This application describes a career development plan and research project designed to promote the transition of Dr. Morgane Thomsen from mentored fellow to an independent career in drug abuse research. Dr. Thomsen has acquired expertise in highly specialized behavioral techniques such as chronic intravenous drug self-administration in mice and rats, specializing in evaluating cocaine self- administration in mutant mice. The present proposal will develop and establish the candidate's mastery of additional procedures, specifically: manipulations of extinction in self-administration assays, and drug discrimination. During the 2-year mentored phase, the candidate plans to distinguish her research from her mentor's and establish a record of productivity in an original line of investigation. She will also gain experience and self-reliance in less technical areas (e.g., staff supervision, grants management) to prepare her for independence. The candidate plans to make muscarinic systems and their potential implications in drug addiction disorders her long-term focus as an academic researcher in behavioral pharmacology and genetics. Anticipated future directions include extending findings of the present proposal to models of polydrug abuse. The project will be conducted at the Alcohol and Drug Abuse Research Center at the McLean Hospital, Harvard Medical School. The institution generally, and the mentor S. Barak Caine and co-mentor Nancy Mello specifically, have extremely well-established records in drug abuse research, providing an ideal environment for fostering the careers of young researchers dedicated to this field. Dr. Thomsen's research project for this application proposes to evaluate the potential of drugs acting at specific muscarinic receptors to reduce abuse-related effects of cocaine. With the help of collaborators Professors P. Jeffery Conn and J?rgen Wess, Dr. Thomsen will combine novel, highly selective drugs with gene knockout technology to evaluate which muscarinic receptor subtypes mediate anti-cocaine effects of muscarinic agonists, and which mediate undesirable effects. First, a wide array of drugs will be tested in mice trained to discriminate cocaine from saline. Drugs that attenuate the discriminative stimulus of cocaine with little or no adverse effect (reduction in rates of behavior) will then be tested in mice and rats trained to self-administer cocaine chronically. With these latter assays, Dr. Thomsen will evaluate the ability of the drugs to selectively reduce cocaine self-administration (without decreasing food-maintained behavior) as acute and chronic treatment, and to facilitate extinction of a behavior associated with cocaine (in a strain of mice that show resistance to extinction). The ultimate goal of the project is to identify potential targets for treatment of cocaine addiction.
The focus of the five-year research plan as well as the lifelong career-objective of the young investigator is to develop new medications that target brain acetylcholine receptors. This is aimed principally at treating cocaine and amphetamine addictions, for which no effective medications currently exist, and secondly to improve upon existing dopamine-based medications with far fewer side-effects for disorders including Parkinson's Disease, Attention Deficit Hyperactivity Disorder, and Schizophrenia. Finally, because acetylcholine is known to modulate memory and cognition, it is highly likely that any breakthrough from this work would improve the lives of patients suffering from Alzheimer's Disease and other cognitive deficits.
|Stoll, Kevin; Hart, Rachel; Lindsley, Craig W et al. (2018) Effects of muscarinic M1 and M4 acetylcholine receptor stimulation on extinction and reinstatement of cocaine seeking in male mice, independent of extinction learning. Psychopharmacology (Berl) 235:815-827|
|Thomsen, Morgane; Sørensen, Gunnar; Dencker, Ditte (2018) Physiological roles of CNS muscarinic receptors gained from knockout mice. Neuropharmacology 136:411-420|
|Thomsen, Morgane; Barrett, Andrew C; Butler, Paul et al. (2017) Effects of Acute and Chronic Treatments with Dopamine D2 and D3 Receptor Ligands on Cocaine versus Food Choice in Rats. J Pharmacol Exp Ther 362:161-176|
|Joseph, Lauren; Thomsen, Morgane (2017) Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M1, M2, and M4 receptor knockout mice. Behav Brain Res 329:75-83|
|Sørensen, Gunnar; Caine, S Barak; Thomsen, Morgane (2016) Effects of the GLP-1 Agonist Exendin-4 on Intravenous Ethanol Self-Administration in Mice. Alcohol Clin Exp Res 40:2247-2252|
|Thomsen, Morgane; Caine, Simon Barak (2016) Effects of dopamine D1-like and D2-like antagonists on cocaine discrimination in muscarinic receptor knockout mice. Eur J Pharmacol 776:71-80|
|Thomsen, Morgane; Fulton, Brian S; Caine, S Barak (2014) Acute and chronic effects of the M1/M4-preferring muscarinic agonist xanomeline on cocaine vs. food choice in rats. Psychopharmacology (Berl) 231:469-79|
|Thomsen, Morgane (2014) Locomotor activating effects of cocaine and scopolamine combinations in rats: isobolographic analysis. Behav Pharmacol 25:259-66|
|Thomsen, Morgane; Barrett, Andrew C; Negus, S Stevens et al. (2013) Cocaine versus food choice procedure in rats: environmental manipulations and effects of amphetamine. J Exp Anal Behav 99:211-33|
|Caine, S Barak; Thomsen, Morgane; Barrett, Andrew C et al. (2012) Cocaine self-administration in dopamine D? receptor knockout mice. Exp Clin Psychopharmacol 20:352-63|
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