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.

Partially purified extracts of bovine brain were previously found to inhibit competitively the binding of [3HJ-diazepam to-rat brain synaptosomal membranes. The purines inosine and hypoxanthine were subsequently identified as the compounds responsible for this inhibitory activity. Intracerebroventricular administration of inosine to mice of the C3H/ HEN and NIH general purpose strains caused a dose-and time-dependent increase in the latency to clonicotonic seizures produced by intraperitoneal administration of the convulsant pentylenetetrazole. Intracerebroventricular administration of equimolar doses of 2'-deoxyinosine, which is more potent than inosine in inhibiting the binding of [3H1diazepam in vitro, significantly increased pentylenetetrazole-evoked seizure latency. In contrast, both 7-methylinosine and thymidine were ineffective in inhibiting the in vitro binding of [3Hldiazepam and increasing the latency to pentylenetetrazole-induced seizures in vivo. These results suggest that endogenously occurring purines such as inosine exhibit diazepam like effects when administered intracerebroventricularly, and these effects may be related to the interaction of inosine and related compounds with benzodiazepine receptors in the central nervous system.The characterization of saturable, high affinity, and stereospecific benzodiazepine binding sites in the central nervous system has been described in vitro and in vivo (1-7). The good correlations obtained between the binding affinity of a series of benzodiazepines in vitro and their anticonvulsant (4), anxiolytic (8), and muscle relaxant properties (4) strongly suggests that these sites may be receptors mediating the pharmacologic actions of the benzodiazepines. However, neither the regional distribution of benzodiazepine binding sites within the central nervous system nor the screening of a large number of putative neurotransmitter substances (1, 8) has provided evidence that such receptor sites are associated with classical neurotransmitter pathways. These findings have prompted a search for an endogenously occurring compound(s) that binds to the benzodiazepine receptor and functions as a physiological ligand (9, 10).Low molecular weight substances that are heat stable, dialyzable, and competitively inhibit [3H]diazepam binding to synaptosomal membranes in vitro have been isolated from bovine brain (9, 11). These substances have been subsequently identified as the purines inosine and hypoxanthine, and it has been suggested that they may modulate the benzodiazepine receptor in vivo (11). Since the inhibition of pentylenetetrazole (PTZ)-induced seizures has been used as a sensitive measure for assessing benzodiazepinelike activity in vivo, the effects of inosine and related compounds have been examined by using this paradigm. We now report that the intracerebroventricular (ICV) administration of inosine elicits a dose-and time-dependent increase in the latency period between the intraperitoneal injection of PTZ After the recovery period, mice were injected IC...

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