Nicotine Withdrawal During Contextual Fear Extinction Causes Sex Specific Impacts in the Murine Dorsal and Ventral Hippocampus

Abstract

<b>Abstract ID 15496</b> <b>Poster Board 404</b> Over 30 million Americans are smokers and more than 16 million have been diagnosed with a disease caused by smoking. The negative health risks of smoking are well known, and 70% of smokers express a desire to quit. However, the two current FDA approved medications for smoking cessation, Varenicline and Bupropion, have a maximal 25% quit success rate in a 1 year follow up. The lack of long-term efficacy of these drugs is often attributed to their ineffectiveness on non-craving related withdrawal symptoms such as cognitive deficits and affective dysfunction, both of which are predictors of smoking relapse. The hippocampus has well-defined roles in both contextual memory and affective responding, the dorsal hippocampus (DHIPP) and ventral hippocampus (VHIPP) respectively, suggesting these subregions are potential targets for mechanistic evaluation of two major predictive factors of smoking relapse. Previous data from our lab demonstrates that both male and female mice experience anxiety-like phenotypes following spontaneous nicotine withdrawal, which can be attenuated by knocking down the transcription factor CREB in the VHIPP, but not the DHIPP. However, we have yet to evaluate the mechanism that underlays the cognitive impairments associated with nicotine withdrawal. In order to study the impacts of chronic nicotine exposure and withdrawal on contextual memory, we chronically treated male and female 7 to 12- week-old mice with either saline or intermittent nicotine (18 mg/kg/day) via osmotic minipumps (Alzet 1002 model). On the twelfth day of treatment, the subjects were trained in a fear conditioning paradigm with two CS-US pairings (CS 89 dB tone and US 0.5 mA shock). The next morning the mice underwent the baseline assessment for contextual fear extinction, then in the afternoon had spontaneous withdrawal from nicotine via minipump removal or sham control surgery. The mice then underwent 5 days of contextual fear extinction. Following the 5^th extinction session, the DHIPP and VHIPP were collected and assessed for transcriptomic and proteomic changes. Female mice undergoing nicotine withdrawal had modest deficits in contextual fear extinction, but there were no impacts of drug treatment observed in males. Preliminary transcriptomic results suggest males have higher baseline expression of Immediate Early Genes and Neuregulin Signaling Pathway genes in the DHIPP than females, which is attenuated by withdrawal from nicotine. Further examination of treatment by sex effects in the VHIPP are ongoing to determine if changes so far observed are subregion specific within the hippocampus. Support/Funding Information: NIH/NIDA grant DA044311