[I-123] IOMAZENIL SPECT IMAGING DEMONSTRATES SIGNIFICANT BENZODIAZEPINE RECEPTOR RESERVE IN HUMAN AND NONHUMAN PRIMATE BRAIN

SPECT imaging with [I-123]iomazenil was used to measure benzodiazepine (BZ) neuroreceptor occupancy of the agonist lorazepam administered at therapeutically relevant doses in humans and supratherapeutic doses i n monkeys. Lorazepam at therapeutic doses (0.03 mg/kg, i.v.) administe red 90 min after the bolus injection of [I-123]iomazenil had no statis tically significant effect (P > 0.12) on the washout rates of regional brain activities compared to that in control subjects, although human subjects demonstrated marked sedation from the lorazepam. In baboons, the effects of higher doses of lorazepam (cumulative 0.5 mg/kg) were examined in a stepwise displacement paradigm. The in vivo potency was expressed as the ED50 (or dose required to displace 50% of receptor bo und activity) and was equal to 0.34 +/- 0.01 mg/kg (mean +/- SD, n = 1 2). Log logit analyses of displacement data corrected for endogenous w ashout showed that therapeutic doses of lorazepam were associated with <3% BZ receptor occupancy. To examine if endogenous GABA modulates po tency of the BZ agonist, the ED50 of lorazepam was compared with and w ithout concurrent administration of tiagabine, a GABA reuptake inhibit or. These experiments were designed to measure an in vivo GABA shift o f agonist potency. In vivo microdialysis demonstrated that tiagabine ( up to 1 mg/kg, i.v.) increased extracellular GABA levels up to 200% of baseline, but these doses had only a minimal enhancement of lorazepam 's potency to displace [I-123]iomazenil. This study strongly suggests that single therapeutically relevant doses of lorazepam occupy a relat ively small percentage (i.e. <3%) of BZ receptors and that BZ binding sites have a significant (i.e. >97%) receptor reserve.