Ethanol-induced conditioned taste aversion and associated neural activation in male rats: Impact of age and adolescent intermittent ethanol exposure.

Individuals that initiate alcohol use at younger ages and binge drink during adolescence are more susceptible to developing alcohol use disorder. Adolescents are relatively insensitive to the aversive effects of alcohol and tend to consume significantly more alcohol per occasion than adults, an effect that is conserved in rodent models. Adolescent typical insensitivity to the aversive effects of alcohol may promote greater alcohol intake by attenuating internal cues that curb its consumption. Attenuated sensitivity to the aversive effects of alcohol is also retained into adulthood following protracted abstinence from adolescent intermittent ethanol (AIE) exposure. Despite these effects, much remains unknown regarding the neural contributors. In the present study, we used a conditioned taste aversion (CTA) paradigm to investigate neuronal activation in late-developing forebrain structures of male adolescents and adult cFos-LacZ transgenic rats as well as in AIE adults following consumption of 0.9% sodium chloride previously paired with an intraperitoneal injection of 0, 1.5 or 2.5 g/kg of ethanol. Adults that were non-manipulated or received water exposure during adolescence showed CTA to both ethanol doses, whereas adolescents displayed CTA only to the 2.5 g/kg ethanol dose. Adults who experienced AIE did not show CTA. Adults displayed increased neuronal activation indexed via number of ß-galactosidase positive (ß-gal+) cells in the prefrontal and insular cortex that was absent in adolescents, whereas adolescents but not adults had a reduced number of ß-gal+ cells in the central amygdala. Adults also displayed greater cortical-insular functional connectivity than adolescents as well as insular-amygdalar and prefrontal cortex-accumbens core functional connectivity. Like adolescents, adults previously exposed to AIE displayed reduced prefrontal-insular cortex and prefrontal-accumbal core functional connectivity. Taken together, these results suggest that attenuated sensitivity to the aversive effects of ethanol is related to a loss of an insular-prefrontal cortex-accumbens core circuit.

General Anesthetic Exposure During Early Adolescence Persistently Alters Ethanol Responses.

BACKGROUND: Adolescent alcohol abuse can lead to behavioral dysfunction and chronic, relapsing alcohol use disorder (AUD) in adulthood. However, not all adolescents that consume alcohol will develop an AUD; therefore, it is critical to identify neural and environmental risk factors that contribute to increases in susceptibility to AUDs following adolescent alcohol (ethanol [EtOH]) exposure. We previously found that adolescent anesthetic exposure led to strikingly similar behavioral and neural effects as adolescent alcohol exposure. Therefore, we tested the hypothesis that general anesthetic exposure during early adolescence would alter EtOH responses consistent with an exacerbation of the adolescent alcohol phenotype. METHODS: To test this hypothesis, early-adolescent male Sprague-Dawley rats were exposed for a short duration to the general anesthetic isoflurane and tested on multiple EtOH-induced behaviors in mid-late adolescence or adulthood. RESULTS: Adolescent rats exposed to isoflurane exhibited decreases in sensitivity to negative properties of EtOH such as its aversive, hypnotic, and socially suppressive effects, as well as increases in voluntary EtOH intake and cognitive impairment. Select behaviors were noted to persist into adulthood following adolescent isoflurane exposure. Similar exposure in adults had no effects on EtOH sensitivity. CONCLUSIONS: This study demonstrates for the first time that early-adolescent isoflurane exposure alters EtOH sensitivity in a manner consistent with an exacerbation of adolescent-typical alcohol responding. These findings suggest that general anesthetic exposure during adolescence may be an environmental risk factor contributing to an enhanced susceptibility to developing AUDs in an already vulnerable population.

Measures of the aversive effects of drugs: A comparison of conditioned taste and place aversions.

The present experiments directly compared the ability of the conditioned taste and place aversion designs (CTA and CPA, respectively) to measure the aversive effects of lithium chloride (LiCl) in male Sprague-Dawley rats. In the CTA assessment (Experiment 1), rats were given one of two novel tastes paired with LiCl (0, 0.18, 0.32, 0.56 or 1mEq/kg) and the alternate novel taste paired with vehicle the next day. This was repeated three times, followed by a final two-bottle test. In the CPA assessment (Experiment 2), rats were given LiCl at the same doses and placed on one side of an unbiased two-chambered apparatus, followed by vehicle injection and placement on the opposite side on alternating days. This was repeated three times followed by free access to both sides in an assessment of relative preference. LiCl induced robust, dose-dependent taste aversions with rats receiving 0.32mEq/kg or greater consuming a smaller percentage of the drug-paired taste than that of controls. LiCl did not induce place aversions at any dose with LiCl- and vehicle-treated subjects displaying comparable preferences for the drug-paired side. The basis for the differences of the two designs in indexing LiCl's aversive effects was discussed.