Glutamate Receptors in the Frontal Cortex of Alcoholics

Abstract

This study tests the hypothesis that glutamate receptors are altered in the brains of alcoholics as a result of chronic alcohol neurotoxicity. Release of the neurotransmitter glutamate after seizures or brain ischemia may damage postsynaptic neurons by increasing calcium flux through N-methyl-D-aspartate (NMDA) receptor-gated ion channels. Alcohol has two opposite effects on glutamate receptor ion channel complexes, depending upon the duration of exposure. Acute exposure to alcohol inhibits ion flow through these receptor-channel complexes, whereas chronic exposure up-regulates the number of these receptors and thereby increases ion flow. Acute withdrawal from alcohol results in hyperexcitability and seizures in the presence of up-regulated channels, thereby making postsynaptic neurons vulnerable to excitotoxic damage. We selected 13 histologically normal brains from alcoholics and 13 brains from controls from our brain bank that were matched for age, postmortem interval, and storage time. Maximal binding and affinities of glutamate receptor subtypes were determined by quantitative autoradiography in the superior frontal cortex, Brodmann area 8. The most alcohol-sensitive subtype, NMDA receptor-channel complexes, were modestly but consistently increased in alcoholics. This included agonist sites (NMDA-sensitive [3H]glutamate), and antagonist site ([3H]CGP-39653), and a [3H]MK-801 binding site in the channel interior, although the increase of the latter did not reach statistical significance. Age, autopsy delay, time in storage, liver diseases, thiamine deficiency, CNS medications, and various diseases causing acute and chronic hypoxia did not significantly affect receptor density or affinity. In contrast, the other two glutamate channel subtypes, AMPA and kainate receptors, were not significantly different in alcoholics compared with controls. In conclusion, chronic alcoholism moderately increases the density of the NMDA subtype of glutamate receptors in the frontal cortex. This up-regulation may represent a stage of alcohol-induced chronic neurotoxicity.

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

“…According to earlier reports, it was observed in both in vivo and in vitro studies that chronic ethanol treatment leads to an increase in the density of NMDARs leading to facilitated receptor functions [62,64,88,89,90,147,215]. However, up-regulation of NMDAR expression has not been found in all studies after chronic ethanol exposition [55,186].…”

Altered NMDA Glutamate Receptor Antagonist Response in Recovering Ethanol-Dependent Patients

“…Upregulation of NMDA receptors by chronic ethanol administration may contribute to the altered sensitivity to ketamine effects observed in patients in this study. However, preclinical (Kalluri et al, 1998) and clinical (Freund and Anderson, 1996) studies suggest that increased NMDA receptor binding attributable to chronic ethanol administration is time-limited. Thus, ethanol-related NMDA receptor upregulation may play a greater role in acute rather than protracted withdrawal.…”

“…Sustained or chronic administration of ethanol and other NMDA receptor antagonists increases the mRNA or protein levels of some NMDA receptor subunits and the density of ligand binding to NMDA receptors in rodents and in cell lines (Darstein et al, 2000;Follesa and Ticku, 1996a, b;Gulya et al, 1991;Hu et al, 1996;Hu and Ticku 1995;Kalluri et al, 1998;Snell et al, 1996Snell et al, , 1993Trevisan et al, 1994). In post-mortem studies, NMDA receptor upregulation is associated with human ethanol dependence (Freund and Anderson, 1996;Michaelis et al, 1993). Preclinical studies suggest that this NMDA receptor upregulation contributes to ethanol tolerance and the complications of ethanol withdrawal, including seizures and neurotoxicity (Crews et al, 1999;Hoffman et al, 1990;Thomas and Morrisett, 2000;.…”

Alcohol use in bipolar disorder: A neurobiological model to help predict susceptibility, select treatments and attenuate cortical insult

“…The result of which is reduced sensitivity to ethanol that is believed to contribute to alcohol tolerance (Krystal et al, 2003c). This is evidenced by postmortem studies of people with alcohol dependence that found an increased binding capacity of NMDA receptors in cortical tissue (Freund and Anderson, 1996), suggesting that a greater amount of alcohol is required to elicit the same effect.…”

“…Notably, the same study found no differences in binding capacity at AMPA and kainite receptors between groups, highlighting the specificity of these effects (Freund et al, 1996).…”