CONTRASTING EFFECTS OF ADENOSINE-A1 AND ADENOSINE-A2 RECEPTOR LIGANDSIN DIFFERENT CHEMOCONVULSIVE RODENT MODELS

The pro- and anticonvulsive properties of selective adenosine A1 and A 2 receptor agonists and antagonists were investigated in mice using se izure models involving a specific blockade of adenosine A1 and A 2 rec eptors, modulation of the gamma-aminobutyric acid/benzodiazepine recep tor complex or activation with the excitatory amino acid glutamate. Th e selective adenosine A1 receptor agonists N-cyclopentyladenosine (CPA ) and R-N-(phenylisopropyl)adenosine (R-PIA) in doses of 1 and 10 mg/k g i.p. potentiated seizures induced by the selective adenosine A1 rece ptor antagonist ]carbonyl]methyl]oxy]-phenyl]-1,3-dipropylxanthine (XA C). Likewise, the selective adenosine A2 receptor agonists N-[(2-methy lphenyl)methyl]adenosine (metrifudil) and dimethoxyphenyl)-2-(2-methyl phenyl)ethyl]adenosine (DPMA), in doses of 30 and 100 mg/kg i.p., resp ectively, potentiated seizures induced by the selective adenosine A2 r eceptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX). In contras t, the adenosine A1 and A2 receptor agonists both antagonized seizures induced by 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM - an inverse agonist at benzodiazepine receptors) and the adenosine A1 receptor agonists also protected against seizures induced by glutamate . Paradoxically, the selective adenosine A1 receptor antagonist 8-cycl opentyl-1,3-dimethytxanthine (CPT) antagonized DMCM- and pentylenetetr azole-induced seizures. Thus, it appears that adenosine A1 and A2 rece ptor agonists can be both pro- and anticonvulsive depending on the mec hanism of action of the chemoconvulsant used in the seizure model. The findings with CPT suggest that other types of adenosine analogues tha n agonists may possess anticonvulsive properties.