Professor, Department of Behavioral Sciences, University of Kentucky, Lexington, Kentucky; Dr. Carl G. Leukefeld, Director
Associate, Center for Membrane Sciences, University of Kentucky, Lexington, Kentucky; Dr. Allan Butterfield, Director
Professor, Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky; Dr. Joseph Chappell, Chairman; Dr. Timothy Tracy, Dean
Associate, Center on Drug and Alcohol Research, University of Kentucky, Lexington, Kentucky; Dr. Carl G. Leukefeld, Director
Associate, Associate, Center on Drug Abuse Research Translation, University of Kentucky, Lexington, Kentucky; Dr. Michael T. Bardo, Director
Adjunct Faculty, University of Kentucky Graduate Center of Toxicology, Lexington, Kentucky; Dr. Mary Vore, Director
Dr. Linda Dwoskin
Dr. Dwoskin is an Endowed Professor in Pharmaceutical Education at the University of Kentucky College of Pharmacy. She also is Director and Principal Investigator of a National Cooperative Drug Discovery Group (NCDDG) which collaborates with the National Institutes of Health (NIH) to discover novel treatments for tobacco smoking cessation. She received her B.S. (1974) in psychology from Syracuse University, and Ph.D. (1983) from the Department of Pharmacology at the University of Minnesota. She was a postdoctoral fellow in endocrinology at the Oregon Health Science Center and in the Department of Pharmacology at the University of Colorado Health Science Center. Dr. Dwoskin joined the faculty at the University of Kentucky in 1988 as an assistant professor. She currently holds several other academic appointments including: professor, Department of Behavioral Sciences; adjunct faculty, University of Kentucky Graduate Center; associate, University of Kentucky Center on Drug Abuse Translation; associate, Multi-disciplinary Research Center on Drug and Alcohol Abuse; and associate, Center of Membrane Sciences. Dr. Dwoskin has been awarded the University of Kentucky Wethington Award for Meritorious Performance in Research (2002-2006). She was chosen in 2005-2006 for a University Research Professorship, recognizing her outstanding research and her distinguished record of achievement in her field. Her research has resulted in over 145 peer-reviewed research articles, 250 abstracts of research presentations and 49 patents and patent applications. Dr. Dwoskin's major research focus is drug discovery in neuropharmacology, i.e., the development of novel therapeutic candidates for the treatment of psychostimulant abuse, specifically for nicotine and methamphetamine abuse. In particular, her focus is the design and discovery of subtype-selective neuronal nicotinic receptor antagonists as novel tobacco smoking cessation agents and of modulators of vesicular monoamine transporter function as novel treatments for methamphetamine abuse. In her collaborators labs, promising therapeutic candidates are also tested in locomotor activity assays and drug discrimination assays to determine if they inhibit the stimulant effects and interoceptive cues associated with psychostimulant use, as well as in intravenous self-administration assays to determine if they inhibit the rewarding effect of these drugs of abuse. Another focus of Dr. Dwoskin's research is to determine the role of environmental and genetic factors as determinants of individual responsiveness to drugs of abuse and as determinants of an individual's potential for abuse liability. Using an animal model, the relationship between dopaminergic function (release, reuptake and metabolism) in striatum, nucleus accumbens, medial prefrontal cortex and orbital prefrontal cortex and an individual's behavior in novelty-seeking, psychostimulant self-administration and delay-discounting assays are evaluated as predictors of an individual's responsiveness to drugs of abuse. Several drugs discovered in her laboratory at the University of Kentucky are currently in various phases of clinical development. Dr. Dwoskin has graduated 3 Ph.D. students and 1 Masters student and has 4 graduate students in her laboratory currently. She has trained 17 postdoctoral fellows in her laboratory.
My laboratory’s research focus is drug discovery in the field of neuropharmacology, specifically the development of novel treatments for psychostimulant drug abuse. Drugs within the psychostimulant class investigated include nicotine, amphetamine, methamphetamine and cocaine. Novel analogs are synthesized by our collaborators, and, their mechanism of action is elucidated in my laboratory. The ability of these novel drugs to modulate dopaminergic neuronal function is a focus as the dopaminergic system has been implicated in reward and reinforcement obtained during self-administration of drugs of abuse.Techniques employed in this regard include dopamine release, dopamine metabolism and dopamine reuptake or clearance using rodent brain slices, synaptosomes and synaptic vesicles, dopamine transporter trafficking (cellular localization), dopamine autoreceptor function, as well as heterologous modulation by other neurotransmitter receptors. Dopaminergic presynaptic terminal function in striatum, nucleus accumbens and subregions of frontal cortex is primarily studied. We also study the effects of our novel compound’s using cultured cells expressing specific neurotransmitter receptors and transporters. Whole animal models are also used to study the pharmacological effects of the psychostimulants and of the potential therapeutic agents using in vivo voltammetry and microdialysis. In the process of therapeutic development, lead analogs from the neurochemical assays are tested to determine their effects on behavior using whole animal models. Analogs are tested in locomotor activity assays, specifically to determine if they block the stimulant effects of these abused drugs. Promising therapeutic candidates are also tested using operant behavior in the lab of our collaborators to determine if they decrease intravenous self-administration of the stimulant drugs of abuse, reinstatement of drug seeking following extinction of self-administration, as well as their effects on measures of impulsivity including delay discounting and cued go-no go. In another important ongoing project, the role of genetic factors and environmental factors as determinants of individual responsiveness to drugs of abuse and as determinants of an individual’s potential for abuse liability are also a focus of my research. Another important project is focused on determining if adolescents with ADHD have greater vulnerability to cocaine addiction as a consequence of treatment with stimulant and non-stimulant ADHD medications and determining the underlying neurochemical mechanism of this increased vulnerability. A more recent focus is the elucidation of the role dopamine reward mechanisms in chronic consumption of high fat diets leading to obesity and evaluation of the reversibility and prevention of the effects of high fat diets by environmental enrichment and/or exposure to a low fat diet. The latter obesity research is complemented by our previous focus on understanding presynaptic dopaminergic function and the discovery and development of lead compounds and candidate therapeutics for the treatment of drug abuse.
Nickell Justin Robert, Culver J P, Janganati V, Zheng Guangrong, Dwoskin Linda P, Crooks Peter A. (2016). Synthesis and in vitro evaluation of water-soluble 1,4-diphenethylpiperazine analogs as novel inhibitors of the vesicular monoamine transporter-2.Bioorganic & medicinal chemistry letters,
Nickell Justin Robert, Culver J P, Janganati V, Zheng Guangrong, Dwoskin Linda P, Crooks Peter A. (2016). 1,4-Diphenalkylpiperidines: A new scaffold for the design of potent inhibitors of the vesicular monoamine transporter-2.Bioorganic & medicinal chemistry letters, 26(13), 2997-3000.
Joolakanti S R, Nickell Justin Robert, Janganati V, Zheng Guangrong, Dwoskin Linda P, Crooks Peter A. (2016). Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [(3)H]dopamine uptake at the vesicular monoamine transporter-2.Bioorganic & medicinal chemistry letters, 26(10), 2422-7.
Ding D, Nickell Justin Robert, Dwoskin Linda P, Crooks Peter A. (2015). Quinolyl analogues of norlobelane: novel potent inhibitors of [(3)H]dihydrotetrabenazine binding and [(3)H]dopamine uptake at the vesicular monoamine transporter-2.Bioorganic & medicinal chemistry letters, 25(13), 2613-6.