Prenatal ethanol exposure significantly increases later predisposition for alcohol intake, but the mechanisms associated with this phenomenon remain hypothetical. This study analyzed (Exp. 1) ethanol intake in adolescent inbred WKAH/Hok Wistar rats prenatally exposed to ethanol (2.0 g/kg) or vehicle, on gestational days 17–20. Subsequent Experiments (2, 3 and 4) tested several variables likely to underlie the effect of gestational ethanol on adolescent ethanol preference, including ethanol-induced locomotor activation (LMA), ethanol-induced emission of ultrasonic vocalizations (USVs) after exposure to a rough exteroceptive stimulus, and induction of the immediate early gene C-fos in brain areas associated with processing of reward stimuli and with the retrieval and extinction of associative learning. Prenatal ethanol induced a two-fold increase in ethanol intake. Adolescents exhibited significant ethanol-induced LMA, emitted more aversive than appetitive USVs, and postnatal ethanol administration significantly exacerbated the emission of USVs. These effects, however, were not affected by prenatal ethanol. Adolescents prenatally exposed to ethanol as fetuses exhibited reduced neural activity in infralimbic cortex (but not in prelimbic cortex or nucleus accumbens core or shell), an area that has been implicated in the extinction of drug-mediated associative memories. Ethanol metabolism was not affected by prenatal ethanol. Late gestational exposure to ethanol significantly heightened drinking in the adolescent offspring of an inbred rat strain. Ethanol-induced LMA and USVs were not associated with differential ethanol intake due to prenatal ethanol exposure. Prenatal ethanol, however, altered basal neural activity in the infralimbic prefrontal cortex. Future studies should analyze the functionality of medial prefrontal cortex after prenatal ethanol and its potential association with predisposition for heightened ethanol intake.

Background Prenatal exposure to moderate ethanol doses during late gestation modifies postnatal ethanol palatability and ingestion. The use of Pavlovian associative procedures, has indicated that these prenatal experiences broaden the range of ethanol doses capable of supporting appetitive conditioning. Recently, a novel operant technique aimed at analyzing neonatal predisposition to gain access to ethanol has been developed. Experiment 1 tested the operant conditioning technique for developing rats described by Arias et al. (2007) and Bordner et al. (2008). In Experiment 2 we analyzed changes in the disposition to gain access to ethanol as a result of moderate prenatal exposure to the drug. Methods In Experiment 1 newborn pups were intraorally cannulated and placed in a supine position that allowed access to a touch-sensitive sensor. Paired pups received an intraoral administration of a given reinforcer (milk or quinine) contingent upon physical contact with the sensor. Yoked controls received similar reinforcers only when Paired pups activated the circuit. In Experiment 2, natural reinforcers (water or milk) as well as ethanol (3% or 6 % v/v) or an ethanol-related reinforcer (sucrose compounded with quinine) were tested. In this Experiment pups had been exposed to water or ethanol (1 or 2 g/kg) during gestational days 17–20. Results Experiment 1 confirmed previous results showing that 1-day-old pups rapidly learn an operant task to gain access to milk, but not to gain access to a bitter tastant. Experiment 2 showed that water and milk were highly reinforcing across prenatal treatments. Furthermore, general activity during training was not affected by prenatal exposure to ethanol. Most importantly, prenatal ethanol exposure facilitated conditioning when the reinforcer was 3% v/v ethanol or a psychophysical equivalent of ethanol’s gustatory properties (sucrose-quinine). Conclusions The present results suggest that late prenatal experience with ethanol changes the predisposition of the newborn to gain access to ethanol-related stimuli. In conjunction with prior literature, this study emphasizes the fact that intrauterine experience with ethanol not only augments ethanol’s palatability and ingestion, but also facilitates the acquisition of response-stimulus associations where the drug acts as an intraoral reinforcer.