Modulation of hippocampal long-term potentiation by slow increases in ethanol concentration

Abstract

To determine how acute ethanol intoxication may alter memory processing, we examined the effects of stepwise increases in ethanol on long-term potentiation (LTP) in hippocampal slices. LTP was inhibited by acute administration of 60 mM ethanol, but was readily induced if ethanol was increased gradually to 60 mM over 75 min. Administration of 2-amino-5 phosphonovalerate (APV), an Nmethyl-D-aspartate receptor antagonist, during the stepwise increase in ethanol inhibited LTP, suggesting involvement of NMDA receptors in the development of tolerance. However, APV and nifedipine, an inhibitor of L-type calcium channels, failed to inhibit LTP when administered following the slow increase in ethanol. Ethanol-tolerant LTP was inhibited by thapsigargin, suggesting a major role for intracellular calcium release in this form of plasticity. The unique properties of ethanol-tolerant LTP suggest that memories formed during binge drinking are not acquired by standard synaptic mechanisms and that acute tolerance may involve the induction of novel mechanisms to maintain function. KeywordsAlcohol (ethanol); tolerance ; desensitization; allostasis Acute alcohol intoxication is a significant public health problem. During the intoxicated state, problems with motor coordination and cognitive processing are common. Some individuals exhibit profound deficits in memory that may include a complete inability to learn new information, a condition referred to as a 'blackout' (White, 2003). Cognitive and behavioral manifestations associated with acute intoxication are often determined by how ethanol is consumed. Thus, it is possible that both the rate of alcohol consumption and the amount of ethanol consumed are key factors in determining overall effects on the CNS.In hippocampal slices, numerous studies have shown that ethanol inhibits long-term potentiation (LTP), a cellular model of memory and learning (Sinclair and Lo, 1986;Morrisett and Swartzwelder, 1993;Schummers and Browning, 2001). The concentration of ethanol required for LTP inhibition, however, has varied widely among reports. While many studies have found that ethanol inhibits LTP induction at concentrations of 50 mM or more (Randall et al., 1995;Sugiura et al., 1995;Schummers et al., 1997), some reports have shown that concentrations as low as 5 mM also impair LTP induction (Blitzer et al., 1990). The inconsistencies in these studies may reflect experimental differences including slice Correspondence: Yukitoshi Izumi, M.D., Ph.D., Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, Box 8134, St. Louis, MO 63110, USA, Phone: +1 314 362 8659, Fax: +1 314 747 2983, Email: izumiy@psychiatry.wustl.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note tha...

Emergence of NMDAR‐independent long‐term potentiation at hippocampal CA1 synapses following early adolescent exposure to chronic intermittent ethanol: Role for sigma‐receptors

“…6C). Previous studies have reported LTP depression by acute ethanol treatment at the same low intoxicating concentrations used here (i.e., 33 mM; Blitzer et al, 1990;Randall et al, 1995); however, an ethanol-tolerant form of LTP mediated by intracellular Ca 21 release has also been described at CA1 synapses in response to acute incremental administration of ethanol in vitro (60 mM; Tokuda et al, 2007). Together with these studies, our findings point to the existence of multiple pathways of hippocampal LTP that differ in sensitivity to acute and chronic ethanol actions.…”

“…In adult animals, the acute (Sinclair and Lo, 1986;Blitzer et al, 1990) and chronic (Durand and Carlen, 1984;Roberto et al, 2002) administration of ethanol consistently produces decrements in LTP levels at CA1 synapses in hippocampus, which is believed to reflect the ability of acute ethanol to inhibit NMDA-and/or potentiate GABA-receptor-mediated synaptic potentials (Morrisett and Swartzwelder, 1993;Schummers and Browning, 2001;Izumi et al, 2005). Ethanol-induced depression in LTP may also reflect ethanol interactions at pathways of synaptic plasticity not involving these receptors (Hendricson et al, 2003;Tokuda et al, 2007).…”

Accumulated hippocampal formaldehyde induces age-dependent memory decline

“…3). An analogous study has shown that ethanol inhibits LTP formation by blocking the NMDA receptor, possibly because the cysteine residues of NR2B are sensitive to ethanol (Herin et al 2001), and leads to amnesia (Brioni et al 1989;Dildy and Leslie 1989;Tokuda et al 2007;Wirkner et al 1999). Some studies have shown that formaldehyde can spontaneously modify the cysteine residues of proteins (Metz et al 2006;Toews et al 2008).…”

Acute and chronic effects of ethanol on learning-related synaptic plasticity

“…This makes it unlikely that during a bout of oral intoxication a rise to 50 mM or greater will occur within minutes even during binge consumption. Tokuda, Zorumski, & Izumi (2007) examined the effects of slower changes in ethanol concentration by increasing ethanol levels in 10 mM increments every 15 min to achieve a final level of 60 mM, a concentration that routinely blocks LTP when administered acutely. Under these circumstances, 60 mM ethanol no longer completely inhibited CA1 LTP.…”

“…Furthermore, and differing from effects of ethanol on LTD, LTP inhibition by 60 mM ethanol persists following drug washout (Izumi, Nagashima, et al, 2005c). These observations, coupled with the finding that complete NMDAR block during ethanol administration overcame acute tolerance (Tokuda et al, 2007), led to experiments examining whether complete NMDAR block during ethanol exposure could also overcome effects on LTP. Taking advantage of the prolonged block of LTP following ethanol washout and the fact that APV can be washed out rapidly, Tokuda et al (2011) found that co-administration of 60 mM ethanol with APV allowed LTP 30 min after both drugs were removed, whereas ethanol alone resulted in persistent LTP inhibition (Fig.…”