The effects of convulsant and anticonvulsant drugs on the release of radiolabeled GABA, glutamate, noradrenaline, serotonin and acetylcholine from rat cortical slices.
A possible presynaptic site of action of convulsant and anticonvulsant drugs has been evaluated by studying their effect on depolarization-induced transmitter release using radiolabeled GABA, glutamate, noradrenaline, serotonin and acetylcholine. The antiepileptic diphenylhydantoin (DPH) inhibited the release of noradrenaline and serotonin at concentrations that are antiepileptic in vivo. The release of the other transmitters was affected only with higher concentrations. Phenobarbital (PhB) reduced the release of all transmitters studied at concentrations much above the levels that are considered antiepileptic in vivo. Comparison with the anesthetic barbiturate pentobarbital (PB) further indicated that the presynaptic effects of PhB were related to its sedative rather than antiepileptic properties. Diazepam and sodium valproate had little effect; only GABA release was slightly reduced with diazepam at the highest concentration studied. The convulsants penicillin and pentylenetetrazole both increased the release of glutamate at concentrations that induce epileptiform activity in vivo or in vitro. Other transmitter systems were differentially affected by the two convulsants. A small increase of noradrenaline and serotonin release was observed with penicillin, but not with pentylenetetrazole. A presynaptic site of action for some, but not all, epileptogenic and antiepileptic drugs probably exists in addition to other, postsynaptic mechanisms. Glutamate is probably a major excitatory neurotransmitter in the brain and many physiological studies have suggested a role of excitatory pathways in the generation of epileptiform activity. The observed increase of glutamate release in the presence of two epileptogenic drugs observed in this in vitro study is in agreement with such a hypothesis.
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D046508:Culture Techniques; D003975:Diazepam / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D000091402:Prohibitins; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000927:Anticonvulsants; D005971:Glutamates; C000717332:Phb protein, rat; D000091402:Prohibitins; D012701:Serotonin; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D010672:Phenytoin; D000109:Acetylcholine; D003975:Diazepam; D011188:Potassium; D009638:Norepinephrine; D010634:Phenobarbital