Long-Term Effects of Chronic Intermittent Ethanol Exposure in Adolescent and Adult Rats: Radial-Arm Maze Performance and Operant Food Reinforced Responding

Abstract

BackgroundAdolescence is not only a critical period of late-stage neurological development in humans, but is also a period in which ethanol consumption is often at its highest. Given the prevalence of ethanol use during this vulnerable developmental period we assessed the long-term effects of chronic intermittent ethanol (CIE) exposure during adolescence, compared to adulthood, on performance in the radial-arm maze (RAM) and operant food-reinforced responding in male rats.Methodology/Principal FindingsMale Sprague Dawley rats were exposed to CIE (or saline) and then allowed to recover. Animals were then trained in either the RAM task or an operant task using fixed- and progressive- ratio schedules. After baseline testing was completed all animals received an acute ethanol challenge while blood ethanol levels (BECs) were monitored in a subset of animals. CIE exposure during adolescence, but not adulthood decreased the amount of time that animals spent in the open portions of the RAM arms (reminiscent of deficits in risk-reward integration) and rendered animals more susceptible to the acute effects of an ethanol challenge on working memory tasks. The operant food reinforced task showed that these effects were not due to altered food motivation or to differential sensitivity to the nonspecific performance-disrupting effects of ethanol. However, CIE pre-treated animals had lower BEC levels than controls during the acute ethanol challenges indicating persistent pharmacokinetic tolerance to ethanol after the CIE treatment. There was little evidence of enduring effects of CIE alone on traditional measures of spatial and working memory.Conclusions/SignificanceThese effects indicate that adolescence is a time of selective vulnerability to the long-term effects of repeated ethanol exposure on neurobehavioral function and acute ethanol sensitivity. The positive and negative findings reported here help to further define the nature and extent of the impairments observed after adolescent CIE and provide direction for future research.

Adolescent binge ethanol exposure alters specific forebrain cholinergic cell populations and leads to selective functional deficits in the prefrontal cortex

“…AIE has been associated with dysfunction in key learning and memory structures in adult rodents. Although AIE leads to decreased neurogenesis within the hippocampus (Geil et al, 2014; Vetreno and Crews, 2015; Sakharkar et al, 2016), AIE’s detrimental effects on spatial memory are inconclusive (Risher et al, 2013; Swartzwelder et al, 2015; Beaudet et al, 2016). Following AIE, there is also a significant loss in the number of cholinergic neurons within the medial septum/diagonal band (MS/DB), which projects to the hippocampus, and the Nucleus basalis of Meynert (NbM) that projects to the cortex (Ehlers et al, 2011; Vetreno et al, 2014; Boutros et al, 2015).…”

Alcohol Use in Adolescence and Later Working Memory: Findings From a Large Population-Based Birth Cohort

“…For example, research in animal models has demonstrated lasting consequences of adolescent exposure to alcohol, including alterations in later WM performance (White et al , 2000; Risher et al , 2013). Human brain imaging studies have identified neural functioning correlates of adolescent heavy drinking.…”

Adolescent Alcohol Exposure Alters GABAA Receptor Subunit Expression in Adult Hippocampus

“…More specifically, the results indicate that the long-term expression of specific GABA receptor subunits in the hippocampal formation is altered by AIE, but not by CIE, and this may help to explain why AIE, but not CIE, alters subsequent vulnerability to the effects of acute ethanol on spatial learning (White et al, 2000; Risher et al, 2013a) and why AIE alters the induction of hippocampal LTP and spatial learning in adulthood (Risher et al, 2013b). The specific focus on GABA receptor subunits regulation at mRNA and protein levels in this report adds a mechanistic focus to the important and growing literature on the long-term effects of alcohol exposure during adolescence, and the importance of this developmental period for subsequent hippocampal function and related phenotypes.…”

“…The EtOH naïve rats from which tissue was extracted on PD46 also served as saline controls in the subsequent study of adolescent ethanol exposure. A recent study from this laboratory using identical EtOH exposure protocols have generated average BECs (in mg/dl ± sem) of 199.7 ± 19.9 60 min after the first dose, and 172.8 ± 13.3 60min after the last dose (Risher et al, 2013a). Those blood ethanol concentrations are consistent with BECs achieved in our previous studies (Acheson et al, 2013), and by adolescent humans during binge drinking episodes serving as part of the binge drinking criteria (NIAAA, 2004).…”