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This Article Full Text Full Text (PDF) All Versions of this Article: 102/1/224    most recent 90484.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Liang, J. Articles by Olsen, R. W. PubMed PubMed Citation Articles by Liang, J. Articles by Olsen, R. W.

Tolerance to Sedative/Hypnotic Actions of GABAergic Drugs Correlates With Tolerance to Potentiation of Extrasynaptic Tonic Currents of Alcohol-Dependent Rats

¹Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, and ²Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, California

Submitted 18 April 2008; accepted in final form 21 April 2009

Alcohol tolerance resulting from chronic administration is well known to be accompanied by cross-tolerance to sedative/anesthetic drugs, especially those acting on the -aminobutyric acid type A receptors (GABA_ARs). Rats treated with chronic intermittent ethanol (CIE) show decreased function and altered pharmacology of GABA_ARs in hippocampal neurons, consistent with cell- and location-specific changes in GABA_AR subunit composition. We previously observed variably altered sensitivity to GABAergic drugs in vivo and in hippocampal neurons using whole cell patch-clamp recording in brain slices. Here, we examined additional clinical GABAergic drugs to correlate CIE-induced tolerance to potentiation of neuronal GABA_AR-mediated currents with tolerance of these agents to sedative/anesthetic effects in vivo. Typical of several drug classes and two cell types, in CA1 pyramidal neurons, the benzodiazepine diazepam doubled the total charge transfer (TCT) of miniature postsynaptic inhibitory currents (mIPSCs), whereas it quadrupled the TCT of tonic currents. CIE treatment altered these responses to variable extent, as it did to loss of righting reflex (LORR) induced by these same drugs: 90–95% tolerance to flurazepam, the neuroactive steroid alphaxalone, and ethanol; 30–40% to pentobarbital, etomidate, and the GABA agonist gaboxadol; and no tolerance to propofol. There was a strong correlation between tolerance in the LORR assay and tolerance to enhancement of tonic currents, but not mIPSCs. The striking correlation suggests that the sedative/anesthetic actions of GABAergic drugs may be mediated primarily via the potentiation of extrasynaptic GABA_ARs. This requires the reasonable assumption that the same types of GABA_ARs in other brain regions involved directly in hypnotic drug actions show similar tolerance.