Rochester, MN, United States
Rochester, MN, United States

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Klee E.W.,Mayo Medical School | Klee E.W.,Mayo Addiction Research Center | Ebbert J.O.,Mayo Addiction Research Center | Ebbert J.O.,Mayo Medical School | And 5 more authors.
Nicotine and Tobacco Research | Year: 2011

Introduction: Zebrafish are emerging as a powerful animal model for studying the molecular and physiological effects of nicotine exposure. The zebrafish have many advantageous physical characteristics, including small size, high fecundity rates, and externally developing transparent embryos. When combined with a battery of molecular-genetic tools and behavioral assays, these attributes enable studies to be conducted that are not practical using traditional animal models.Methods: We reviewed the literature on the application of the zebrafish model as a preclinical model to study the biological effects of nicotine exposure. Results: The identified studies used zebrafish to examine the effects of nicotine exposure on early development, addiction, anxiety, and learning. The methods used included green fluorescent protein-labeled proteins to track in vivo nicotine-altered neuron development, nicotine-conditioned place preference, and locomotive sensitization linked with high-throughput molecular and genetic screens and behavioral models of learning and stress response to nicotine. Data are presented on the complete homology of all known human neural nicotinic acetylcholine receptors in zebrafish and on the biological similarity of human and zebrafish dopaminergic signaling. Conclusions: Tobacco dependence remains a major health problem worldwide. Further understanding of the molecular effects of nicotine exposure and genetic contributions to dependence may lead to improvement in patient treatment strategies. While there are limitations to the use of zebrafish as a preclinical model, it should provide a valuable tool to complement existing model systems. The reviewed studies demonstrate the enormous opportunity zebrafish have to advance the science of nicotine and tobacco research. © The Author 2011. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.


Clark K.J.,Mayo Addiction Research Center | Voytas D.F.,University of Minnesota | Ekker S.C.,Mayo Addiction Research Center
Zebrafish | Year: 2011

Genome editing appears poised to enter an exciting new era. Targeted double-stranded breaks due to custom restriction enzymes are powerful nucleating events for the induction of local changes in the genome. The zinc finger nuclease (ZFN) platform established the potential of this approach for the zebrafish, but access to high quality reagents has been a major bottleneck for the field. However, two groups recently report successful somatic and germline gene modification using a new nuclease architecture, transcription activator-like effector nucleases (TALENs). TALEN construction is simpler, potentially more reliable, and in the few cases examined, shows fewer off-target effects than corresponding ZFNs. TALENs promise to bring gene targeting to the majority of zebrafish laboratories. © Copyright 2011, Mary Ann Liebert, Inc. 2011.


Blackburn P.R.,Mayo Addiction Research Center | Campbell J.M.,Mayo Addiction Research Center | Clark K.J.,Mayo Addiction Research Center | Ekker S.C.,Mayo Addiction Research Center
Zebrafish | Year: 2013

We are entering a new era in our ability to modify and edit the genomes of model organisms. Zinc finger nucleases (ZFNs) opened the door to the first custom nuclease-targeted genome engineering in the late 1990s. However, ZFNs remained out of reach for most research labs because of the difficulty of production, high costs, and modest efficacy in many applications. Transcription activator-like effector nucleases (TALENs) were built upon a DNA binding system discovered in a group of plant bacterial pathogens and broadened custom nuclease technology, showing significant improvements in both targeting flexibility and efficiency. Perhaps most importantly, TALENs are open source and easy to produce, providing zebrafish laboratories around the world with affordable tools that can be made in-house rapidly, at low cost, and with reliably high activity. Now a new system for targeted genome engineering derived from the CRISPR/Cas system in eubacteria and archaea promises to simplify this process further. Together, these tools will help overcome many of the bottlenecks that have constrained gene targeting in zebrafish, paving the way for advanced genome engineering applications in this model teleost. © Copyright 2013, Mary Ann Liebert, Inc. 2013.


Morales-Rosado J.A.,University of Puerto Rico at San Juan | Cousin M.A.,Mayo Addiction Research Center | Ebbert J.O.,Mayo Addiction Research Center | Klee E.W.,Mayo Addiction Research Center
Assay and Drug Development Technologies | Year: 2015

Tobacco use disorder is the leading cause of preventable death and disability in the United States, with one in five Americans currently smoking cigarettes. Only two non-nicotine medications are FDA approved for treating tobacco use disorder, and advances in drug discovery are profoundly outpaced by the morbidity and mortality caused by tobacco dependence. Drug repurposing may provide an approach for addressing this health hazard, offering hope to tobacco users attempting to quit who have failed existing therapies. The focus of this review is to evaluate the potential role of apomorphine (APO) in treating tobacco dependence. Previously described in the literature as a non-specific dopamine agonist effective in treating Parkinson's disease and erectile dysfunction, APO's dopaminergic targeting activity may be effective in counteracting the modified response arising from tobacco use. Here, the literature describing APO's activity is reviewed and presented in the context of known nicotine-induced response in neurotransmitter systems. Based on these data, whether APO may be an effective smoking cessation agent by ameliorating a tobacco user's anhedonic state is critically appraised, along with withdrawal symptoms and the chemical reinforcement associated with drug-seeking behaviors. © Mary Ann Liebert, Inc. 2015.


Peng Y.,Mayo Medical School | Clark K.J.,Mayo Medical School | Clark K.J.,Mayo Addiction Research Center | Clark K.J.,Center for Clinical and Translational Science | And 9 more authors.
Development (Cambridge) | Year: 2014

Recent advances in the targeted modification of complex eukaryotic genomes have unlocked a new era of genome engineering. From the pioneering work using zinc-finger nucleases (ZFNs), to the advent of the versatile and specific TALEN systems, and most recently the highly accessible CRISPR/Cas9 systems, we now possess an unprecedented ability to analyze developmental processes using sophisticated designer genetic tools. In this Review, we summarize the common approaches and applications of these still-evolving tools as they are being used in the most popular model developmental systems. Excitingly, these robust and simple genomic engineering tools also promise to revolutionize developmental studies using less well established experimental organisms. © 2014 Company of Biologists Ltd. All rights reserved.


Cousin M.A.,Mayo Addiction Research Center | Cousin M.A.,Center for Clinical and Translational Science | Ebbert J.O.,Mayo Addiction Research Center | Ebbert J.O.,Mayo Medical School | And 7 more authors.
PLoS ONE | Year: 2014

Cigarette smoking remains the most preventable cause of death and excess health care costs in the United States, and is a leading cause of death among alcoholics. Long-term tobacco abstinence rates are low, and pharmacotherapeutic options are limited. Repositioning medications approved by the U.S. Food and Drug Administration (FDA) may efficiently provide clinicians with new treatment options. We developed a drug-repositioning paradigm using larval zebrafish locomotion and established predictive clinical validity using FDA-approved smoking cessation therapeutics. We evaluated 39 physicianvetted medications for nicotine-induced locomotor activation blockade. We further evaluated candidate medications for altered ethanol response, as well as in combination with varenicline for nicotine-response attenuation. Six medications specifically inhibited the nicotine response. Among this set, apomorphine and topiramate blocked both nicotine and ethanol responses. Both positively interact with varenicline in the Bliss Independence test, indicating potential synergistic interactions suggesting these are candidates for translation into Phase II clinical trials for smoking cessation. © 2014 Cousin et al.


PubMed | Mayo Addiction Research Center
Type: Journal Article | Journal: Zebrafish | Year: 2011

Genome editing appears poised to enter an exciting new era. Targeted double-stranded breaks due to custom restriction enzymes are powerful nucleating events for the induction of local changes in the genome. The zinc finger nuclease (ZFN) platform established the potential of this approach for the zebrafish, but access to high quality reagents has been a major bottleneck for the field. However, two groups recently report successful somatic and germline gene modification using a new nuclease architecture, transcription activator-like effector nucleases (TALENs). TALEN construction is simpler, potentially more reliable, and in the few cases examined, shows fewer off-target effects than corresponding ZFNs. TALENs promise to bring gene targeting to the majority of zebrafish laboratories.


PubMed | Mayo Addiction Research Center
Type: Journal Article | Journal: Human genetics | Year: 2012

Drug abuse and dependence are multifaceted disorders with complex genetic underpinnings. Identifying specific genetic correlates is challenging and may be more readily accomplished by defining endophenotypes specific for addictive disorders. Symptoms and syndromes, including acute drug response, consumption, preference, and withdrawal, are potential endophenotypes characterizing addiction that have been investigated using model organisms. We present a review of major genes involved in serotonergic, dopaminergic, GABAergic, and adrenoreceptor signaling that are considered to be directly involved in nicotine, opioid, cannabinoid, and ethanol use and dependence. The zebrafish genome encodes likely homologs of the vast majority of these loci. We also review the known expression patterns of these genes in zebrafish. The information presented in this review provides support for the use of zebrafish as a viable model for studying genetic factors related to drug addiction. Expansion of investigations into drug response using model organisms holds the potential to advance our understanding of drug response and addiction in humans.

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