Impaired inhibition of epileptiform activity by baclofen, but not by adenosine in the weaver hippocampus.
The weaver defect results in a loss of baclofen- and adenosine-gated K+ conductance in the hippocampus of adult homozygous (wv/wv) mice. In addition, suppression of hippocampal epileptiform activity by baclofen is impaired (Jarolimek, W., Bäurle, J., Misgeld, U., 1998. Pore mutation in a G protein-gated inwardly rectifying K+ channel subunit causes loss of K+ dependent inhibition in weaver hippocampus. Journal of Neuroscience 18, 4001-4007). We used wv/wv and wild-type (+/+) mice to determine whether K+ conductance increases are essential for the suppression of epileptiform activity by R-baclofen and adenosine in disinhibited hippocampal slices. In wv/wv mice R-baclofen was less potent by two orders of magnitude in reducing the frequency of spontaneous synchronous burst discharges than in +/+ mice. Endogenous adenosine and adenosine A1 receptor agonists differed only slightly in their efficacy to inhibit spontaneous synchronous burst discharges in wv/wv and +/+ mice. The findings on adenosine A1 receptors suggest that the varied efficacy of R-baclofen in wv/wv and +/+ mice may not be explained solely on the basis of a loss of ligand-gated K+ conductance. Therefore, we investigated the affinity of GABA(B) receptors for the antagonist CGP55845A in wv/wv and +/+ hippocampi. Schild plot analysis revealed a K(D) for the GABA(B) antagonist CGP55845A 10 fold higher in wv/wv than in +/+ mice. The data suggest that an alteration of GABA(B) receptors could contribute to the reduced efficacy of R-baclofen to suppress hippocampal epileptiform activity in weaver mice, while the suppression by adenosine remains largely unaffected.
Jarolimek
W
W
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Bäurle
J
J
Misgeld
U
U
D015761:4-Aminopyridine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008818:Mice, Neurologic Mutants; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology
D000700:Analgesics; D018755:GABA Agonists; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D010721:Phosphinic Acids; D011412:Propanolamines; C085075:CGP 55845A; D015761:4-Aminopyridine; D001418:Baclofen; D000241:Adenosine