We have studied the effects of selective and non-selective
adenosine receptor agonists and antagonists in audiogenic-seizure-sensitive DBA/2 mice, an animal model of generalized
reflex epilepsy. With the exception of the
adenosine A3 receptor agonist, N6-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine (
IB-MECA), all the agonists studied prevented the development of audiogenic
seizures in a dose-dependent manner. The ED50 values against the clonic phase of the audiogenic
seizures were low, that is: 0.06 mg/kg, i.p., for the
adenosine A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), 0.02 and 0.03 mg/kg, i.p., for the
adenosine A2A receptor agonists, 2-(4-(2-carboxyethyl)-phenylamino)-5'-N-ethylcarboxamidoadenosine (
CGS 21680) and 2-hexynyl-5'-N-ethyl-carboxamidoadenosine (2-HE-NECA), and 0.7 mg/kg, i.p., for the
adenosine A1/A3 receptor agonist, N6-2-(4-aminophenyl)ethyladenosine (
APNEA). Conversely, the non-selective agonist, N-ethyl-carboxamidoadenosine (
NECA), was highly potent, the ED50 being 0.0005 mg/kg, i.p. In the absence of auditory stimulation, the
adenosine receptor antagonists increased the incidence of both clonic and
tonic seizures in DBA/2 mice. The ED50 values were: for
caffeine, 207.5 mg/kg, i.p., for the
adenosine A1 receptor antagonist,
8-cyclopentyl-1,3-dipropylxanthine (
DPCPX), 327.8 mg/kg i.p., for the
adenosine A2A receptor antagonists, 3,7-dimethyl-1-propylxanthine (DPMX), 86.7 mg/kg i.p., for the (E,18%-Z,82%)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine (
KF 17837), 69.1 mg/kg i.p., and 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-(4,3-c)1,2,4-triazolo(1,5 -c)-pyrimidine (
SCH 58261), 321.8 mg/kg i.p. The rank order of
convulsant potency in our epileptic model, following intracerebroventricular administration, was
DPCPX >
DMPX >
1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC) >
KF 17837 >
Caffeine >
SCH 58261 > 5-amino-9-chloro-2-(2-furyl)-1,2,4-triazolo(1,5-c)quinazoline (
CGS 15943). Following a subconvulsant audiogenic stimulus of 83 dB, all
adenosine receptor antagonists induced both tonic and
clonic seizures. The ED50 values for such proconvulsant effects were: for
caffeine 0.04 mg/kg, i.p., for the
adenosine A receptor antagonist,
DPCPX, 5.84 mg/kg, i.p., for the
adenosine A2A receptor antagonists,
DMPX, 0.02 mg/kg, i.p.,
CGS 15943, 0.29 mg/kg i.p.,
KF 17837, 0.57 mg/kg, i.p., CSC 0.12 mg/kg, i.p. and
SCH 58261 0.07 mg/kg, i.p., respectively. These data suggest that stimulation of
adenosine A1 and A2A receptors is involved in the suppression of
seizures.