Date of Award

2015

Document Type

Open Access Dissertation

Department

College of Pharmacy

Sub-Department

Pharmaceutical Sciences

First Advisor

Jun Zhu

Abstract

Tobacco use is the number one preventable cause of death in the world. Nicotine is the principal, addictive component in tobacco responsible for its reinforcing properties that drive the behavioral manifestations of nicotine addiction. Environment is becoming increasingly implicated in nicotine susceptibility. However, the molecular mechanisms that underlie susceptibility to nicotine addiction remain unknown. An ideal animal model that addresses environmental factors uses rats raised in an enriched condition (EC), a standard condition (SC), and an impoverished condition (IC); which differ in novelty, social cohorts, handling, and physical activity. EC rats exhibit a neuroprotective-like phenotype in the behavioral resistance to drugs of abuse; however, the impact of enrichment on nicotine-mediated behaviors and the subsequent molecular mechanisms underlying these behavioral adaptations remain unidentified. EC rats were found to have increased behavioral sensitization, an indirect measure of drug-mediated motivation, in response to repeated experimenter-delivered nicotine in comparison to IC and SC rats. Additionally, EC rats have decreased nicotine-maintained responding compared to IC rats in a self-administration paradigm, the most reliable experimental model to evaluate the reinforcing properties of drugs of abuse. One commonality we observed in both behavioral paradigms was that phosphorylated extracellular signal-regulated kinase1/2 (pERK1/2), an intracellular signaling protein kinase involved in drug-induced neuroplasticity, levels in the prefrontal cortex (PFC) were significantly increased in response to nicotine in IC rats, whereas nicotine-mediated increases in pERK1/2 activity were attenuated in EC rats. MicroRNAs (miRs) are post-transcriptional regulators of gene expression that have recently been implicated in drug-mediated neuroadaptations. MiR-221 was found to be highly enriched strictly in the PFC of EC rats in response to repeated nicotine administration. Lentiviral overexpression of miR-221 in the PFC of IC rats enhanced nicotine-mediated locomotor sensitivity while attenuating nicotine-mediated increases in pERK1/2 activity. However, enrichment-induced decreases in nicotine-intake were associated with an attenuation in nicotine-mediated orexin receptor-1 (OX1R) upregulation within the PFC. Additionally, although not as robustly as in the repeated model of repeated nicotine administration, miR-221 was increased significantly within the PFC of EC rats that underwent nicotine self-administration. Collectively, these studies implicate miR-221-dependent regulation of ERK1/2 within the PFC in response to nicotine in mediating the increased behavioral sensitivity observed in EC rats, as well as an OXR1-dependent regulation of ERK1/2 within the PFC in decreasing nicotine-intake in EC rats. Moreover, these studies suggest that miR-221 may be a universal mediator of the enrichment-induced protective-like phenotype in response to nicotine exposure. Future studies examining the upstream and downstream mechanisms in which miR-221 is mediating its effects will better clarify the exact mechanism of miR-221 and lead to potential therapeutic targets for nicotine addiction.

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