Age-related differences in ethanol withdrawal, withdrawal-induced anxiety, cognition, and response to allopregnanolone.
Research with humans and rodents suggests that symptoms of alcohol withdrawal may be more severe in the elderly compared with younger adults. However, investigations of the effects of repeated ethanol intoxications and withdrawals on persistent deficits in motor and cognitive performance in aged rats are limited. The present study thus sought to investigate age-related differences in the severity of ethanol withdrawal in adult and aged rats and examine potential long-term deficits resulting from chronic liquid ethanol diet. Results revealed that adult rats exhibited robust signs of ethanol withdrawal using a four-item behavioral scale (rigidity, hypoactivity, irritability, and intentional tremors) but showed only a non-significant trend of anxiety-like behavior and hyperactivity in the elevated plus maze and open field tasks during withdrawal. In contrast, aged animals consumed significantly less ethanol per body weight than adults and achieved minimal withdrawal scores using the standardized scale, but exhibited profound anxiety-like behavior during withdrawal. After a 14 day cessation from ethanol, adult and aged rats treated with chronic ethanol diet showed spatial learning deficits in water maze acquisition and a cognitively-challenging reversal paradigm. Chronic ethanol consumption did not result in significant motor impairments in either age group as assessed by the aerial righting reflex. When challenged with an acute dose of ethanol, adult and aged animals demonstrated metabolic but not cognitive tolerance to ethanol. Finally, we investigated the effects of an acute dose of allopregnanolone on spatial memory in aged rats. In accordance with previous research, adult animals showed impaired performance when treated with allopregnanolone. However, the results for the aged animals were not statistically significant. Interestingly, animals receiving an acute ethanol challenge showed greater allopregnanolone-induced impairments in the water maze compared to those receiving saline. The current study thus demonstrates that aged rats are especially vulnerable to anxiety-like behavior during ethanol withdrawal, and that repeated ethanol intoxications and withdrawals impair cognition in both age groups. Research targeting mechanisms and treatment of withdrawal-induced anxiety in the elderly is a promising avenue of future investigation.