- Alcohol produces sedative, anxiolytic and anticonflict effects similar to other drugs such as benzodiazepines, barbiturates and GABA agonists that facilitate GABA function.
- Alcohol effects are additive or synergistic with drugs that facilitate GABA function and these drugs demonstrate cross-tolerance with alcohol.
- Drugs that facilitate GABA function suppress alcohol withdrawal symptoms.
- Drugs that have effects that are opposite to the benzodiazepines (benzodiazepine inverse agonists) block many alcohol effects.
- Alcohol increases GABA receptor-mediated chloride flux and inhibits postsynaptic potentials.
- Alcohol increases brain neurosteroid levels and neurosteroids act to increase GABA function.
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Alcohol Increases Serum Neurosteroid Levels
12 white male adolescents (age 13 – 17) had blood obtained in the emergency room, where they were diagnosed with alcohol intoxication (mean blood alcohol = 85 mg/100 mL). Controls were same aged males with mild trauma (blood alcohol = 0). Serum progesterone levels were also elevated in the intoxicated group. Allopregnanolone is a neurosteroid with rewarding properties. (Constructed from data in Torres, J.M. and Ortega, E. et al. Psychopharmacology, 172: 352, 2004) © 2011 NBEP
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The alcohol induced increase in neurosteroids relates to alcohol preference.
Alcohol Increases Brain Neurosteroid Levels and This Is Greater in Alcohol Preferring Rats
Sardinian rats bred to be alcohol non-preferring or alcohol preferring (42 generations) were given alcohol 1 g/kg I.P. The neurosteroids allopregnanolone (ALLO) and allotetrahydrodeoxycorticosterone (THDOC) were measured in cortex, hippocampus and plasma. Alcohol increased both neurosteroids in cortex and hippocampus and this was greater in the S-preferring rats. Alcohol increased ALLO equally in plasma of both S-non preferring and S-preferring rats, but increased THDOC in the plasma of S-preferring rats more than the S-non preferring rats. Neurosteroids are potent endogenous modulators of GABA-A receptors and the increased release in S-preferring rats may be an important factor in their alcohol preferences. (Constructed from data in Barbaccia, M.L. et al European J Pharmacology, 384: R1-2, 1999) © 2011 NBEP
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There is tolerance to the alcohol induced increase in neurosteroids.
Acute Alcohol Increases Deoxycorticosterone (DOC) and This Response Is Reduced Following 15 Days of Liquid Diet Alcohol Consumption
The neurosteroid allotetrahydrodeoxycorticosterone (THDOC) is synthetized in adrenals and brain from deoxycorticosterone (DOC). Alcohol increased DOC levels in plasma and in the 5 brain areas studied 60 min after injection (2 g/kg). A 15 day liquid diet of alcohol resulted in a reduces DOC response to alcohol even though blood alcohol levels were higher (324 mg/dL on alcohol diet vs. 195 mg/dL controls [saline injected rats in the alcohol fed group: 126 mg/dL]). This data indicated that chronic alcohol consumption produces tolerance to the acute effects of alcohol on DOC levels. This may relate to alcohol tolerance at the behavioral level. (Constructed from data in Khisti, R.T. et al Brain Research, 1049: 104, 2005) © 2011 NBEP
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The alcohol induced increase in neurosteroids is followed by reduced neurosteroid levels during withdrawal.
Plasma Neurosteroids Are Low during Early Alcohol Withdrawal
Nine male alcohol dependent subjects and 6 hospitalized controls had plasma neurosteroids (allotetrahydrodeoxycorticosterone (THDOC) and allopregnanolone (ALLO)measured following hospital admissions. ALLO levels were also low in the alcoholics on withdrawal days 4 and 5. Measures of anxiety and depression were elevated on withdrawal days 4 and 5 and were normal by days 15 and 28. (Constructed from data in Romeo, E. et al Clinical Neuropharmacology, 19: 366, 1996) ©2011 NBEP
