title: Role of protein kinase A in GABAA receptor dysfunction in CA1 pyramidal cells following chronic benzodiazepine treatment.
abstract: One-week treatment with the benzodiazepine (BZ) flurazepam (FZP), results in anticonvulsant tolerance, associated with reduced GABAA receptor (GABAR) subunit protein and miniature inhibitory post-synaptic current (mIPSC) amplitude in CA1 neurons of rat hippocampus. Because protein kinase A (PKA) has been shown to modulate GABAR function in CA1 pyramidal cells, the present study assessed whether GABAR dysfunction is associated with changes in PKA activity. Two days after 1-week FZP treatment, there were significant decreases in basal (- 30%) and total (- 25%) PKA activity, and a 40% reduction in PKA RIIbeta protein in the insoluble fraction of CA1 hippocampus. The soluble component of CA1 showed a significant increase in basal (100%) but not total PKA activity. Whole-cell recording in vitro showed a 50% reduction in mIPSC amplitude in CA1 pyramidal cells, with altered sensitivity to PKA modulators. Neurons from FZP-treated rats responded to 8-bromo-cAMP with a significant increase (31%) in mIPSC amplitude. Likewise, vasoactive intestinal polypeptide (VIP), an endogenous PKA activator, caused a significant 36% increase in mIPSC amplitude in FZP-treated cells. Neither agent had a significant effect on mIPSC amplitude in control cells. This study supports a role for PKA in GABAR dysfunction after chronic FZP treatment.
authors.affiliation: Department of Pharmacology, Medical College of Ohio, 3035 Arlington Avenue, Toledo, OH 43614, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lilly
authors.forename: X J
authors.initials: XJ
authors.lastname: Zeng
authors.forename: E I
authors.initials: EI
authors.lastname: Tietz
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D002458:Cell Fractionation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D004334:Drug Administration Schedule; D004789:Enzyme Activation / Q000187:drug effects; D005479:Flurazepam / Q000008:administration & dosage*; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics / Q000502:physiology; D008297:Male; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D007527:Isoenzymes; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D015124:8-Bromo Cyclic Adenosine Monophosphate; D014660:Vasoactive Intestinal Peptide; D017868:Cyclic AMP-Dependent Protein Kinases; D005479:Flurazepam