A1
adenosine receptors in the rat prepiriform cortex play an important role in the inhibition of
bicuculline methiodide-induced convulsions. In the present study we evaluated manipulation of endogenous
adenosine in this brain area as a strategy to effect seizure suppression. All compounds evaluated were unilaterally microinjected into the rat prepiriform cortex. Administration of exogenous
adenosine afforded a dose-dependent protection (ED50 = 48.1 +/- 8.4 nmol) against
bicuculline methiodide-induced
seizures, and these
anticonvulsant effects were significantly potentiated by treatment with an
adenosine kinase inhibitor, 5'-amino-5'-
deoxyadenosine; by the
adenosine transport blockers,
dilazep or nitrobenzylthioinosine 5'-monophosphate; and by an
adenosine deaminase inhibitor,
2'-deoxycoformycin. When administered alone,
5'-amino-5'-deoxyadenosine, 5'-iodotubercidin and
dilazep were found to be highly efficacious as
anticonvulsants with respective ED50 values of 2.6 +/- 0.8, 4.0 +/- 2.7 and 5.6 +/- 1.5 nmol. In contrast,
2'-deoxycoformycin was both less potent and less efficacious. These results suggest that accumulation of endogenous
adenosine may contribute to seizure suppression, and that
adenosine kinase and
adenosine transport may play a pivotal role in the regulation of extracellular levels of
adenosine in the central nervous system. The
adenosine antagonist,
8-(p-sulfophenyl)theophylline, increased markedly the severity of
bicuculline methiodide-induced
seizures. Moreover, reduction of extracellular
adenosine formation by a focal injection of an
ecto-5'-nucleotidase inhibitor, alpha, beta-methyleneadenosine
diphosphate, produced
generalized seizures (ED50 = 37.3 +/- 22.7 nmol). Together the proconvulsant effect of an
adenosine receptor antagonist and the
convulsant action of an
ecto-5'-nucleotidase inhibitor further support the role of endogenous
adenosine as a tonically active antiepileptogenic substance in the rat prepiriform cortex.