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REDUCED MICROSCOPIC GABAR SENSITIVITY IN RAT HIPPOCAMPAL CA1 NEURONS DURING BENZODIAZEPINE WITHDRAWAL IS REVERSED BY CAMKII INHIBITION
Author(s) -
Das Paromita,
Greenfield L. John,
Tietz Elizabeth I.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.760.13
Subject(s) - chemistry , gabaa receptor , flurazepam , hippocampal formation , benzodiazepine , endocrinology , medicine , antagonist , stimulation , pharmacology , biophysics , receptor , biology , biochemistry
Two days after 1‐week oral treatment with the benzodiazepine (BZ), flurazepam (FZP), L‐type voltage‐gated channel (L‐VGCC) whole‐cell Ca 2+ current density is doubled and γ‐amino butyric acid type A receptor (GABAR) single‐channel open probability (Po) is reduced in cell‐attached patches from dissociated hippocampal CA1 neurons. Blockade of Ca 2+ influx by systemic injection of the L‐VGCC antagonist, nimodipine 1 day after FZP treatment, restored sensitivity of FZP neurons to 5 µM GABA, increasing Po from 0.04 to 0.54 after 2 days to near control levels (0.68). We hypothesized that BZ‐induced elevation of [Ca 2+ ]i may suppress GABAR function by activating Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII). Single‐channel recordings were obtained after slice pre‐incubation with membrane‐permeant CaMKII inhibitors. At 1 µM GABA, Po in control patches was 0.19, while no openings were observed in FZP patches. After pre‐incubation with KN93, Po in FZP patches was 0.73. No openings were seen with the inactive analog KN92. Pre‐incubation with mAIP, activated 'silent' single channels in FZP patches (Po=0.69) and increased the basal response of control patches (Po=0.57). Membrane‐impermeant AIP and the PKC inhibitor, chelerythrine had no effect. Persistent activation of CaMKII is required to maintain basal GABAR function as well as for BZ‐induced, negative modulation of GABAR function associated with BZ tolerance.