What does ethanol do to the brain?

T.J. Feuerstein, Sektion Klinische Neuropharmakologie der Neurologischen Universitätsklinik, Breisacherstr. 64., D-79106 Freiburg

Ethanol is primarily a CNS depressant. The apparent stimulation following low concentrations of ethanol results largely from depression of inhibitory control mechanisms in the brain. Garrulity is a well-known symptom. Among the first mental processes to be affected are those that depend on training and previous experience. Typically, impaired skillfulness results from low concentrations of alcohol which may be ignored subjectively. With higher doses the personality becomes expansive and vivacious. Motor inccordination and sleepiness follow. Ultimately, a general impairment of all nervous functions is followed by a condition of general anaesthesia with little margin between the full surgical anesthetic dose and that which is dangerous to respiration. Apart from these acute effects of intoxication massive ethanol ingestion may induce further symptoms and signs, e.g. alcohol hangover (Wiese et al. 2000) and, after the development of dependence, the alcohol withdrawal syndrome. This syndrome is characterized by alcohol craving, tremor, irritability, nausea, sleep disturbance, tachycardia, hypertension, sweating, perceptual distortion, seizures and delirium tremens. The latter comprises severe agitation, confusion, visual hallucinations, fever, diarrhea and dilated pupils in addition to the physical symptoms of the withdrawal. It becomes likely when the withdrawal occurs in conjunction with other problems, such as infection, trauma, malnutrition or electrolyte imbalance.

Alcohol-related CNS disorders include (among others) amblyopia, the Wernicke and the Korsakoff syndrome, cerebellar degeneration and dementia. In alcohol amblyopia clinical recovery can occur even without patient abstinence from alcohol abuse as long as B-vitamin supplementation is employed. Alcoholics are especially thiamine deficient as a result of poor diet, gastrointestinal disorders and liver disease. Also the Wernicke and the Korsakoff syndrome are nutritional disorders, due to thiamine deficiency. The same is partly true for alcoholic cerebellar degeneration and dementia where alcohol and its metabolite acetaldehyde, which are both directly neurotoxic, thiamine deficiency and liver disease combine synergistically to contribute to the phenomenon of alcoholic brain damage (Butterworth 1995).

Current concepts of the mechanisms underlying many of the effects ot ethanol on the CNS involve disruption of ion channel function via the interaction of ethanol with specific hydrophobic sites of channel subunit proteins (Chandler et al. 1998). Especially the GABAergic, glycinergic, glutamatergic and serotonergic neurotransmissions are affected. Altered receptor composition is a mechanism for receptor adaptation produced by chronic ethanol exposure. The resulting effects and the interactions of the neurotransmissions lead to the above mentioned symptoms and signs due to increasing and decreasing ethanol concentrations in the brain.

Ethanol augments GABAergic neurotransmission by increasing fluxes of chloride through GABA_A receptor channels (Grobin et al. 1998). GABA_A receptor activation mediates many of the behavioural effects of ethanol including motor incoordination, anxiolysis and sedation. Also another receptor-coupled supraspinal chloride channel is affected by this drug: Ethanol acts as competitive antagonist at strychnine-sensitive glycine receptors which increase the release of [³H]-acetylcholine ([³H]-ACh, Darstein et al. 1997). This is at variance to the potentiation by ethanol of the effects of glycine at the classical inhibitory strychnine-sensitive receptors in the spinal cord. The facilitatory glycine receptors in the rat striatum are expressed by cholinergic interneurons (Darstein et al. 2000) and by cholinergic neurons in the human amygdala where we could also elicit [³H]-ACh release through strychnine-sensitive glycine receptors. Again, ethanol antagonized [³H]-ACh release in the human amygdala (data to be published), a region of psychobiological importance. Actions of ethanol in this region may therefore be related to the emotional effects of this drug.

Ethanol affects NMDA receptors at concentrations that are reached during mild intoxication. Acute ethanol reduces the cation fluxes through the NMDA receptor channel. However, chronic administration of ethanol leads to an increased expression of NMDA receptors which should lead to increased responses upon NMDA receptor activation. This phenomenon has been confirmed functionally (Wirkner et al. 1999, Darstein et al. 1998). As a consequence, chronic ethanol abuse may facilitate glutamate excitotoxicity through NMDA receptors. Also the excitatory cation-selective channel linked to 5-HT₃ receptors is influenced by ethanol: The effect of 5-HT is potentiated at low ethanol concentrations which enhances the drive of inhibitory interneurons where 5-HT₃ receptors are primarily located. Both 5-HT₃ receptor agonists and ethanol increase dopamine release in the nucleus accumbens and 5-HT₃ receptor antagonists decrease ethanol-induced dopamine release in this region. This effect on the release of dopamine may explain the rewarding properties of ethanol (Lovinger 1999).

Inhibition of NMDA and potentiation of GABA_A receptors by acute ethanol results in reduced synaptic activity that is likely to contribute to the intoxicating effects of ethanol. A pathophysiological role of the recently discovered new site of action of ethanol, the supraspinal facilitatory glycine receptors, has yet to be elucidated. The development of tolerance and dependence involves changes in excitatory and inhibitory neurotransmissions, i.e. up- and down regulation of receptor density, changes in the subunit composition of receptors and post-translational modifications such as receptor (de)phosphorylation, resulting in altered receptor function.

References:

Butterworth RF (1995) Pathophysiology of alcoholic brain damage: synergistic effects of ethanol, thiamine deficiency and alcoholic liver disease. Metab Brain Dis 10:1-8

Chandler LJ, Harris RA, Crews FT (1998) Ethanol tolerance and synaptic plasticity. Trends Pharmacol Sci 19:491-495

Darstein M, Löschmann PA, Knörle R, Feuerstein TJ (1997) Strychnine-sensitive glycine receptors inducing [³H]-acetylcholine release in rat caudatoputamen: A new site of action of ethanol? Naunyn-Schmiedeberg´s Arch Pharmacol 356: 738-745

Darstein M, Albrecht C, López-Francos L, Knörle R, Hölter SM, Spanagel R, Feuerstein TJ (1998) Release and accumulation of neurotransmitters in the rat brain: acute effects of ethanol in vitro and effects of long-term voluntary ethanol intake. Alcohol Clin Exp Res 22: 704-709

Darstein M, Becker CM, Kling C, Landwehrmeyer GB, Feuerstein TJ (2000) Strychnine-sensitive glycine receptors in rat caudatoputamen are expressed by cholinergic interneurons. Neurosci 96:33-39

Grobin AC, Matthews DB, Devaud LL, Morrow AL (1998) The role of GABA(A) receptors in the acute and chronic effects of ethanol. Psychopharmacology 139:2-19

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Wiese JG, Shlipak MG, Browner WS (2000) The alcohol hangover. Ann Intern Med 132:897-902

Wirkner K, Poelchen W, Koles L, Mühlberg K, Scheibler P, Allgaier C, Illes P (1999) Ethanol-induced inhibition of NMDA receptor channels. Neurochem Int 35:153-162