Activin is a member of the TGF-beta superfamily. In the adult brain, activin was originally identified as a neuroprotective factor in various forms of acute brain injury. More recent work from our and other laboratories demonstrated that activin has also a significant impact on glutamatergic and GABAergic synapses under physiological conditions (TINS 34:421-429, 2011). Using transgenic mice that express a dominant-negative activin receptor mutant (dnActRIB) under the control of the CaMKIIalpha promoter in forebrain neurons, we found that activin serves as a homeostatic regulator of hippocampal GABAergic synapses, thereby controlling anxiety-like behavior (Mol Psychiatry 14:332-346, 2009). In particular, activin enhanced the benzodiazepine sensitivity of synaptic (phasic) GABA(A) receptors, whereas it reduced tonic inhibition through extrasynaptic GABA(A) receptors. Alcohol is known to augment both phasic and tonic GABAergic inhibition, with low ("social") concentrations acting primarily on the tonic component. Since these targets of alcohol are both regulated by activin, we wondered whether activin receptor signaling would be capable of modifying the effects of alcohol. For this purpose, we performed whole-cell recordings from adult hippocampal CA1 pyramidal cells and from dentate granule cells of normal and dnActRIB mice and measured the effects of ethanol on synaptically evoked and tonic GABA(A) receptor-mediated currents. Throughout the concentration range examined (30 - 150 mM), the ethanol-induced enhancement of peak amplitude and area of evoked IPSCs was significantly stronger in mutant than in wild-type hippocampi. In contrast, we found no difference between dnActRIB and wild-type mice when we compared the magnitude of the GABA(A) receptor-mediated tonic current recorded in dentate granule cells in response to a low ethanol concentration (30 mM) in the presence of a GABA(B) receptor antagonist. Our data suggest that activin receptor signaling serves primarily to prevent low concentrations of alcohol from augmenting phasic GABAergic inhibition, thereby leaving tonic inhibition as a major GABAergic target of alcohol to exert its recreational effects.