Background: Acamprosate decreases relapse rates in alcohol-dependent patients by approximately 10-20 % within the first year after detoxification. Psychological stress is a major risk factor for relapse and is associated with activation of the hypothalamic-pituitary-adrenocortical (HPA) system. In recently detoxified alcoholics, the HPA system is dysregulated with non-suppression of cortisol after dexamethasone administration. We therefore investigated whether acamprosate normalizes HPA hyperactivity in alcoholics within the first 3 weeks of abstinence, employing a combined dexamethasone/corticotropin-releasing hormone (Dex-CRH)-test. Methods: Thirty alcohol-dependent patients were tested one week after withdrawal signs had disappeared. In 15 patients, acamprosate, 1332-1998 mg/day, was administered orally and a second Dex-CRH test was performed 1 week later. In the other 15 patients, acamprosate treatment was offered only after the second test. Results: CRH-stimulated cortisol secretion was significantly increased in both the acamprosate group and the group receiving no anti-relapse medication compared to a control group of 15 healthy subjects. Acamprosate treatment had no effect on basal or CRH-stimulated ACTH or cortisol secretion. Conclusions: We conclude that 1 week of acamprosate treatment does not attenuate the HPA dysregulation observed during early abstinence.
References
-
1
Adinoff B, Martin P R, Bone G HA, Eckardt M J, Roehrich L, George D T, Moss H B, Eskay R, Linnoila M, Gold P W.
Hypothalamic-pituitary-adrenal axis functioning and cerebrospinal fluid corticotropin releasing hormone and corticotropin levels in alcoholics after recent and long-term abstinence.
Arch Gen Psychiat.
1990;
47
325-330
-
2
al Qatari M, Khan S, Harris B, Littleton J.
Acamprosate is neuroprotective against glutamate-induced excitotoxicity when enhanced by ethanol withdrawal in neocortical cultures of fetal rat brain.
Alcohol Clin Exp Res.
2001;
25
1276-1283
-
3
Berton F, Francesconi W G, Madamba S G, Zieglgansberger W, Siggins G R.
Acamprosate enhances N-methyl-D-apartate receptor-mediated neurotransmission but inhibits presynaptic GABA(B) receptors in nucleus accumbens neurons.
Alcohol Clin Exp Res.
1998;
22
183-191
-
4
Brady K T, Sonne S C.
The role of stress in alcohol use, alcoholism treatment, and relapse.
Alcohol Res Health.
1999;
23
263-271
-
5
Dahchour A, De Witte P.
Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate.
Prog Neurobiol.
2000;
60
343-362
-
6
Feuerlein W, Ringer C, Kufner H, Antons K.
Diagnosis of alcoholism: the Munich Alcoholism Test (MALT).
Curr Alcohol.
1979;
7
137-147
-
7
Gerra G, Caccavari R, Delsignore R, Vourna S, Maestri D, Ugolotti G, Passeri M.
Pituitary responses to Ca-acetyl-homotaurinate in normal subjects and alcoholics.
Neuroendocrinol Lett..
1992;
14
119-126
-
8
Heinz A, Jones D W, Bissette G, Hommer D, Ragan P, Knable M, Wellek S, Linnoila M, Weinberger D R.
Relationship between cortisol and serotonin metabolites and transporters in alcolholism.
Pharmacopsychiatry.
2002;
35
127-134
-
9
Heyser C J, Schulteis G, Durbin P, Koob G F.
Chronic acamprosate eliminates the alcohol deprivation effect while having limited effects on baseline responding for ethanol in rats.
Neuropsychopharmacology.
1998;
18
125-133
-
10
Holsboer F.
The corticosteroid receptor hypothesis of depression.
Neuropsychopharmacology.
2000;
23
477-501
-
11
Hundt W, Zimmermann U, Pöttig M, Hahn K, Holsboer F.
The combined dexamethasone suppression/ CRH stimulation test in alcoholics during and after acute withdrawal.
Alcohol Clin Exp Res.
2001;
25
687-691
-
12
Jezova D, Tokarev D, Rusnak M.
Endogenous excitatory amino acids are involved in stress-induced adrenocorticotropin and catecholamine release.
Neuroendocrinology.
1995;
62
326-332
-
13
Madamba S G, Schweitzer P, Zieglgansberger W, Siggins G R.
Acamprosate (calcium acetylhomotaurinate) enhances the N-methyl- D-aspartate component of excitatory neurotransmission in rat hippocampal CA1 neurons in vitro.
Alcohol Clin Exp Res.
1996;
20
651-658
-
14
Mayer S, Harris B R, Gibson D A, Blanchard J A, Prendergast M A, Holley R C, Littleton J.
Acamprosate, MK-801, and ifenprodil inhibit neurotoxicity and calcium entry induced by ethanol withdrawal in organotypic slice cultures from neonatal rat hippocampus.
Alcohol Clin Exp Res.
2002;
26
1468-1478
-
15
Naassila M, Hammoumi S, Legrand E, Durbin P, Daoust M.
Mechanism of action of acamprosate. Part I. Characterization of spermidine-sensitive acamprosate binding site in rat brain.
Alcohol Clin Exp Res.
1998;
22
802-809
-
16 Oliver C, Jezova D, Grino M et al., Brann D W, Mahesh V B, editors. Excitatory amino acids. Their role in neuroendocrine function. 1 ed. Vol. 5, Excitatory amino acids and the hypothalamic-pituitary-adrenal axis. Boca Raton; CRC Press 1996: 167-185
-
17
Pelc I, Verbanck P, Le Bon O, Gavrilovic M, Lion K, Lehert P.
Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients. A 90-day placebo- controlled dose-finding study.
Br J Psychiat.
1997;
171
73-77
-
18
Popp R L, Lovinger D M.
Interaction of acamprosate with ethanol and spermine on NMDA receptors in primary cultured neurons.
Eur J Pharmacol.
2000;
394
221-231
-
19
Rammes G, Mahal B, Putzke J, Parsons C, Spielmanns P, Pestel E, Spanagel R, Zieglgansberger W, Schadrack J.
The anti-craving compound acamprosate acts as a weak NMDA-receptor antagonist, but modulates NMDA-receptor subunit expression similar to memantine and MK-801.
Neuropharmacology.
2001;
40
749-760
-
20
Ravi S D, Dorus W, Park Y N, Collins M C, Reid R W, Borge G F.
The dexamethasone suppression test and depressive symptoms in early and late withdrawal from alcohol.
Am J Psychiat.
1984;
141
1445-1448
-
21
Sass H, Soyka M, Mann K, Zieglgansberger W.
Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence.
Arch Gen Psychiat.
1996;
53
673-680
-
22
Schule C, Laakmann G, Baghai T, Neukam C, Soyka M.
Lack of effects of acamprosate on anterior pituitary hormone secretion in healthy subjects [letter].
J Clin Psychopharmacol.
1999;
9
387-389
-
23
Spanagel R, Hölter S M, Allingham K, Landgraf R, Zieglgansberger W.
Acamprosate and alcohol. 1. Effects on alcohol intake following alcohol deprivation in the rat.
Eur J Pharmacol.
1996;
305
39-44
-
24
Sullivan J T, Sykora K, Schneiderman J, Naranjo C A, Sellers E M.
Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar).
Br J Addict.
1989;
84
1353-1357
-
25
Tsai G, Gastfriend D R, Coyle J T.
The glutamatergic basis of human alcoholism.
Am J Psychiat.
1995;
152
332-340
-
26
Wetterling T, Veltrup C, Junghanns K, Kromer-Olbrisch T, Schneider U.
Acceptance of pharmacotherapy for relapse prevention by chronic alcoholics.
Pharmacopsychiatry.
2001;
34
142-146
-
27
Whitworth A B, Fischer F, Lesch O M, Nimmerrichter A, Oberbauer H, Platz T, Potgieter A, Walter H, Fleischhacker W.
Comparison of acamprosate and placebo in long-term treatment of alcohol dependence.
Lancet.
1995;
347
1438-1442
-
28
Zimmermann U, Hundt W, Spring K, Grabner A, Holsboer F.
Hypothalamic-pituitary-adrenal system adaptation to detoxification in alcohol-dependent patients is affeced by family history of alcoholism.
Biol Psychiat.
2003;
53
75-84
-
29
Zobel A W, Nickel T, Sonntag A, Uhr M, Holsboer F, Ising M.
Cortisol response to the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression: A prospective study.
J Psychiat Res.
2001;
35
83-94
Ulrich Zimmermann
Max Planck Institute of Psychiatry
Kraepelinstr. 10
80804 Munich
Germany
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eMail: zimm@mpipsykl.mpg.de