Cerebral Cortex, Vol. 11, No. 5, 424-429,
May 2001
© 2001 Oxford University Press
GHB Depresses Fast Excitatory and Inhibitory Synaptic Transmission via GABAB Receptors in Mouse Neocortical Neurons
Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USA
Gamma-hydroxybutyrate (GHB) is a drug of abuse which induces sedation and euphoria. However, overdoses can severely depress the level of consciousness or can be fatal especially when combined with other substances. Studies have suggested that the GHB-effects are mediated via actions on thalamocortical pathways and local neocortical circuits, although the effect of GHB at the level of single neocortical neurons is not clear. Using whole-cell patch-clamp recordings, we studied the effects of GHB on neocortical neurons in brain slices from 12- to 33-day-old mice. We found that GHB depressed the frequency and amplitude of GABAergic and glutamatergic spontaneous inhibitory and excitatory post-synaptic currents (IPSCs and EPSCs) driven by presynaptic action potential firing, while the amplitude and frequency of Ca2+ entry-independent miniature IPSCs were not affected. Using minimal stimulation, GHB reduced the probability of release at inhibitory synapses onto neocortical layer 2/3 pyramidal cells. Also, GHB directly hyperpolarized layer 2/3 non-pyramidal cells by up to 11 mV and inhibited action potential firing. All these effects of GHB were mediated via GABAB-receptors. In conclusion, GHB activates both pre- and postsynaptic GABAB-receptors in neocortical neurons participating in fast synaptic transmission, leading to a powerful depression of neocortical network activity. We propose that GABAB-receptor antagonists may be useful in the treatment of acute GHB intoxication.
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