General Anesthetic Exposure During Early Adolescence Persistently Alters Ethanol Responses

Abstract

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.

Keywords: Adolescence; Alcohol; Anesthesia; Isoflurane; Memory.

Figure 1.

Adolescent anesthetic exposure reduces aversive ethanol properties. Adolescent air controls exhibited conditioned taste aversion (CTA) at higher ethanol doses. However, isoflurane-exposed adolescents (n = 5-11/group) did not exhibit CTA at any ethanol dose tested. Adults exposed to isoflurane did not differ from air controls (n = 7-9/group), as both exhibited CTA at both ethanol doses (A). Adolescent rats exposed to isoflurane exhibited a reduction in loss of righting reflex time when tested in mid adolescence (n = 3-6/group), late adolescence (n = 4-5/group), and adulthood (n = 6-7/group), compared to air controls. Adults exposed to isoflurane did not differ in loss of righting reflex recovery time compared to controls when tested one (n = 5-7/group) or three (n = 5-6/group) weeks following exposure (B). Data are represented as mean ± SEM. * = p < 0.05, ** = p < 0.01.

Figure 2.

Adolescent isoflurane exposure increases memory-impairing effects of ethanol. Only isoflurane-exposed adolescents exhibit a reduction in time spent with the novel object following 1.0g/kg ethanol administration, compared to air-exposed saline controls when tested during adolescence. Air-exposed adolescents did not differ from saline controls (represented by dashed line, n = 5-7; A). When tested in adulthood, air- and isoflurane-exposed adolescents did not differ in the % time spent with the novel object compared to air-exposed saline controls (represented by dashed line, n = 7-9, B). Data are represented as mean ± SEM. * = p < 0.05.

Figure 3.

Adolescent anesthetic exposure reduces ethanol-induced social suppression. As expected, control rats exhibited a decrease in social investigation following 1.0g/kg ethanol exposure compared to rats exposed to saline (as represented by dashed line). However, isoflurane-exposed adolescents did not exhibit the expected ethanol-induced reduction in social investigation relative to saline controls. Data are represented as mean ± SEM. * = p < 0.05, n = 10/group.

Figure 4.

Impact of early adolescent isoflurane exposure on voluntary ethanol consumption in mid-adolescence or adulthood. All data are averaged across 5 drinking days and shown in mL/kg. Isoflurane-exposed adolescents consumed more ethanol than air counterparts (n = 6-7/group) when tested one week following exposure (A). Levels of supersaccharin consumption (B) and % EtOH preference (C) did not differ between groups 1 week later (n=8-10/group). When tested in adulthood, rats exposed to isoflurane during adolescence consumed less ethanol than air-control counterparts (n = 7-11/group; D). Supersaccharin consumption was slightly increased 6.5 weeks later, although not significant (E). % EtOH preference was decreased in isoflurane-exposed adolescents when tested in adulthood (F). Data are represented as mean ± SEM. * = p < 0.05.