The pro- and anticonvulsive properties of selective
adenosine A1 and A2 receptor agonists and antagonists were investigated in mice using seizure models involving a specific blockade of
adenosine A1 and A2 receptors, modulation of the
gamma-aminobutyric acid/
benzodiazepine receptor complex or activation with the
excitatory amino acid glutamate. The selective
adenosine A1 receptor agonists N-cyclopentyladenosine (CPA) and R-N-(phenylisopropyl)
adenosine (
R-PIA) in doses of 1 and 10 mg/kg i.p. potentiated
seizures induced by the selective
adenosine A1 receptor antagonist 8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]oxy]-phenyl]-
1,3-dipropylxanthine (XAC). Likewise, the selective
adenosine A2 receptor agonists N-[(2-methylphenyl)methyl]
adenosine (
metrifudil) and N-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]
adenosine (
DPMA), in doses of 30 and 100 mg/kg i.p., respectively, potentiated
seizures induced by the selective
adenosine A2 receptor antagonist
3,7-dimethyl-1-propargylxanthine (
DMPX). In contrast, the
adenosine A1 and A2 receptor agonists both antagonized
seizures induced by methyl-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-cyclopentyl-1,3-dimethylxanthine (
CPT) antagonized
DMCM- and
pentylenetetrazole-induced
seizures. Thus, it appears that
adenosine A1 and A2 receptor agonists can be both pro- and anticonvulsive depending on the mechanism of action of the chemoconvulsant used in the seizure model. The findings with
CPT suggest that other types of
adenosine analogues than agonists may possess anticonvulsive properties.