Abstract
Depression is a commonly reported co-morbidity during rehabilitation from alcohol use disorders and its presence is associated with an increased likelihood of relapse. Interventions which impede the development of depression could be of potential benefit if incorporated into treatment programs. We previously demonstrated an ameliorative effect of physical exercise on depressive behaviors in a mouse model of alcohol abstinence. Here, we show that environmental enrichment (cognitive and social stimulation) has a similar beneficial effect. The hypothalamic-pituitary-adrenal (HPA) axis is a key physiological system regulating stress responses and its dysregulation has been separably implicated in the pathophysiology of depression and addiction disorders. We performed a series of dexamethasone challenges and found that mice undergoing 2 weeks of alcohol abstinence had significantly greater corticosterone and ACTH levels following a DEX-CRH challenge compared to water controls. Environmental enrichment during alcohol abstinence corrected the abnormal DEX-CRH corticosterone response despite a further elevation of ACTH levels. Examination of gene expression revealed abstinence-associated alterations in glucocorticoid receptor (Gr), corticotrophin releasing hormone (Crh) and pro-opiomelanocortin (Pomc1) mRNA levels which were differentially modulated by environmental enrichment. Overall, our study demonstrates a benefit of environmental enrichment on alcohol abstinence-associated depressive behaviors and HPA axis dysregulation.
Highlights
One of the biggest impediments to recovery programs for alcohol use disorders is the development of psychological disturbances by patients, such as post-dependent dysphoric syndromes
ETHANOL ABSTINENCE-ASSOCIATED DEPRESSIVE PHENOTYPE IS CORRECTED BY ENVIRONMENTAL ENRICHMENT Saccharin preference test One-way analysis of variance (ANOVA) revealed a significant difference in saccharin preference between the groups [F(2, 29) = 44.6, p < 0.001] (Figure 1B)
Forced swim test One-way ANOVA revealed a significant difference between the groups for total immobility time in the FORCED-SWIM TEST (FST) [F(2, 29) = 10.29, p < 0.001] (Figure 1D)
Summary
One of the biggest impediments to recovery programs for alcohol use disorders is the development of psychological disturbances by patients, such as post-dependent dysphoric syndromes. This is a significant issue to be addressed because the presence of comorbid psychiatric conditions such as depression and anxiety during abstinence is linked to a greater probability of relapse (Pelc et al, 2002). Several studies have established that the withdrawal phase itself is marked by specific cellular and molecular changes in the brain (Crews et al, 2004; Nixon and Crews, 2004; Aberg et al, 2005; He et al, 2009; Stevenson et al, 2009). Vendruscolo and colleagues proposed that the phases of acute withdrawal and protracted abstinence are distinct within themselves, marked by differences in hypothalamic-pituitary-adrenal (HPA) axis activity and expression levels of the glucocorticoid receptor (Vendruscolo et al, 2012)
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