Elsevier

Neuroscience

Volume 156, Issue 4, 28 October 2008, Pages 1017-1027
Neuroscience

Neuropharmacology
Selective increases in regional brain glucocorticoid: A novel effect of chronic alcohol

https://doi.org/10.1016/j.neuroscience.2008.08.029Get rights and content

Abstract

The hypothalamo-pituitary–adrenal axis shows functional changes in alcoholics, with raised glucocorticoid release during alcohol intake and during the initial phase of alcohol withdrawal. Raised glucocorticoid concentrations are known to cause neuronal damage after withdrawal from chronic alcohol consumption and in other conditions. The hypothesis for these studies was that chronic alcohol treatment would have differential effects on corticosterone concentrations in plasma and in brain regions. Effects of chronic alcohol and withdrawal on regional brain corticosterone concentrations were examined using a range of standard chronic alcohol treatments in two strains of mice and in rats. Corticosterone was measured by radioimmunoassay and the identity of the corticosterone extracted from brain was verified by high performance liquid chromatography and mass spectrometry. Withdrawal from long term (3 weeks to 8 months) alcohol consumption induced prolonged increases in glucocorticoid concentrations in specific regions of rodent brain, while plasma concentrations remained unchanged. This effect was seen after alcohol administration via drinking fluid or by liquid diet, in both mice and rats and in both genders. Shorter alcohol treatments did not show the selective effect on brain glucocorticoid levels. During the alcohol consumption the regional brain corticosterone concentrations paralleled the plasma concentrations. Type II glucocorticoid receptor availability in prefrontal cortex was decreased after withdrawal from chronic alcohol consumption and nuclear localization of glucocorticoid receptors was increased, a pattern that would be predicted from enhanced glucocorticoid type II receptor activation. This novel observation of prolonged selective increases in brain glucocorticoid activity could explain important consequences of long term alcohol consumption, including memory loss, dependence and lack of hypothalamo-pituitary responsiveness. Local changes in brain glucocorticoid levels may also need to be considered in the genesis of other mental disorders and could form a potential new therapeutic target.

Section snippets

Animals

Mice of TO (outbred) and C57/BL10 strains, were aged 6–8 weeks at start of experiments and Hooded Lister rats aged 2 months at start. Animals were bred in house, on reverse phase lighting in group housing from birth (lights on 20:00 h to 08:00 h). Housing was in groups of 8 to 10 for mice and 3 to 4 for rats. All animals were male except those for which results are illustrated in Fig. 2a and 2b.

Alcohol treatments

In order to establish the generality of the changes, several well-established chronic alcohol

Brain corticosterone concentrations: male TO mice given alcohol via a liquid diet

During the alcohol consumption (i.e. when there was no alcohol withdrawal) there were no significant differences between chronic alcohol and controls in either brain or plasma corticosterone levels (Fig. 1a). Three weeks alcohol liquid diet, then 6 days abstinence from alcohol, however, resulted in significantly raised concentrations of corticosterone in the hippocampus and the striatum of male TO strain mice, but not the cerebral cortex (Fig. 1b). Plasma corticosterone concentrations were

Discussion

When measurements were made during alcohol consumption, the regional brain concentrations appeared to parallel the plasma levels, increases being observed in both plasma and brains of alcohol-treated animals compared with controls. After alcohol withdrawal, however, a dissociation was seen between brain and plasma corticosterone concentrations. Plasma corticosterone levels rose during the first few hours after alcohol withdrawal (as expected from previous studies, Tabakoff et al., 1978) but

Acknowledgments

We thank the National Institute on Alcohol Abuse and Alcoholism for financial support (R01 AA13932).

References (66)

  • J.J. Kril et al.

    The cerebral cortex is damaged in chronic alcoholics

    Neuroscience

    (1997)
  • A.L. Morrow et al.

    The role of GABAergic neuroactive steroids in ethanol action, tolerance and dependence

    Brain Res Rev

    (2001)
  • D. O'Donnell et al.

    Effects of adrenalectomy and corticosterone replacement on glucocorticoid receptor levels in rat-brain tissue: a comparison between Western blotting and receptor-binding assays

    Brain Res

    (1995)
  • P.V. Piazza et al.

    Glucocorticoids as a biological substrate of reward: physiological and pathological implications

    Brain Res Rev

    (1997)
  • G. Rachamin et al.

    Neither chronic exposure to ethanol nor aging affects type I or type II corticosteroid receptors in rat hippocampus

    Exp Neurol

    (1989)
  • A.H. Schinkel et al.

    Disruption of the mouse mdr1a p-glycoprotein gene leads to a deficiency in the blood-brain-barrier and to increased sensitivity to drugs

    Cell

    (1994)
  • W.P. Watson et al.

    Effects of chronic ethanol consumption on responses to nicotine: interaction with environmental cues

    Neuropharmacology

    (1999)
  • W.P. Watson et al.

    Selectivity of the effects of dihydropyridine calcium channel antagonists against the alcohol withdrawal syndrome

    Brain Res

    (2002)
  • B. Adinoff et al.

    Hypothalamic-pituitary adrenal axis functioning and cerebrospinal fluid corticotrophin releasing hormone and corticotropin levels in alcoholics after recent and long term abstinence

    Arch Gen Psychiatry

    (1990)
  • A. Ahmed et al.

    Induction of hepatic 11β-hydroxysteroid dehydrogenase type 1 in patients with alcoholic liver disease

    Clin Endocrinol

    (2008)
  • M.E. Bates et al.

    Neurocognitive impairment associated with alcohol use disorders: implications for treatment

    Exp Clin Psychopharmacol

    (2002)
  • S.C. Bowdon et al.

    Neurotoxicity and neurocognitive impairments with alcohol and drug-use disorders: potential roles in addiction and recovery

    Alchohol Clin Exp Res

    (2001)
  • S.P. Brooks et al.

    Nimodipine prior to alcohol withdrawal prevents memory loss during the abstinence phase; possible involvement of brain glucocorticoid

    Neuroscience

    (2008)
  • J.C. Butte et al.

    Rat and mouse brain corticosterone

    Endocrinology

    (1972)
  • A.P. Croft et al.

    Effects of minor laboratory procedures, adrenalectomy, social defeat or acute alcohol on regional brain concentrations of corticosterone

    Brain Res

    (2008)
  • E. Davies et al.

    Extra-adrenal production of corticosteroids

    Clin Exp Pharmacol Physiol

    (2003)
  • J.A. Diez et al.

    Postnatal development of mouse plasma and brain corticosterone levels: new findings contingent upon the use of a competitive protein-binding assay

    Endocrinology

    (1975)
  • D. Durand et al.

    Decreased neuronal inhibition in vitro after long-term administration of ethanol

    Science

    (1984)
  • F. Fadda et al.

    Chronic ethanol consumption: from neuroadaptation to neurodegeneration

    Prog Neurobiol

    (1998)
  • C. Fahlke et al.

    Effect of adrenalectomy and exposure to corticosterone on alcohol intake in alcohol preferring and alcohol avoiding rat lines

    Alcohol Alcohol

    (2000)
  • Global status report on alcohol

    (2004)
  • J. Haorah et al.

    Alcohol-induced blood-brain barrier dysfunction is mediated via inositol 1,4,5-triphosphate receptor (IP3R)-gated intracellular calcium release

    J Neurochem

    (2007)
  • C. Harper

    The neuropathology of alcohol-specific brain damage, or does alcohol damage the brain?

    J Neuropathol Exp Neurol

    (1998)
  • Cited by (0)

    View full text