Adolescent ethanol drinking promotes hyperalgesia, neuroinflammation and serotonergic deficits in mice that persist into adulthood

Abstract

Adolescent alcohol use can permanently alter brain function and lead to poor health outcomes in adulthood. Emerging evidence suggests that alcohol use predispose to pain disorders or exacerbate existing pain conditions, but the neural mechanisms are currently unknown. Here we report that mice exposed to adolescent intermittent access to ethanol (AIE) exhibit increased pain sensitivity and depressive-like behaviors that persist after alcohol cessation and are accompanied by elevated CD68 expression in microglia and reduced numbers of serotonin (5-HT)-expressing neurons in the dorsal raphe nucleus (DRN). 5-HT expression was also reduced in the thalamus, anterior cingulate cortex (ACC) and amygdala as well as the lumbar dorsal horn of the spinal cord. We then found that chronic minocycline administration after AIE alleviated hyperalgesia and social deficits, while chemogenetic activation of microglia in the DRN of Cx3cr1-cre-GFP mice reproduced the effects of AIE on pain and social interaction. Taken together, these results indicate that microglial activation in the DRN may be a primary driver of pain and negative affect after AIE.

Serotonergic dysfunction may mediate the relationship between alcohol consumption and Alzheimer’s disease

“…Comparatively little is known about the effects of alcohol on the median raphe (MR), although we recently found that chronic alcohol exposure during adolescence reduces 5-HT expression in both the DR and the MR [ 76 ]. This suggests that these two areas may be equally sensitive to the effects of alcohol, though surprisingly, chronic heavy alcohol use is not associated with loss of 5-HT neurons in the MR in humans [ 77 ].…”