Ethanol acts via the ventral tegmental area to influence hippocampal physiology

Abstract

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.

Role of hippocampus in alcohol-induced memory impairment: implications from behavioral and immediate early gene studies

“…Tabakoff and Hoffman 1992;Koob 1996). While electrophysiological data from hippocampal slice preparations suggest that alcohol can exert direct effects on hippocampus (Sinclair and Lo 1986;Mulkeen et al 1987;Blitzer et al 1990;Weiner et al 1994;Wan et al 1996), several in vivo electrophysiological studies suggest that some effects of alcohol on hippocampal physiology are directed through its pharmacological action on other brain regions (Steffensen et al 1993;Criado et al 1994;Wayner et al 1997).…”

Ethanol, memory, and hippocampal function: A review of recent findings

“…As discussed above, systemic ethanol enhances paired-pulse inhibition in the dentate gyrus (Steffensen and Henriksen, 1992). Ventral tegmental area (VTA) lesions block the increase in paired-pulse inhibition produced by ethanol, suggesting that ethanol influences hippocampal function by interacting with the VTA (Criado et al, 1994). Ethanol's interactions with the raphe nuclei might also contribute to the drug's effects on hippocampal function.…”

“…Support for the hypothesis of Steffensen and Henriksen (1992) comes from evidence that ethanol, whether administered systemically or locally into the dentate, enhances paired-pulse inhibition in the dentate gyrus (Steffensen and Henriksen, 1992;Steffensen et al, 1993;Criado et al, 1994). Dentate granule cells generate action potentials in response to stimulation of fibers in the perforant path.…”

Neuroadaptations in dentate gyrus function following repeated methamphetamine administration

“…We measured population spike (PS) amplitudes and peak PS latencies from waveforms evoked in the DG by stimulation of the angular bundle of the perforant path (coordinates: 3.6 mm posterior, 2.8 mm lateral, and 2.0 -2.5 mm ventral from dura) with insulated, bipolar stainless steel electrodes (0.3-2.0 mA; 0.10 ms duration; average frequency, 0.1 Hz). Details of the surgical and electrophysiological procedures are described elsewhere (Criado et al, 1994).…”

“…Moreover, several brain regions that are part of the mesolimbic neural circuit regulating the behavioral effects of METH, including the raphe nucleus, locus coeruleus, ventral tegmental area, and medial septum, also facilitate the activation of hippocampal DG neurons. (Assaf and Miller, 1978;Segal, 1979;Dahl and Winson, 1986;Harley et al, 1989;Mizumori et al, 1989;Babstock and Harley, 1992;Criado et al, 1994). While studies have also shown that mesolimbic DA neurons play a role in the regulation of septohippocampal cholinergic transmission and cognitive processes (Assaf and Miller, 1977;Robinson et al, 1979;Simon et al, 1986), the functional significance of the mesohippocampal DAergic system is unclear.…”