The effects of various metabolically-stable analogs of
adenosine on the threshold for
seizures in rats was determined by measuring the dose of
pentylenetetrazol (PTZ), infused through a tail vein, required to elicit a
myoclonic jerk. The
adenosine receptor agonists,
2-chloroadenosine (2-ClAdo), cyclohexyladenosine (CHA) and L- and D-
phenylisopropyladenosine (L- and D-PIA), all produced dose-dependent elevations of the seizure threshold for
pentylenetetrazol in rats. L-Phenylisopropyl-
adenosine was the most potent analog of
adenosine tested with a dose as small as 5 micrograms/kg (i.v.) producing a 23% increase in seizure threshold for
pentylenetetrazol. The rank order of the potency of
adenosine agonists in increasing the seizure threshold was L-PIA greater than 2-ClAdo greater than CHA greater than D-PIA, with L-PIA being 79 times more potent than D-PIA. In contrast to these effects, the
adenosine receptor antagonist,
theophylline, elicited a proconvulsant effect in doses from 15 to 60 mg/kg (i.p.). The effect of
theophylline in reducing seizure threshold for
pentylenetetrazol peaked at 30 mg/kg, a dose which reduced the seizure threshold by approx. 27%. Support for the involvement of recognition sites for
adenosine in the observed modulation of seizure threshold was provided by the antagonism of the elevation of the seizure threshold for
pentylenetetrazol induced by 2-ClAdo, by pretreatment with
theophylline (5 mg/kg, i.v.). These findings provide support for the idea that endogenous
adenosine may function as a regulator of seizure susceptibility.