Ethanol acts via the ventral tegmental area to influence hippocampal physiology

Ethanol selectively alters hippocampal dentate physiology, in part by increasing recurrent inhibition and suppressing long-term potentiation (LTP), a result of ethanol modulation of subcortical inputs. One of these inputs includes the ventral tegmental area (VTA) in the midbrain, whose neurons have been shown to discharge faster following systemic ethanol. To further understand how subcortical inputs regulate hippocampal physiology and their modulation by ethanol, we studied the effects of acute intoxicating levels of ethanol on VTA facilitation of the perforant path to dentate (PPD) responses. Furthermore, to test the role of the VTA on known pharmacological effects of ethanol on hippocampal physiology, we studied the effects of disruption of the VTA-dentate inpute on ethanol actions on recurrent inhibition. Stimulation of the perforant path produced well-characterized evoked responses in the ipsilateral dentate gyrus. Whereas VTA stimulation had no effect on PPD population EPSPs, VTA conditioning markedly increased perforant path-evoked PS amplitudes (140%). The maximum facilitation was observed at VTA conditioning intervals of 30-40 ms. PS amplitudes returned to baseline levels immediately following cessation of VTA conditioning. Intraperitoneal injections of ethanol (1.2 g/kg) markedly decreased VTA facilitation of PPD PS amplitudes. Lesions of the VTA blocked the ethanol-mediated increase in PPD paired-pulse inhibition. These results demonstrate that, to a great extent, the effects of intoxicating doses of ethanol on hippocampal physiology are mediated by remote pharmacological effects on the ventral tegmental area, whose direct or indirect influences on dentate physiology are described.