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

Abstract

Alcoholism is associated with acute and long-term cognitive dysfunction including memory impairment, resulting in substantial disability and cost to society. Thus, understanding how ethanol impairs cognition is essential for developing treatment strategies to dampen its adverse impact. Memory processing is thought to involve persistent, use-dependent changes in synaptic transmission, and ethanol alters the activity of multiple signaling molecules involved in synaptic processing, including modulation of the glutamate and gamma-aminobutyric acid (GABA) transmitter systems that mediate most fast excitatory and inhibitory transmission in the brain. Effects on glutamate and GABA receptors contribute to ethanol-induced changes in long-term potentiation (LTP) and long-term depression (LTD), forms of synaptic plasticity thought to underlie memory acquisition. In this paper, we review the effects of ethanol on learning-related forms of synaptic plasticity with emphasis on changes observed in the hippocampus, a brain region that is critical for encoding contextual and episodic memories. We also include studies in other brain regions as they pertain to altered cognitive and mental function. Comparison of effects in the hippocampus to other brain regions is instructive for understanding the complexities of ethanol's acute and long-term pharmacological consequences.

Keywords: Acetaldehyde; Alcohol; GABA receptors; Long-term depression; Long-term potentiation; NMDA receptors; Neurosteroids.

Figure 1

This figure highlights several features of ethanol’s acute effects on LTP in the CA1 region of hippocampal slices from P30 rats. A. The graph shows the ability of 60 mM ethanol administered for 15 min (black bar) to block LTP in the Schaffer collateral pathway (black circles). This LTP inhibition is overcome by pre-treatment with 1 μM finasteride (red triangles) or 1 μM dutasteride (purple squares). Finasteride and dutasteride block the synthesis of alloP and other 5α-reduced neurosteroids. Control LTP is shown in white circles. B. The graph shows that 60 mM ethanol inhibits LTP for at least 30 min following washout (black triangles) and that full block of NMDARs with 50 μM APV during ethanol administration overcomes LTP inhibition (blue triangles) when both drugs are washed out 30 min prior to high frequency stimulation (HFS, arrow; 100 Hz × 1 s tetanus). Traces to the right show EPSPs recorded during baseline (dashed traces) and 60 min following HFS (solid traces). Calibration: 1 mV, 5 ms. This figure is reproduced from Tokuda et al., Journal of Neuroscience, 2011.

Figure 2

The diagram depicts a scheme for acute block of LTP by ethanol in the CA1 region. Acute LTP inhibition requires high concentrations of ethanol (triple blue arrows) that partially inhibit NMDARs. Perhaps via local metabolism to acetaldehyde (Tokuda et al., 2013a, ; right side of figure), high concentrations of ethanol paradoxically promote activation of unblocked NMDARs, perhaps through elevation of glutamate levels. This untimely NMDAR activation, in turn, promotes local synthesis of GABA-enhancing neurosteroids (alloP) and enhanced GABA_AR function, resulting in dampened LTP induction. The diagram also depicts key steps in the synthesis of alloP from cholesterol. The effects of high ethanol can be mimicked by lower ethanol in combination with exogenous alloP. The effects of low ethanol (single blue arrow) are not completely known, but include partial NMDAR antagonism (Izumi, Nagashima, et al., 2005c). Importantly, low ethanol alone does not enhance endogenous alloP production (Tokuda et al., 2011; left side of figure). Some actions of ethanol can be mimicked by other stressors that promote NMDAR activation. These include behavioral and metabolic stresses and can be mimicked, in part, by other drugs that enhance neurosteroid synthesis (Zorumski & Izumi, 2012). These latter conditions enhance the potency of ethanol to block LTP.