Faculty

Schulich Neuroscience

Supervisor Name

Dr. Peter Ossenkopp, Dr. Martin Kavaliers

Keywords

anticipatory nausea, conditioned disgust, estrogen, letrozole, rats

Description

Anticipatory Nausea (AN) is a form of classical conditioning in which the effects of a nausea-inducing toxin become associated with a specific environmental context. AN is often experienced by individuals receiving chemotherapy treatment, whereby the emetic effects of the chemotherapy agents become associated with the treatment context (i.e. hospital, clinic), such that exposure to the context alone can cause an individual to experience nausea and potentially withdraw from treatment. Chemotherapy-associated AN is suggested to have a higher incidence in females compared to males.

AN can be represented in a rodent model (conditioned disgust) through the occurrence of conditioned gaping behaviour displayed upon re-exposure to a context previously paired with the nausea-inducing toxin lithium chloride (LiCl). The female-biased sex difference of AN is also found in rodents and is suggested to be related to the elevated levels of estrogen during the proestrous phase of the rodent estrous cycle. Estrogen is suggested to enhance the hippocampal-dependent spatial memory involved in the learning of AN. The enzyme aromatase is involved in the conversion of androgens to estrogens in estrogen-producing tissues of the body, including the gonads, brain and other organs. The purpose of this study was to investigate the effect of letrozole, an aromatase inhibitor, on the learning of environmentally-conditioned disgust behaviour. It was hypothesized that for rats conditioned with LiCl in a novel context, daily administration of letrozole for 10 days prior to LiCl-free context re-exposure would significantly decrease the frequency of conditioned gaping behaviour compared to control groups.

Twenty adult male Long-Evans rats received daily administrations of either letrozole (Let, 1 mg/kg, 10 ml/kg, i.p.) or the vehicle control (Veh, 0.9% NaCl, 5% Ethanol, 5% Tween-80, 10 ml/kg, i.p.) for 10 days. On days 2, 4, 6, and 8, rats were injected with either lithium chloride (LiCl, 128 mg/kg, 20 ml/kg, i.p.), or saline (0.9% NaCl, 20 ml/kg, i.p.) at a matched volume. Immediately after LiCl or NaCl administration, rats were placed in the conditioning context, a white, plexi-glass box, for 30 min while being video-recorded to later score the frequency of conditioned gaping behaviour. On day 10, rats were re-exposed to the conditioning context in a LiCl-free state for 30 min while being recorded. Ten days after re-exposure, rats received a 1 ml injection of saline (0.9% NaCl) as conditioning-cue prior to being placed in the context for 30 min while being recorded. Four experimental groups were established based on the drugs they received; Let-LiCl (n=8), Veh-LiCl (n=8), Let-NaCl (n=2), and Veh-NaCl (n=2).

The frequency of conditioned gaping behaviour was scored for each day and analyzed using a univariate ANOVA analysis on SPSS. Compared to other groups, the Let-LiCl group displayed a greater frequency of gaping behaviour on day 6 (CND 3, p = 0.06), day 8 (CND 4, p = 0.246), day 10 (EXT, p = 0.323) and ten-day re-exposure (SR, p = 0.176). Contrary to the hypothesis it was found that letrozole administration did not significantly decrease the frequency of conditioned gaping behaviour compared to controls, but rather, resulted in a non-significant increase in conditioned gaping behaviour compared to other groups. Given the small sample size of NaCl controls, the results can be considered marginally significant, thus warranting further exploration into the effects of letrozole on conditioned disgust. Limitations of this study include the use of only one dose of letrozole, the small sample size of controls, and the lack of measurement of estrogen and testosterone levels.

Acknowledgements

I would like to thank my supervisors, Dr. Peter Ossenkopp and Dr. Martin Kavaliers for their guidance and feedback throughout the project. I would also like to thank Indra Bishnoi for her assistance throughout the project. Finally, I would like to thank Western Research for the opportunity provided through the USRI program

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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Poster

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The effects of the aromatase inhibitor, Letrozole, on lithium chloride (LiCl)-induced conditioned disgust behaviour (anticipatory nausea) in male rats

Anticipatory Nausea (AN) is a form of classical conditioning in which the effects of a nausea-inducing toxin become associated with a specific environmental context. AN is often experienced by individuals receiving chemotherapy treatment, whereby the emetic effects of the chemotherapy agents become associated with the treatment context (i.e. hospital, clinic), such that exposure to the context alone can cause an individual to experience nausea and potentially withdraw from treatment. Chemotherapy-associated AN is suggested to have a higher incidence in females compared to males.

AN can be represented in a rodent model (conditioned disgust) through the occurrence of conditioned gaping behaviour displayed upon re-exposure to a context previously paired with the nausea-inducing toxin lithium chloride (LiCl). The female-biased sex difference of AN is also found in rodents and is suggested to be related to the elevated levels of estrogen during the proestrous phase of the rodent estrous cycle. Estrogen is suggested to enhance the hippocampal-dependent spatial memory involved in the learning of AN. The enzyme aromatase is involved in the conversion of androgens to estrogens in estrogen-producing tissues of the body, including the gonads, brain and other organs. The purpose of this study was to investigate the effect of letrozole, an aromatase inhibitor, on the learning of environmentally-conditioned disgust behaviour. It was hypothesized that for rats conditioned with LiCl in a novel context, daily administration of letrozole for 10 days prior to LiCl-free context re-exposure would significantly decrease the frequency of conditioned gaping behaviour compared to control groups.

Twenty adult male Long-Evans rats received daily administrations of either letrozole (Let, 1 mg/kg, 10 ml/kg, i.p.) or the vehicle control (Veh, 0.9% NaCl, 5% Ethanol, 5% Tween-80, 10 ml/kg, i.p.) for 10 days. On days 2, 4, 6, and 8, rats were injected with either lithium chloride (LiCl, 128 mg/kg, 20 ml/kg, i.p.), or saline (0.9% NaCl, 20 ml/kg, i.p.) at a matched volume. Immediately after LiCl or NaCl administration, rats were placed in the conditioning context, a white, plexi-glass box, for 30 min while being video-recorded to later score the frequency of conditioned gaping behaviour. On day 10, rats were re-exposed to the conditioning context in a LiCl-free state for 30 min while being recorded. Ten days after re-exposure, rats received a 1 ml injection of saline (0.9% NaCl) as conditioning-cue prior to being placed in the context for 30 min while being recorded. Four experimental groups were established based on the drugs they received; Let-LiCl (n=8), Veh-LiCl (n=8), Let-NaCl (n=2), and Veh-NaCl (n=2).

The frequency of conditioned gaping behaviour was scored for each day and analyzed using a univariate ANOVA analysis on SPSS. Compared to other groups, the Let-LiCl group displayed a greater frequency of gaping behaviour on day 6 (CND 3, p = 0.06), day 8 (CND 4, p = 0.246), day 10 (EXT, p = 0.323) and ten-day re-exposure (SR, p = 0.176). Contrary to the hypothesis it was found that letrozole administration did not significantly decrease the frequency of conditioned gaping behaviour compared to controls, but rather, resulted in a non-significant increase in conditioned gaping behaviour compared to other groups. Given the small sample size of NaCl controls, the results can be considered marginally significant, thus warranting further exploration into the effects of letrozole on conditioned disgust. Limitations of this study include the use of only one dose of letrozole, the small sample size of controls, and the lack of measurement of estrogen and testosterone levels.

 

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