Low doses of AMPA exert anticonvulsant effects on pentylenetetrazol-kindled seizures

Excitatory amino acids (EAAs) are critically involved in the initiation and propagation of seizures. N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors appear to be of special interest in this regard. Besides receptor binding by antagonists, the function of glutamatergic synapses can be altered via autoreceptor-mediated mechanisms or by receptor desensitisation. Therefore, the effect of AMPA (1, 10 or 100 pmol per animal, intracerebroventricular injection) was tested on acutely induced pentylenetetrazol (PTZ) seizures. The lowest dose exerted clear anticonvulsant effects. Furthermore, 1 and 10 pmol AMPA were tested for their efficacy to suppress PTZ kindling. The lower dose reduced seizure severity significantly but 10 pmol AMPA was ineffective. In reaction to a test dose of PTZ, the kindled groups pretreated with AMPA reached seizure scores similar to saline-pretreated kindled rats, suggesting that the kindled state was reached. In a further experiment, we tested the effect of cyclothiazide (CYC, which blocks AMPA receptor desensitisation) on the 1 pmol AMPA-mediated anticonvulsant effect. The AMPA response was not altered. These results suggest that autoreceptor-mediated mechanisms rather than desensitisation might contribute to the anticonvulsant effect found.