Alterations in hypothalamo‐pituitary adrenal (HPA) function have been described in alcoholics and in rodents after chronic alcohol consumption but the role of glucocorticoids in alcohol consumption, and the mechanisms involved, has received little attention until recently. Both alcohol consumption and withdrawal from chronic alcohol intake raise circulating glucocorticoid levels, and prolonged high concentrations of glucocorticoids are known to have detrimental effects on neuronal function and cognition. This minireview covers the ways in which glucocorticoids may be involved in drinking behavior, from social drinking to dependence, and the negative consequences of alcohol consumption seen during withdrawal which may have a detrimental effect on treatment outcome. Research shows prolonged increases in brain glucocorticoid concentrations and decreased brain glucocorticoid receptor availability (consistent with increased levels of endogenous ligand) after withdrawal from chronic alcohol treatment. Evidence suggests that increased glucocorticoid levels in the brain after chronic alcohol treatment are associated with the cognitive deficits seen during abstinence which impact on treatment efficacy and quality of life. Studies on organotypic cultures also demonstrate the importance of glucocorticoids in the neuropathological consequences of alcohol dependence.

Neurotoxicity

Alcohol Dependence

10.1111/j.1530-0277.2010.01298.x

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Citations (90)

Brain monoamines and the high pressure neurological syndrome

Neuropharmacology (1980)

Donald D. Koblin H.J. Little A.R. Green Stephen R. Daniels E. B. Smith

Reserpine

Pentylenetetrazol

Convulsion

10.1016/0028-3908(80)90098-2

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Citations (21)

Acetylcholinesterase activity in regions of mouse brain following acute and chronic treatment with a benzodiazepine inverse agonist

British Journal of Pharmacology (1990)

Margaret E. Appleyard Stuart C. Taylor H.J. Little

Chronic administration of the benzodiazepine inverse agonist FG 7142 has previously been shown to induce seizure activity in mice. In the present study we have investigated the effects of acute and chronic treatment with FG 7142 in mice on the levels of acetylcholinesterase activity in cortex, hippocampus, midbrain and striatum. We have also investigated the effects of acute and chronic stress in the form of handling (vehicle‐injection) on acetylcholinesterase levels. A single dose of FG 7142 produced a marked elevation of total acetylcholinesterase activities in the hippocampus and midbrain when compared with vehicle‐injected control levels, but the levels were not different from those in unhandled animals. Acute stress, in the form of vehicle‐injection produced decreases in cortical and hippocampal soluble acetylcholinesterase activity but FG 7142 had no effect upon these stress‐induced changes. Total cortical and hippocampal acetylcholinesterase activities were increased by 56% and 16% respectively in the chronic FG 7142‐treated mice that exhibited seizure activity (compared with vehicle‐injected controls). Soluble acetylcholinesterase activity in the midbrain was decreased to 82% of control levels only in animals that had undergone FG 7142‐induced kindling. Smaller or no changes in acetylcholinesterase activity in the midbrain were observed in chronically FG 7142‐treated animals that exhibited no seizure activity. Mice that did not demonstrate seizure activity in response to chronic FG 7142 treatment showed alterations in the soluble acetylcholinesterase activities of the hippocampus and midbrain. It is concluded that chronic treatment with the benzodiazepine inverse agonist FG 7142 produces alterations in the acetylcholinesterase activities of various brain regions, in a manner related to the kindling that can be produced by this treatment. Chronic mild stress, in the form of repeated handling (vehicle injection), induced changes in brain activity with decreases in total activity occurring in the cortex and hippocampus, and an increase in soluble acetylcholinesterase activity occurring in the midbrain. All these stress‐induced changes appeared to be prevented by administration of FG 7142 at the time of the stress. It would appear therefore that FG 7142 can prevent the effects of chronic stress on brain acetylcholinesterase activity.

Inverse agonist

10.1111/j.1476-5381.1990.tb14127.x

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Citations (16)

Selective changes in the in vivo effects of benzodiazepine receptor ligands after chemical kindling with FG 7142

Neuropharmacology (1987)

H.J. Little David Nutt Stuart C. Taylor

Inverse agonist

Flurazepam

Kindling model

Convulsants

10.1016/0028-3908(87)90040-2

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Citations (25)

Chronic treatment with a benzodiazepine agonist in vivo increases the actions of the benzodiazepine partial inverse agonist, FG7142, on the hippocampal slice in vitro

Brain Research (1992)

H.J. Little Mogens Myrup Andreasen J.D.C. Lambert

Inverse agonist

Flurazepam

10.1016/0006-8993(92)90769-6

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Citations (2)

The calcium channel antagonist, nimodipine, decreases operant self-administration of low concentrations of ethanol

Behavioural Pharmacology (1999)

J. W. Smith William P. Watson D.N. Stephens H.J. Little

This study examined effects of the dihydropyridine calcium channel antagonist, nimodipine, on operant self-administration of ethanol, under a progressive-ratio schedule of reinforcement, by hooded Lister rats. Calcium channel antagonists have been reported to decrease the ethanol withdrawal syndrome, the development of tolerance to ethanol and ethanol consumption; and dihydropyridine binding site density in the central nervous system (CNS) is increased by chronic alcohol treatment. In addition, these drugs decrease reinforcing effects of psychostimulants. In the present studies, nimodipine was administered, once weekly, at either 10 or 50 mg/kg intraperitoneally (i.p.). At 10 mg/kg, nimodipine decreased the break point, and number of reinforcers obtained, for ethanol concentrations of 5, 10 and 15%. At 50 mg/kg, nimodipine only decreased the break point, and number of reinforcers, for 5% ethanol. Responding for higher concentrations of ethanol was unaffected by nimodipine, as was responding when ethanol was replaced by water. The break point for 10% sucrose, but not for 1% or 0.1%, was decreased by 50 mg/kg nimodipine, but 10 mg/kg nimodipine had no effect on sucrose-reinforced responding. The 50 mg/kg dose of nimodipine decreased motor activity, but 10 mg/kg nimodipine only slightly decreased static activity counts. The results suggest that nimodipine, at the lower dose tested, decreased the reinforcing properties of low concentrations of ethanol. © 1999 Lippincott Williams & Wilkins.

Nimodipine

10.1097/00008877-199912000-00011

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Citations (13)