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Vol. 305, Issue 1, 264-270, April 2003
(PKC) and PKC
Null Mice
Department of Veterans Affairs Medical Center, Research Service,
Denver, Colorado (W.R.P., T.V.D.); Department of Pharmacology,
University of Colorado Health Sciences Center, Denver Colorado (W.R.P.,
W.P., T.V.D.); Institute for Behavioral Genetics and Colorado Alcohol
Research Center, University of Colorado, Boulder, Colorado (B.J.B.,
J.M.W.); and the Ernest Gallo Clinic and Research Center, Department of
Neurology, University of California at San Francisco, Emeryville,
California (R.O.M.)
Ethanol intoxication results partly from actions of ethanol at
specific ligand-gated ion channels. One such channel is the GABAA receptor complex, although ethanol's effects on
GABAA receptors are variable. For example, we found that
hippocampal neurons from selectively bred mice and rats with high
hypnotic sensitivity to ethanol have increased GABAA
receptor-mediated synaptic responses during acute ethanol treatment
compared with mice and rats that display low behavioral sensitivity to
ethanol. Here we investigate whether specific protein kinase C (PKC)
isozymes modulate hypnotic and GABAA receptor sensitivity
to ethanol. We examined acute effects of ethanol on GABAA
receptor-mediated inhibitory postsynaptic currents (IPSCs) in mice
lacking either PKC
(PKC
/) or PKC
(PKC/) isozymes and compared the results to those
from corresponding wild-type littermates (PKC+/+ and
PKC+/+). GABAA receptor-mediated IPSCs were
evoked in CA1 pyramidal neurons by electrical stimulation in
stratum pyramidale, and the responses were recorded in voltage-clamp
mode using whole-cell patch recording techniques. Ethanol (80 mM)
enhanced the IPSC response amplitude and area in PKC+/+
mice, but not in the PKC/ mice. In contrast, ethanol
markedly potentiated IPSCs in the PKC/ mice, but not
in PKC+/+ littermates. There was a positive correlation
between ethanol potentiation of IPSCs and the ethanol-induced loss of
righting reflex such that mice with larger ethanol-induced increases in GABAA receptor-mediated IPSCs also had higher hypnotic
sensitivity to ethanol. These results suggest that PKC and PKC
signaling pathways reciprocally modulate both ethanol enhancement of
GABAA receptor function and hypnotic sensitivity to ethanol.
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