Developmental changes in the brain add to the age-specific behavioral uniqueness of adolescence, including the inherent increased propensity to use drugs . Thus, within the context of the present study a key question is the connection between fetal ethanol exposure, chemosensory plasticity, and adolescence. From a teleological standpoint, it has been argued that animals benefit from chemosensory mechanisms that emphasize the animal's attention to stimuli that are "presumed" significant for survival and reproductive fitness (e.g., the odor/taste of foods eaten by their mother) . This may be particularly true for adolescent animals, which are in the process of separating from their mothers and learning which foods are "safe" to eat. Given that chemical stimuli in a mother's diet can contaminate the fetal environment and provide sensory stimulation [e.g., [7–9]], it has been suggested that it is highly adaptive for developing embryos to tune their chemosensory systems to the molecules present in the amniotic fluid, and feed selectively on specific foods after weaning.
Unfortunately, however, an adaptive mechanism that should work to the advantage of the animal may within the context of fetal ethanol exposure work to its disadvantage. Youngentob and colleagues  demonstrated that prenatal ethanol exposure results in an alteration in olfactory system function that is manifested both behaviorally and neurophysiologically in the P15 rat and that these effects, although persistent into adolescence , are absent in adults (P90). Notably, fetal exposure results in enhanced ethanol intake in P15 rats  that is causally related to both the altered response to ethanol odor as well as altered gustatory perception [Youngentob and Glendinning, submitted]. These effects are also absent in adult littermates. The ages at which these studies observed a consequence of fetal exposure are in keeping with earlier literature on early postnatal [e.g., [14, 17, 18, 46]] and adolescent ethanol intake effects [22–24], and at least one adult study that used a similar gestational exposure model and studied ethanol intake at similar early and late developmental ages . Thus, the available data point to adolescence as a potentially critical transition point for perpetuating the olfactory experience-induced effects of fetal ethanol exposure into adulthood. Such a proposition is clinically relevant since, as previously noted, adolescence is a key transition point for emergent patterns of ethanol abuse and especially so following prior fetal exposure .
Social interaction has been shown to play an important role in adolescent decision-making and is highly correlated with ethanol use in adolescence . In the present study, we utilized a well-established social transmission of food odor preference paradigm [30–32] to provide a second ethanol odor experience during adolescence. This paradigm centers on the finding that rodents obtain information regarding foods to ingest based, at least in part, on an interaction with a known peer that has recently ingested a "novel" diet. In other words, olfactory cues perceived on the breath of another animal (i.e., the demonstrator in our study) are known to impact later food choices of a conspecific (i.e., the observer). Importantly, several studies have demonstrated that both naïve infant and adolescent observer animals will increase their ethanol intake as a consequence of interaction with a peer that was administered ethanol [e.g., [33, 34, 48, 49]]. Thus, this procedure permitted us to assess a second chemosensory-related ethanol experience through a potentially relevant form of human adolescent behavior, namely, social interaction with an exposed (i.e., intoxicated) peer .
The results of our study significantly extend upon the prior work investigating experience-induced olfactory plasticity in response to fetal ethanol exposure [[19, 21], Youngentob and Glendinning, submitted]. Behavioral testing in late adolescence demonstrated that: (1) adolescent re-exposure to ethanol odor augments the known olfactory response resulting from fetal experience with the drug; (2) when tested in adolescence, the consequence of adolescent ethanol odor exposure in control animals results in an enhanced olfactory response to ethanol odor similar to those resulting from fetal exposure alone; and (3) those animals receiving combined fetal and adolescent experience with ethanol odor demonstrate an augmented behavioral response to ethanol odor relative to those animals with either one developmental experience (i.e., fetal or adolescent) or no experience with ethanol. Taken together, the results clearly demonstrate a cumulative consequence of the number of developmental time points during which ethanol experience occurs on the response of adolescent animals to ethanol odor.
Testing in adulthood revealed alterations in the behavioral response to ethanol odor only in females having experienced the combination of fetal and adolescent ethanol exposures. No behavioral effects were found in the adult males as a consequence of previous exposures to ethanol odor. Based on our adolescent results illustrating no differential effect of sex on the behavioral response to ethanol, we did not anticipate sex differences to be present in adulthood. Nonetheless, our findings are not overly surprising given the variable evidence in the literature regarding the differential effects of sex on the responsivity to a substance following exposure in a social situation. While several studies do not report an effect of sex when examining both male and female observers [e.g., [31, 49, 50]], others strongly suggest sex may play a critical role in the effects of social interaction. Alterations in voluntary ethanol intake due to familiarity with the demonstrator appear to be sex dependant , as do changes in food preference following administration of a benzodiazepine anxiolytic to reduce social aggression . Areas of social interaction behavior such as play fighting, which were not analyzed in the context of this experiment, have also illustrated sex differences, with males showing increased play fighting in adolescence as compared to females of the same age  While the present study consisted of familiar, same sex littermates, it is not unrealistic to consider that the information received by the observers, through the social transmission of food preference design, could have been altered in a sex dependent manner due to age related changes in social behavior.
Sex dependant alterations in the demonstrators' level of ethanol intoxication could also have contributed to the differential adult effect as well. Although all demonstrators were infused with the same dose of ethanol, recent work in a collaborating lab reveals that adolescent female Long-Evans rats produce a much higher blood alcohol level (BAL) than males after ingesting the same dose of ethanol (F.A. Middleton, personal communication, September 13, 2008). Thus, a higher BAL in the female animals may have resulted in a different level of ethanol odor on the breath of females relative to males. This, in turn, would impact the transmission of the food preference leading to persistence of the behavioral effects into adulthood in the females.
Although the enhanced behavioral response to ethanol odor remains present in adult females, we did not find a persistence of the fetal ethanol induced alterations in the response of the OE for either sex. In considering this finding several issues need to be considered. First, new neurons are continuously integrated into the functional network of the olfactory system (both olfactory sensory [OSN] and olfactory bulb neurons) throughout development and even in adulthood [54–56]. Indeed, expansion of the OE occurs continuously between adolescence and adulthood . Thus, it is possible that as this normal expansion occurs the alteration in the response of the OE to ethanol odor, as a consequence of fetal exposure, became diluted (in short, a potential signal to noise problem) since it is unlikely that the initial fetal exposure effect modified the OE's progenitor cell population [57, 58]. Second, our adolescent ethanol exposures were relatively brief (30 minutes), occurring only 4 times, with non-exposure days interposed. As such, based on previous work demonstrating the need for extensive long-term odor exposure to yield an observable effect on the response of the OE [e.g., [42, 44]] it is not surprising, in retrospect, that our procedure did not yield additional detectable changes in the OE response.
It is also possible that the alterations in the response of the OE, while causally important in the initial priming of the enhanced behavioral odor effect , is not required for behavioral persistence into adulthood. That is, the early tuning of the OE to ethanol odor may reflect a global plasticity response of the olfactory system to ethanol odor that results in effects on more centrally olfactory structures that can be stabilized by adolescent odorant exposure. For example, it has been suggested that neurogenesis in the olfactory bulb plays a key role in information processing and memory storage . With this in mind, we hypothesize that a memory for ethanol has been formed by the alterations in the olfactory system due to prenatal ethanol odor exposure, and that this memory is reinforced by the adolescent ethanol exposure, leading to behavioral manifestations in the adult female.
Finally, with regard to our evaluation of the social interactions, we found that adolescent animals exposed to ethanol prenatally follow an intoxicated peer more frequently than control animals and that this increased behavior was specific to the peers that had ingested ethanol. This subsidiary finding further highlights the experience-induced consequences of fetal ethanol exposure on olfactory-mediated behaviors. Moreover, they suggest that within the context of "at risk" adolescents, prior exposure to ethanol may, among other things, augment the consequences of ethanol related social interaction by increasing the propensity to engage such setting. As such prior fetal exposure may play a key role in the individual affecting its own level of "re-exposure".
In view of the forgoing results, it is important to consider their broader implications to the clinical progression of developing patterns of ethanol abuse. As we have noted, within the context of fetal ethanol exposure, the normal adaptive process of chemosensory plasticity may work to the disadvantage of the adolescent animal: enhancing the already age inherent probability of initial ethanol intake and continued choice behavior in adolescence. Consistent with the implications of our behavioral findings others have shown that the interaction of pre- and postnatal exposure can yield enhanced ethanol avidity relative to the effect of prenatal exposure alone [e.g., [13, 59]]. However, if this second experience does not occur, the available data demonstrate that the fetal effects on olfactory function and ethanol avidity will be absent in adults [e.g., [19, 20]]. Thus, the timing of re-exposure to ethanol appears critical for persistence of the initial fetal effects into adulthood. In keeping with this hypothesis, the human data show an inverse relationship between the age of first adolescent experience and long-term abuse. Mechanistically, our proposed scenario would result from the alternative maintenance or amelioration of ethanol-induced stimulus activity. Indeed, it is a well-studied observation in olfactory development and even adulthood that stimulus-activated neurons are stabilized and survive while inactive ones are compromised and eliminated [60–62]. Given that this type of highly relevant competition is widespread throughout the developing nervous system [e.g., [63–67]] and adolescence is a dynamic developmental period , adolescent re-exposure may be a key element in developing patterns of progressive ethanol abuse.