Suppression of drug-induced epileptiform discharges by cyclic AMP in rat hippocampus

J. P. Apland, Santosh Helekar, F. J. Lebeda

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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'-[α,β-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 μM) of these two derivatives, however, also suppressed bethanechol-induced discharges, while, at a higher concentration (100 μM), 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 dischargesuppressant effect of cAMP.

Original languageEnglish (US)
Pages (from-to)265-278
Number of pages14
JournalMolecular and Chemical Neuropathology
Volume31
Issue number3
DOIs
StatePublished - Jan 1 1997

Keywords

  • Adenosine
  • Anticonvulsant
  • Bethanechol
  • Brain slices
  • Cyclic AMP
  • Seizures
  • Theophylline

ASJC Scopus subject areas

  • Clinical Neurology
  • Molecular Biology
  • Neuroscience(all)

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