Suppression of drug-induced epileptiform discharges by cyclic AMP in rat hippocampus.
The effect of cyclic adenosine 3',5'-monophosphate (cAMP) on epileptiform activity in rat hippocampal slices was investigated. Bath-applied cAMP reversibly decreased the frequency of extracellularly recorded discharges in the CA3 subfield induced by bethanechol- or theophylline-containing solutions. Because cAMP was presumed to be relatively membrane impermeant, we developed and tested the hypothesis that this cAMP-mediated effect occurred extracellularly through the catabolic conversion of cAMP to 5'-AMP and, in turn, to adenosine, a known inhibitory neuromodulator. Three predictions derived from this catabolic hypothesis were tested. First, blockers of the enzymes involved were predicted to antagonize this effect of cAMP. In contrast, the coapplication of a cAMP-phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), or a 5'-nucleotidase inhibitor, adenosine 5'-[alpha, beta-methylene] diphosphate (AMP-CP), enhanced the cAMP-induced suppressive effect. Second, the nonhydrolyzable cAMP analogs, dibutyryl- and 8-bromo-cAMP, were predicted to be ineffective. Low concentrations (5-40 microM) of these two derivatives, however, also suppressed bethanechol-induced discharges, while, at a higher concentration (100 microM), both analogs increased discharge frequencies. Third, enzymatic catabolism of adenosine was predicted to antagonize cAMP's effect, but coapplying adenosine deaminase (10 U/mL) did not diminish this action. Because these data did not support the catabolic hypothesis, other, as yet undefined, mechanisms must be responsible for the discharge-suppressant effect of cAMP.
Apland
J P
JP
Neurotoxicology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA. Dr._James_Apland@ftdetrck-ccmail.army.mil
Helekar
S A
SA
Lebeda
F J
FJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors; D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors; D000818:Animals; D018723:Bethanechol; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology*; D004594:Electrophysiology; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D005110:Extracellular Space / Q000187:drug effects; D006624:Hippocampus / Q000503:physiopathology*; D010277:Parasympathomimetics / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000494:pharmacology
D010277:Parasympathomimetics; D010726:Phosphodiesterase Inhibitors; D018723:Bethanechol; D013806:Theophylline; D000242:Cyclic AMP; D015720:5'-Nucleotidase; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D015056:1-Methyl-3-isobutylxanthine