Given the potent depressant effects of adenosine on spontaneous neuronal firing, it has been proposed that endogenous adenosine may function as an important modulator of neuronal activity involved in the etiology or control of seizures. In accordance with this proposal, metabolically stable adenosine analogs have been shown to elevate pentylenetetrazol (PTZ) seizure threshold in rats. Moreover, the seizure suppressant effects of adenosine analogs were antagonized by the adenosine receptor antagonist, theophylline. This proposal describes the use of the PTZ seizure threshold model in combination with other pharmacological, neuroanatomical and biochemical approaches to further our understanding of the involvement of adenosine in seizure mechanisms. An assignment of the adenosine receptor subtype involved in seizure suppressant effects of adenosine analogs remains to be elucidated. A rigorous pharmacological characterization of the adenosine receptor involve in the regulation of PTZ seizure threshold will be accomplished by determining the rank order potencies of several adenosine analogs administered intracerebroventricularly (i.c.v.) in rats. The rank order potencies of a series of xanthines, administered i.c.v., as proconvulsants in the PTZ seizure threshold model will also be determined. Possible correlations between the rank order potencies of adenosine analogs as seizure suppressants and their affinities for adenosine A1 receptors as labeled by (3H)cyclohexyladenosine will be explored. A delineation of the neuroanatomic substrate for the anticonvulsant actions of adenosine analogs is essential in attempts to elucidate the basic cellular and molecular mechanisms involved. To this end, the effects of adenosine analogs microinjected into various rat brain structures on PTZ seizure threshold will be determined. A further understanding of the biochemical and neuroanatomical mechanisms responsible for the effects of adenosine analogs on seizure susceptibility may provide insight into one of the basic mechanisms of seizure disorders in man.
