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Ethanol enhances GABAB-mediated inhibitory postsynaptic transmission on rat midbrain dopaminergic neurons by facilitating GIRK currents

Authors

  • Mauro Federici,

    1. Laboratory of Experimental Neurology, Fondazione Santa Lucia – IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy
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  • Robert Nisticò,

    1. Laboratory of Experimental Neurology, Fondazione Santa Lucia – IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy
    2. Department of Pharmacobiology, University Center for Adaptive Disorders and Headache (UCHAD), Section of Neuropharmacology of Normal and Pathological Neuronal Plasticity, University of Calabria, 87036 Rende (CS), Italy
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  • Michela Giustizieri,

    1. Laboratory of Experimental Neurology, Fondazione Santa Lucia – IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy
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  • Giorgio Bernardi,

    1. Laboratory of Experimental Neurology, Fondazione Santa Lucia – IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy
    2. Neurological Clinic, University of Rome Tor Vergata, Rome, Italy
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  • Nicola B. Mercuri

    1. Laboratory of Experimental Neurology, Fondazione Santa Lucia – IRCCS, Via del Fosso di Fiorano 64, 00143 Rome, Italy
    2. Neurological Clinic, University of Rome Tor Vergata, Rome, Italy
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Dr N. B. Mercuri, 1Laboratory of Experimental Neurology, as above.
E-mail: mercurin@med.uniroma2.it

Abstract

It is largely accepted that an activation of the dopaminergic system underlies the recreational and convivial effects of ethanol. However, the mechanisms of action of this drug on the dopaminergic neurons are not fully understood yet. In the present study, we have used intracellular electrophysiological techniques (current and single-electrode voltage-clamp) to investigate the actions of ethanol on the γ-aminobutyric acid (GABA)B-mediated inhibitory postsynaptic potentials (IPSPs) in rat midbrain dopaminergic neurons. Ethanol (10–200 mm) augmented, in a concentration-dependent and reversible manner, the amplitude of the GABAB–IPSP. In addition, the GABAB agonist baclofen generated G-protein-gated inward rectifying K+ channels (GIRK)-related membrane hyperpolarizations/outward currents that were potentiated by ethanol. The potentiating effect of ethanol persisted in tetrodotoxin (TTX)-treated neurons, suggesting a postsynaptic site of action. These effects of ethanol were not changed by manipulating adenyl cyclase, protein kinases and phospholipase C activity, or by chelating intracellular Ca2+ with EGTA. Interestingly, the outward current caused by the intracytoplasmatic diffusion of the irreversible G-protein activator GTPγS was transiently enhanced by ethanol. Our observations suggest that the action of ethanol occurs on activated GIRK channels downstream of the GABAB receptors. These enhancing effects of ethanol on GABAB-induced synaptic responses could modulate alcohol intake and the altered mental and motor performance of individuals in an acute intoxicative phase.

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