Microinjection of a benzodiazepine into substantia nigra elevates kindled seizure threshold

The purpose of these experiments was to initiate investigations of the brain site(s) at which the benzodiazepines exert their anticonvulsant effect. We examined the effects of microinjections of clonazepam into substantia nigra (SN) on seizure threshold in the kindling model. We also examined the distribution of microinjected [3H]methylclonazepam with autoradiographic methods. Microinjection of clonazepam bilaterally into substantia nigra pars reticulata (SNR), but not nearby, produced a 75% elevation of generalized seizure threshold. Quantitative analysis of autoradiographic studies indicated that the vast majority of [3H]methylclonazepam was distributed within 400 micron of the injection cannula tip; even optimally placed injections did not result in drug access throughout the entire SN. The data demonstrate that local application of an anticonvulsant benzodiazepine to the substantia nigra alone is sufficient to suppress seizures. We suggest that the substantia nigra is one site at which systemically administered benzodiazepines act to suppress seizures.