Investigating Brain Reward Mechanisms: A Comparative Study In Male And Female Rats

Drug addiction is a serious public health concern. Recently, electronic cigarette use has become increasingly popular among vulnerable populations such as adolescents and women. Previous research on conventional cigarette use has shown significant sex differences in drug-seeking behavior and withdrawal symptoms, which are driven mainly by hormonal differences. However, changes in sex hormones do not completely explain the enhanced reward sensitivity reported in females. Thus, this dissertation aims to examine other alternative reasons that can explain these sex differences, such as differences in reward-seeking and neuronal reactivity. Additionally, there is a dearth of consistency across papers intending to map electrode implantations along the reward pathway using Intracranial Self-Stimulation (ICSS); thus, this study provides steps toward the creation of a neuroanatomical functional map of electrical stimulation in different regions along the reward pathway in both male and female rats. Aim 1 utilized the ICSS paradigm to investigate motivation and reward in 15 male and 15 female rats by stimulating the medial forebrain bundle at the level of the lateral hypothalamic area. This experiment showed significant differences in overall reward threshold sensitivity between males and females, with females having higher rates of electrical stimulation when compared to males. To determine if there were long-term effects of ICSS stimulation on neuronal activation, the two main groups were further divided into a total of 4 groups, where one group of males and females (n=7 each) stopped receiving any electrical stimulation one week prior to tissue collection. Neuroanatomical mapping and immunohistochemistry did not reveal any significant differences between groups; however, a trend for higher numbers of neurons displaying ERK activation in the tenia tectum and lateral septum was observed in females when compared to males, both with recent ICSS experience, although the difference was not significant. Aim 2 also used an ICSS paradigm to investigate the changes in reward threshold after repeated nicotine vapor exposure and cessation. Significant changes in percent thresholds were observed in females who received a regimen of nicotine vapor when compared to the vehicle control group. The nicotine group showed lower levels of reward threshold during the 14-day nicotine exposure regimen and higher levels of reward threshold changes during 14 days of withdrawal. While no significant effects were observed in neuronal activation, there was a trend for more phospho-ERK cell expression in the nicotine-treated group when compared to the control group. Overall, this study demonstrates that nicotine vapor affects the reward system of female rats, similar to that seen in previous research with males. This study also underscores how enhancing rigor in our histological assessments for behavioral neuroscience experiments should be an ongoing process to ensure that we continue to develop our understanding of the neuronal substrates that substances such as nicotine act upon to affect the brain and behavior.