Effects of repeated administration of selective adenosine A(1) and A(2A) receptor agonists on pentylenetetrazole-induced convulsions in the rat

The protective effects of the selective adenosine A, receptor agonist, 2-chloro-N-6-cyclopentyladenosine (CCPA), the selective adenosine A(2A) receptor agonist, 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA), and the non-selective agonist, 5'-N-ethylcarboxamidoadenosine (NECA) were studied against lethal seizures induced by intraperitoneal (i.p.) injection of pentylenetetrazole (80 mg/kg). In acute studies there was a dose-dependent reduction of lethal seizures, as shown by the low dose's protecting 50% of animals (PD50): 0.11, 0.05 and 0.05 mg/kg i.p. for CCPA, 2HE-NECA and NECA, respectively. In the repeated administration studies the animals received either vehicle or drug i.p. twice daily for 12 days. The drug doses were twice the PD50 value: 0.3 mg/kg for CCPA or 0.1 mg/kg for both 2HE-NECA and NECA. 2HE-NECA and NECA maintained their protective activity against pentylenetetrazole-induced seizures (63% or 60% vs. 60% or 58% in acute studies, respectively). Conversely, repeated treatment with CCPA resulted in a marked decrease of its effects (67% vs. 30% in acute studies; P < 0.05). The data indicate that in addition to adenosine A(1) the A(2A) receptors also appear to be involved in the protection from seizures. The anticonvulsant effects induced by repeated stimulation of adenosine A(1) receptors are subject to tolerance, whereas effects depending on adenosine A(2A) receptor activation are maintained.