Targeting the Glucocorticoid Receptors During Alcohol Withdrawal to Reduce Protracted Neurocognitive Disorders

Abstract

Persistent regional glucocorticoid (GC) dysregulation in alcohol-withdrawn subjects emerges as a key factor responsible for protracted molecular and neural alterations associated with long-term cognitive dysfunction. Regional brain concentrations of corticosterone vary independently from plasma concentrations in alcohol-withdrawn subjects, which may account for the treatment of alcohol withdrawal-induced persistent pathology. Thus, from a pharmacological point of view, a main issue remains to determine the relative efficacy of compounds targeting the GC receptors to attenuate or suppress the long-lasting persistence of brain regional GC dysfunctions in abstinent alcoholics, as well as persistent changes of neural plasticity. Data from animal research show that acting directly on GC receptors during the withdrawal period, via selective antagonists, can significantly counteract the development and persistence of cognitive and neural plasticity disorders during protracted abstinence. A critical remaining issue is to better assess the relative long-term efficacy of GC antagonists and other compounds targeting the corticotropic axis activity such as gamma-aminobutyric acid A (GABA_A) and GABA_B agonists. Indeed, benzodiazepines (acting indirectly on GABA_A receptors) and baclofen (agonist of the GABA_B receptor) are the compounds most widely used to reduce alcohol dependence. Clinical and preclinical data suggest that baclofen exerts an effective and more powerful counteracting action on such persistent cognitive and endocrine dysfunctions as compared to diazepam, even though its potential negative effects on memory processes, particularly at high doses, should be better taken into account.

Keywords: alcohol withdrawal and relapse; baclofen; benzodiazepines; corticosterone; gaba receptors; glucocorticoids; prefrontal cortex; working memory.

Figure 1

Parallel evolution of alcohol withdrawal–induced symptoms and plasmatic or brain regional glucocorticoid (GC) levels over time. Acute withdrawal is associated with a release of catecholamines, CRF, and high plasmatic GCs, which mediate physiological and behavioral symptoms initially through non-genomic effects. The early abstinence period is associated with a decrease in plasmatic GC concentration as opposed to a brain regional GC increase, particularly in the PFC, likely involving genomic effects of GC. Although brain GC concentration and affective/cognitive symptoms will be normalized in many dependent subjects, persistence of elevated brain GC levels and cognitive impairments in others is predictive of high risk of relapse (see text for details).

Figure 2

Effects of diazepam treatment on cognitive deficits, prefrontal cortical (PFC) GC levels, and pCREB expression in alcohol-withdrawn C57BL6/J mice. Chronic alcohol consumption lasted 6 months at 12% (v/v). This pharmacological study showed that 1-week-withdrawn mice receiving vehicle exhibited increased levels of corticosterone, reduced pCREB activity in the PFC, and working memory deficits as assessed with a sequential alternation task, 24 h after the last diazepam injection. Diazepam administered i.p. at decreasing doses ranging from 1.0 to 0.25 mg/kg every day during the 9 days of the withdrawal phase transiently (1 week but not 4 weeks) reversed both the endocrine and cognitive impairments observed in vehicle-treated animals (128).