Correlation between benzodiazepine receptor occupation and anticonvulsant effects of diazepam

Abstract

The benzodiazepines are potent anticonvulsants for a wide variety of experimental and clinical seizure disorders. The demonstration of saturable, high-affinity and stereospecific binding sites for the benzodiazepines in the mammalian central nervous system suggests the presence of pharmacological receptors mediating the anticonvulsant properties of these compounds. The good correlation between the anticonvulsant potencies of a series of benzodiazepines and their ability to inhibit 3H-diazepam binding in vitro further supports this hypothesis, but evidence for a direct interaction between benzodiazepines and their receptors, and a subsequent inhibition of seizure activity (or elevation of seizure threshold) is lacking. Recent reports from our laboratory and others have demonstrated the feasibility of labelling benzodiazepine receptors in vivo following parental administration of tritiated benzodiazepine. This technique permits one to study the relationship between the anticonvulsant activity of the benzodiazepines in vivo and the number of 'drug-occupied' receptors in vitro. We now report that there is an excellent correlation between benzodiazepine receptor occupancy by diazepam and protection against pentylenetetrazol-induced seizures. Furthermore, these results demonstrate that only a small fraction of benzodiazepine receptors need be occupied to produce a complete anticonvulsant effect.

The role of the benzodiazepine receptor in mediating long-lasting anticonvulsant effects and the late-appearing reductions in motor activity and exploration

“…Both effects remained significant for longer than ] 5 h. These results are in agreement with previous studies (Paul et al 1979;File et ai. 1985;Wilks et al 1987).…”

Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy.

“…Nonetheless, autoradiographic studies indicate that a significant regional heterogeneity in the distribution of BZ receptor agonists exists in the brains of animals with HE, such that local concentrations of BZ receptor agonists may be much higher than whole-brain concentrations (15). In these studies, radioligand binding to BZ receptors in the cortex and cerebellum of animals with HE was reduced by 22% and 42%, respectively (15), which is similar to the level of BZ receptor occupation observed following the administration of diazepam at 4-18 mg/kg (an anticonvulsant and hypnotic dose) to normal rats (22,23). Moreover, the ability of BZ receptor antagonists to correct both the electrophysiological and behavioral manifestations of HE in animal models (3)(4)(5) and humans (12)(13)(14) indicates that the concentrations of BZ receptor agonists found in liver failure appear sufficient to produce some of the behavioral manifestations of HE.…”

Screening vasoconstriction inhibitors from traditional Chinese medicines using a vascular smooth muscle/cell membrane chromatography‐offline‐liquid chromatography‐mass spectrometry

“…DZ [34] and NZ [35] are benzodiazepine receptor antagonists, but exhibit no retention characteristics as they specifically act on neurons [36] that express abundant benzodiazepine receptors [37]. As such, in the VSM/CMC model, active components against specific targets in the membrane environment could be selectively retained, whereas inactive impurities were directly eliminated.…”