutaneous electrodes were placed on the baboon's skull, the head was positioned inside the positron camera as described previously, and the EEG recording was started.…”

“…The [ "Clflumazenil nondisplaceable binding represents less than 15% of the total binding after 20 rnin (Hantraye et al, 1984;Goeders and Kuhar, 1985;Brouillet et al, 1990). The regional specific binding was estimated at To+,, min by subtracting the regional nondisplaceable binding from the regional total binding (Pappata et al, 1988;Persson et al, 1989;Brouillet et al, 1991) and expressed as percentage of the regional maximal specific binding (measured at time To+*,).…”

“…Positron emission tomography (PET) has made feasible the noninvasive study of the interaction of many ligands with the BZR using the radioligand ["CIflumazenil both in nonhuman primates (MaziZre et a]., 1984; Brouillet et a]., 1990, 199 1 ; De la Sayette et al, 199 1 ; Delforge et al, 1993) and in humans (Samson et al, 1985;Pappata et al, 1988;Persson et al, 1989;Shinotoh et al, 1989). W e recently showed that the PET technique in combination with EEG recording can be used to measure in vivo pharmacological properties of BZR ligands, in particular their in vivo intrinsic efficacy (Brouillet et al, 1991). T h e intrinsic efficacy of a ligand defines, independently of the ligand's potency and affinity, its capability to activate a receptor, which in turn produces the pharmacological effects.…”