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

Liang J, Spigelman I, Olsen RW. Tolerance to sedative/hypnotic actions of GABAergic drugs correlates with tolerance to potentiation of extrasynaptic tonic currents of alcohol- dependent rats. J Neurophysiol 102: 224-233, 2009. First published May 6, 2009; doi: 10.1152/jn.90484.2008. Alcohol tolerance resulting from chronic administration is well known to be accompanied by cross-tolerance to sedative/anesthetic drugs, especially those acting on the gamma-aminobutyric acid type A receptors (GABA(A)Rs). Rats treated with chronic intermittent ethanol (CIE) show decreased function and altered pharmacology of GABA(A)Rs in hippocampal neurons, consistent with cell- and location-specific changes in GABA(A)R 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(A)R-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(A)Rs. This requires the reasonable assumption that the same types of GABA(A)Rs in other brain regions involved directly in hypnotic drug actions show similar tolerance.