Ethanol enhances GABAB-mediated inhibitory postsynaptic transmission on rat midbrain dopaminergic neurons by facilitating GIRK currents.
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 gamma-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 GABA(B)-IPSP. In addition, the GABA(B) 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 Ca(2+) with EGTA. Interestingly, the outward current caused by the intracytoplasmatic diffusion of the irreversible G-protein activator GTPgammaS was transiently enhanced by ethanol. Our observations suggest that the action of ethanol occurs on activated GIRK channels downstream of the GABA(B) receptors. These enhancing effects of ethanol on GABA(B)-induced synaptic responses could modulate alcohol intake and the altered mental and motor performance of individuals in an acute intoxicative phase.
Federici
Mauro
M
Laboratory of Experimental Neurology, Fondazione Santa Lucia - IRCCS, Rome, Italy.
Nisticò
Robert
R
Giustizieri
Michela
M
Bernardi
Giorgio
G
Mercuri
Nicola B
NB
D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D058786:GABA-B Receptor Agonists; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008636:Mesencephalon / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D002492:Central Nervous System Depressants; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D000431:Ethanol; D004298:Dopamine