Chronic intermittent ethanol exposure in early adolescent and adult male rats: effects on tolerance, social behavior, and ethanol intake

Abstract

Background: Given the prevalence of alcohol use in adolescence, it is important to understand the consequences of chronic ethanol exposure during this critical period in development. The purpose of this study was to assess possible age-related differences in susceptibility to tolerance development to ethanol-induced sedation and withdrawal-related anxiety, as well as voluntary ethanol intake after chronic exposure to relatively high doses of ethanol during adolescence or adulthood.

Methods: Juvenile/adolescent and adult male Sprague-Dawley rats were assigned to one of five 10-day exposure conditions: chronic ethanol (4 g/kg every 48 hours), chronic saline (equivalent volume every 24 hours), chronic saline/acutely challenged with ethanol (4 g/kg on day 10), nonmanipulated/acutely challenged with ethanol (4 g/kg on day 10), or nonmanipulated. For assessment of tolerance development, duration of the loss of righting reflex (LORR) and blood ethanol concentrations (BECs) upon regaining of righting reflex (RORR) were tested on the first and last ethanol exposure days in the chronic ethanol group, with both saline and nonmanipulated animals likewise challenged on the last exposure day. Withdrawal-induced anxiety was indexed in a social interaction test 24 hours after the last ethanol exposure, with ethanol-naïve chronic saline and nonmanipulated animals serving as controls. Voluntary intake was assessed 48 hours after the chronic exposure period in chronic ethanol, chronic saline and nonmanipulated animals using an 8-day 2 bottle choice, limited-access ethanol intake procedure.

Results: In general, adolescent animals showed shorter durations of LORR and higher BECs upon RORR than adults on the first and last ethanol exposure days, regardless of chronic exposure condition. Adults, but not adolescents, developed chronic tolerance to the sedative effects of ethanol, tolerance that appeared to be metabolic in nature. Social deficits were observed after chronic ethanol in both adolescents and adults. Adolescents drank significantly more ethanol than adults on a gram per kilogram basis, with intake uninfluenced by prior ethanol exposure at both ages.

Conclusions: Adolescents and adults may differ in their ability and/or propensity to adapt to chronic ethanol exposure, with adults, but not adolescents, developing chronic metabolic tolerance. However, this chronic exposure regimen was sufficient to disrupt baseline levels of social behavior at both ages. Taken together, these results suggest that, despite the age-related differences in tolerance development, adolescents are as susceptible as adults to consequences of chronic ethanol exposure, particularly in terms of disruptions in social behavior. Whether these effects would last into adulthood remains to be determined.

Figure 1

Percent body weight gain across the acclimation and chronic exposure period in adolescents (left) and adults (right) chronically exposed to saline or ethanol. Data are expressed as means ± SEM and asterisks (*) denote a significant difference (p ≤.05) between groups.

Figure 2

Loss of righting reflex (LORR) duration (left) and BECs (right) at regaining of righting reflex (RORR) on the first and last ethanol exposure days of adolescents and adults in the chronic ethanol group (within subjects). Data are expressed as means ± SEM and asterisks (*) denote a significant difference (p ≤.05) between the groups indicated.

Figure 3

LORR duration (top panel) and BECs at RORR (bottom panel) on day 10 of non-manipulated (NM)/acutely challenged with ethanol, saline/acutely challenged with ethanol and chronic ethanol exposed adolescents (left) and adults (right). Data are expressed as means ± SEM and asterisks (*) denote significance (p ≤.05) between the groups indicated.

Figure 4

Locomotor activity (crosses) during the 30 minute habituation period prior to the social interaction test of non-manipulated (NM), chronic saline exposed and chronic ethanol exposed adolescents (left) and adults (right). Data are expressed as means ± SEM. Asterisks (*) denote a significant difference between chronic ethanol and chronic saline groups and (§) denote a significant difference between chronic ethanol and non-manipulated groups.

Figure 5

Frequency of social investigating, social contact, play and locomotor activity (crosses) during the social interaction test of non-manipulated, chronic saline exposed and chronic ethanol exposed adolescents (left portion of each figure) and adults (right portion of each figure). Data expressed as means ± SEM and asterisks (*) denote a significant difference between groups indicated.

Figure 6

Ethanol intake g/kg (top panel) and percent preference (bottom panel) across the 8 day limited access intake procedure in adolescents (left) and adults (right). Data expressed as means ± SEM.