Binge drinking is prevalent during adolescence and may have effects on the adult brain and behavior. The present study investigated whether adolescent intermittent ethanol (AIE) exposure alters adult risky choice and prefrontal dopaminergic and forebrain cholinergic neuronal marker levels in male Wistar rats. Adolescent (postnatal day 28–53) rats were administered 5 g/kg of 25% (v/v) ethanol three times per day in a 2 days on/2 days off exposure pattern. In adulthood, risky choice was assessed in the probability discounting task with descending and ascending series of large reward probabilities and after acute ethanol challenge. Immunohistochemical analyses assessed tyrosine hydroxylase (TH), a marker of dopamine and norepinephrine in the prelimbic and infralimbic cortices and choline acetyltransferase (ChAT), a marker of cholinergic neurons, in the basal forebrain. All of the rats preferred the large reward when it was delivered with high probability. When the large reward became unlikely, control rats preferred the smaller, safe reward, whereas AIE-exposed rats continued to prefer the risky alternative. Acute ethanol had no effect on risky choice in either group of rats. TH (prelimbic cortex only) and ChAT immunoreactivity levels were decreased in AIE-exposed rats compared with controls. Risky choice was negatively correlated with ChAT, implicating decreased forebrain cholinergic activity in risky choice. The decreases in TH and ChAT immunoreactivity suggest that AIE exposure has enduring neural effects that may lead to altered adult behaviors, such as increased risky decision making. In humans, increased risky decision making could lead to maladaptive, potentially harmful consequences.

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.

Five pigeons responded on steady-state concurrent variable-interval variable-interval schedules of food presentation in which half of the foods were removed and replaced with nonfood stimuli. Across conditions, the stimuli were either paired or unpaired with food, and the correlation between the ratio of food deliveries on the two alternatives and the ratio of nonfood stimuli was either -1, 0, or +1. Neither the pairing of stimuli with food, nor the correlation between stimuli and food, affected generalized-matching performance, but paired stimuli had a demonstrable effect at a local level of analysis. This effect was independent of the food-stimulus correlation. These results differ from results previously obtained in a frequently changing environment. We attribute this difference in results to differences in the information value of response-contingent stimuli in frequently changing versus relatively constant environments, as well as to differences between forward pairing and simultaneous pairing of the stimuli with food.

Binge drinking during adolescence and adulthood may have differential long-term effects on the brain. We investigated the long-term effects of chronic intermittent ethanol (CIE) exposure during adolescence and adulthood on impulsivity and anxiety-like behavior. Adolescent (adolescent-exposed) and adult (adult-exposed) rats were exposed to CIE/water on postnatal days (PND) 28-53 and PND146-171, respectively, and a 4-day ethanol/water binge on PND181-184 and PND271-274, respectively. During withdrawal from CIE and 4-day binge exposures, anxiety-like behavior and arousal were measured in the light-potentiated startle (LPS) and the acoustic startle (ASR) procedures, respectively. Impulsive choice was evaluated in the delay discounting task (DDT) at baseline and after ethanol challenges. Independent of age, ASR and LPS were decreased during withdrawal from CIE exposure. In contrast, LPS was increased in adult-exposed, but not adolescent-exposed, rats during withdrawal from the 4-day ethanol binge. CIE exposure had no effect on preference for the large delayed reward at baseline, independent of age. During DDT acquisition, CIE-exposed, compared with water-exposed rats, omitted more responses, independent of age, suggesting CIE-induced disruption of cognitive processes. Ethanol challenges decreased preference for the large reward in younger adolescent-exposed rats but had no effect in older adult-exposed rats independent of previous CIE/water exposure. Taken together, the present studies demonstrate that CIE withdrawal-induced decreases in anxiety and arousal were not age-specific. CIE exposure had no long-term effects on baseline impulsive choice. Subsequent ethanol exposure produced age-dependent effects on impulsivity (increased impulsivity in younger adolescent-exposed rats) and anxiety-like behavior (increased anxiety-like behavior in older adult-exposed rats).

Conditioned reinforcer effects may be due to the stimulus' discriminative rather than its strengthening properties. While this was demonstrated in a frequently-changing choice procedure, a single attempt to replicate in a relatively static choice environment failed. We contend that this was because the information provided by the stimuli was nonredundant in the frequently-changing preparation, and redundant in the steady-state arrangement. In the present experiments, 6 pigeons worked in a steady-state concurrent schedule procedure with nonredundant informative stimuli (red keylight illuminations). When a response-contingent red keylight signaled that the next food delivery was more likely on one of the two alternatives, postkeylight choice responding was reliably for that alternative. This effect was enhanced after a history of extended informative red keylight presentation (Experiment 2). These results lend support to recent characterizations of conditioned reinforcer effects as reflective of a discriminative, rather than a reinforcing, property of the stimulus.

Separate or combined exposure to early life stress and AIE exposure moderately disrupts some aspects of adult executive control functions (e.g., increased compulsivity) but improves others (e.g., increased attention). The relative intensity of either manipulation during neonatal and adolescent periods may influence the direction in which cognitive behaviors are affected in adulthood.

These results demonstrate increased risk of repeated stress-induced anhedonia after AIE exposure, an effect that may be due to alterations in brain CRF and dopamine systems. These results suggest that the increased rates of depression reported in people with a history of adolescent alcohol exposure may be related to alterations in brain reward and stress systems that may contribute to increased stress-induced anhedonia.

Adolescent alcohol use may interfere with neurodevelopment, increasing the likelihood of adult alcohol use disorders (AUDs). We investigated whether adolescent intermittent ethanol (AIE) exposure alters the adult reward response to ethanol. Adolescent rats were administered ethanol once (moderate exposure; Cohort 1) or three times per day (severe exposure; Cohort 2) in a 2 days on/2 days off pattern. In adulthood, subjects responded for electrical stimulation directed at the posterior lateral hypothalamus in a discrete-trials intracranial self-stimulation (ICSS) procedure that provides current-intensity thresholds as a measure of brain reward function. The effects of ethanol administration and withdrawal were assessed. Control rats showed dose-dependent threshold elevations after acute ethanol, indicating reward deficits. A majority of moderately AIE-exposed rats (Cohort 1) showed threshold lowering after ethanol, suggesting ethanol-induced reward enhancement in this sub-set of rats. Rats exposed to severe AIE (Cohort 2) showed no threshold elevation or lowering, suggesting blunted affective ethanol response. Daily ethanol induced threshold elevations 24 h after administration in control but not in either group of AIE-exposed rats, suggesting decreased sensitivity to the negative affective state of ethanol withdrawal. Withdrawal from a 4-day ethanol binge produced robust and enduring threshold elevations in all rats, although threshold elevations were diminished in rats exposed to severe AIE. These results indicate that AIE exposure diminished reward deficits associated with ethanol intoxication and withdrawal and may have increased ethanol-induced reward enhancement in a sub-set of rats. In humans, enhanced ethanol reward accompanied by reduced withdrawal severity may contribute to the development of AUDs.