cgp-39653 and Alcoholism

This study tests the hypothesis that glutamate receptors are altered in the brains of alcoholics as a result of chronic alcohol neurotoxicity. Excessive release of the excitatory neurotransmitter glutamate may damage postsynaptic neurons by increasing calcium flux through N-methyl-D-aspartate (NMDA) receptor-gated ion channels. Alcohol has opposite effects on the NMDA receptor, depending on the duration of exposure. Acute exposure to alcohol inhibits ion flow through NMDA receptors, whereas chronic exposure upregulates the number of these receptors and thereby increases ion flow. Acute withdrawal from alcohol results in hyperexcitability and seizures in the presence of upregulated NMDA receptors, making postsynaptic neurons vulnerable to excitotoxic damage. For this study, 13 grossly and histologically normal brains from alcoholics and 13 brains from nonalcoholic controls were selected from our brain bank. The two groups were matched for age, postmortem interval, and storage time. Maximal binding and affinities of NMDA receptors were determined by quantitative autoradiography in the cingulate cortex, the cornu Ammonis of the hippocampus, and in the cerebellar vermis. Binding was determined with an agonist, L-[3H]glutamate, with a competitive antagonist, [3H]CGP-39653, and with an antagonist binding in the channel interior, [3H]MK-801. No significant differences were found in receptor densities or affinities between alcoholics and controls. Real differences were not likely to be obscured by nonalcohol-related variables because the groups were closely matched for age, autopsy delay, time in storage, and central nervous system medications. Various diseases causing acute and chronic hypoxia did not significantly affect receptor density or affinity. Liver diseases and thiamine deficiency were excluded. A long-lasting upregulation of the number or affinity of NMDA receptors is not a key feature of chronic alcoholics.

Topics: 2-Amino-5-phosphonovalerate; Aged; Alcoholism; Cerebellar Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Gyrus Cinguli; Hippocampus; Humans; Middle Aged; Receptors, Glutamate

The amino acid L-glutamate is a major excitatory neurotransmitter that is involved in many CNS functions, including learning, memory, long-term potentiation, and synaptic plasticity. Acute exposures to ethanol (50 to 200 mM) have been shown to inhibit NMDA receptor responses, whereas chronic exposure to ethanol leads to adaptive supersensitivity thought to be involved in ethanol dependence and tolerance. To investigate the effects of chronic ethanol exposure on glutamate receptor density, we examined the binding of both NMDA and non-NMDA ligands in rat brain after several chronic ethanol treatment protocols using a number of different rat strains. No increases in the binding of [3H]MK-801, [3H]CGP 39653, or the polyamine specific competitive antagonist, [3H]ifenprodil, were seen after two well-used chronic ethanol treatments. These included the 2-week liquid diet developed by Frye et al. (J. Pharmacol. Exp. Ther. 216:306-314, 1981) and the 4-day binge treatment developed by Majchrowicz (Psychopharmacologia 43:245-254, 1975). However, small increases in the binding of both the NMDA noncompetitive antagonist [3H]MK-801, as well as the competitive NMDA antagonist [3H]CGP 39653, were seen in select frontal brain regions after 3 weeks of the Walker-Freund chronic ethanol liquid diet. When this chronic liquid diet treatment was extended to a period of 6 weeks, these increases in receptor binding were diminished to nonsignificant levels. The binding of the non-NMDA ligands [3H]AMPA and [3H]kainate were not significantly affected by either length of Walker-Freund liquid diet exposure. When rats were treated chronically with ethanol for 30 days using the paradigm developed by Tsukamoto et al. (Hepatology 5:224-232, 1985), small, but significant, increases in the binding of [3H]MK-801 were seen in the CA1 and dentate gyrus regions of the hippocampus. These studies indicate that robust increases in NMDA receptor binding do not occur with several chronic ethanol treatment protocols, and suggests that NMDA receptor supersensitivity during the development of tolerance and dependence to ethanol may not simply be due to changes in the density of NMDA receptors, but may involve other mechanisms.

Topics: 2-Amino-5-phosphonovalerate; Alcoholism; Animals; Binding, Competitive; Brain; Brain Mapping; Dizocilpine Maleate; Male; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate