Altered GABAAReceptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using11C-Flumazenil and PET

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Abstract
The aim of the present study was to investigate if flumazenil blood–brain barrier transport and binding to the benzodiazepine site on the γ-aminobutyric acid A (GABAA) receptor complex is altered in an experimental model of epilepsy and subsequently to study if changes in P-glycoprotein (P-gp)–mediated efflux of flumazenil at the blood–brain barrier may confound interpretation of 11C-flumazenil PET in epilepsy. Methods: The transport of flumazenil across the blood–brain barrier and the binding to the benzodiazepine site on the GABAA receptors in 5 different brain regions was studied and compared between controls and kainate-treated rats, a model of temporal lobe epilepsy, with and without tariquidar pretreatment. In total, 29 rats underwent 2 consecutive 11C-flumazenil PET scans, each one lasting 30 min. The tracer was mixed with different amounts of isotopically unmodified flumazenil (4, 20, 100, or 400 μg) to cover a wide range of receptor occupancies during the scan. Before the second scan, the rats were pretreated with a 3 or 15 mg/kg dose of the P-gp inhibitor tariquidar. The second scan was then obtained according to the same protocol as the first scan. Results: GABAA receptor density, Bmax, was estimated as 44 ± 2 ng⋅mL−1 in the hippocampus and as 33 ± 2 ng⋅mL−1 in the cerebellum, with intermediate values in the occipital cortex, parietal cortex, and caudate putamen. Bmax was decreased by 12% in kainate-treated rats, compared with controls. The radiotracer equilibrium dissociation constant, KD, was similar in both rat groups and all brain regions and was estimated as 5.9 ± 0.9 ng⋅mL−1. There was no difference in flumazenil transport across the blood–brain barrier between control and kainate-treated rats, and the effect of tariquidar treatment was similar in both rat groups. Tariquidar treatment also decreased flumazenil transport out of the brain by 73%, increased the volume of distribution in the brain by 24%, and did not influence Bmax or KD, compared with baseline. Conclusion: Bmax was decreased in kainate-treated rats, compared with controls, but no alteration in the blood–brain barrier transport of flumazenil was observed. P-gp inhibition by tariquidar treatment increased brain concentrations of flumazenil in both groups, but Bmax estimates were not influenced, suggesting that 11C-flumazenil scanning is not confounded by alterations in P-gp function.

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