Abstract
Stressful events early in life, later high alcohol consumption and vulnerability to alcohol use disorder (AUD) are tightly linked. Norepinephrine is highly involved in the stress response and the α2A-adrenoceptor, which is an important regulator of norepinephrine signalling, is a putative target in pharmacotherapy of AUD. The aim of the present study was to investigate the effects of early-life stress and adult voluntary alcohol drinking on the α2A-adrenoceptor. The relative expression and promoter DNA methylation of the Adra2a gene were measured in the hypothalamus, a key brain region in stress regulation. A well-characterized animal model of early-life stress was used in combination with an episodic voluntary drinking in adulthood. Alcohol drinking rats with a history of early-life stress had lower Adra2a expression than drinking rats not exposed to stress. Alcohol intake and Adra2a gene expression were negatively correlated in high-drinking animals, which were predominantly rats subjected to early-life stress. The results provide support for a link between early-life stress, susceptibility for high alcohol consumption, and low Adra2a expression in the hypothalamus. These findings can increase our understanding of the neurobiological basis for vulnerability to initiate risk alcohol consumption and individual differences in the response to α2A-adrenoceptor agonists.
Highlights
Preclinical and clinical studies provide strong evidence of a link between stressful life events and high alcohol consumption, vulnerability to alcohol use disorder and relapse [1]
Different drinking patterns were revealed in these subgroups; the high drinking rats increased their ethanol consumption over time whereas the moderate drinkers had a stable intake pattern and the low drinking rats had a decreased intake (Figure 2A)
Single housing is associated with stress [42], and since voluntary drinking designs often include single-housed animals, it is important to discriminate between a possible effect of housing and the effect of alcohol for any endpoint measured. This was tested in the Animal facility reared (AFR) rats and the results indicated that Adra2a gene expression is not affected by single housing in adult animals
Summary
Preclinical and clinical studies provide strong evidence of a link between stressful life events and high alcohol consumption, vulnerability to alcohol use disorder and relapse [1]. Α2A-adrenoceptor agonists decrease availability of norepinephrine in the synaptic cleft and reduce alcohol consumption [15,16], as well as alcohol deprivation effect, alcohol seeking behaviour, and cue/priming-induced reinstatement in high drinking rats [16]. These facts, together with the findings of an association between polymorphisms in the Adra2a gene and positive family history of AUD [17], call for molecular studies of the link between the α2A-adrenoceptor, stress and alcohol drinking
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