Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Neuroscience

Supervisor

Laviolette, Steven R.

Abstract

Nicotine dependence is causally linked to increased risk of mood/anxiety disorders in later life. Females are reported to experience a higher prevalence of anxiety/depressive disorders and challenges in smoking cessation therapies, suggesting a potential sex-specific response to nicotine exposure and mood/anxiety disorder risk. However, pre-clinical evidence of sex-specific responses to adolescent nicotine exposure is unclear. Thus, to determine any sex differences in anxiety/depressive-related outcomes, adolescent male and female Sprague Dawley rats received nicotine (0.4 mg/kg; 3x daily) or saline injections for 10 consecutive days, followed by behavioural testing, in-vivo electrophysiology and Western Blot analyses. Our results revealed that adolescent nicotine exposure caused long-lasting anxiety/depressive-like behaviours, disrupted neuronal activity patterns and molecular signaling pathway targets in nicotine-treated male rats, but no significant effects in female cohorts, suggesting possible compensatory actions related to estrogen/progesterone signaling pathways in female. These novel results serve as a foundation for future investigations examining how adolescent nicotine exposure may differentially impact the male vs. female brains.

Summary for Lay Audience

Smoking-related diseases remain the highest cause of preventable mortality worldwide. In recent years, the increase in teen vaping trends is particularly concerning since adolescence represents a critical stage of brain development. The main psychoactive component in these products, nicotine, can affect the brain’s addiction pathways by changing different neurotransmitter levels, such as glutamate, GABA and dopamine. Many animal and human studies have demonstrated nicotine addiction could cause anxiety and depressive disorders. In human studies, females have a higher prevalence of anxiety and depression symptoms. They also experience more difficulty in quitting nicotine products and rehabilitation with nicotine replacement therapies, which suggests a potential sex-specific sensitivity to nicotine. However, most animal studies only used male animals for experiments. Sex-specific responses to nicotine exposure are therefore currently unclear. Hence, the objective of this thesis is to determine any sex differences in mood and anxiety-related outcomes following nicotine exposure during adolescence. Adolescent male and female Sprague Dawley rats received either nicotine or saline injections, 3 times daily for 10 consecutive days. Once animals reached adulthood, they performed a series of mood and anxiety-related behavioural tests, such as the elevated plus maze, forced swim test and novel object recognition task. Next, either in-vivo electrophysiology or Western Blot was conducted to investigate neuron firing patterns and changes in protein level. Our results revealed that nicotine-treated male rats displayed anxiety and depressive-like behaviours and cognitive deficits. Alterations in glutamate and dopamine signaling as well as brain oscillation waves were observed in this same group. Furthermore, there were changes in expression levels of anxiety and depressive-related molecular targets. On the contrary, the nicotine-treated female rats showed no significant changes in behaviours or neuronal activity states, but displayed opposite trends to the male cohorts in some molecular markers. This indicates possible interactions between estrogen/progesterone and nicotine exposure in the female body. To conclude, these results are consistent with reports suggesting female is less sensitive to the pharmacological effects of nicotine. The current project could also serve as a starting point for future studies to investigate how the adolescent female brain is protected against anxiety and depressive disorders following prolonged nicotine exposure.

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