Studies are proposed to use gene-targeted """"""""knockout"""""""" mice to analyze the roles of different dopaminergic systems in the reinforcing effects of cocaine. Compelling pharmacological and neurobiologic evidence suggests that the abuse-related effects of cocaine are mediated by dopaminergic systems, and dopamine-based strategies provide promising avenues for development of new medications to treat cocaine abuse and dependence. The more specific identification of molecular targets for design and synthesis of dopamine-related medications may be greatly assisted by systematic analyses of mechanisms mediating cocaine's reinforcing effects in knockout mice. Although drugs acting at the dopamine transporter or at D1-like or D2- like receptors can modify some abuse-related effects of cocaine, the roles of these proteins in cocaine's effects are not fully understood. Genetic technology in mice that permits the deletion of a single protein by """"""""knockout"""""""" of its functional gene provides a highly specific tool that may help to elucidate the roles pharmacologically. For example, the modification of cocaine self-administration by mixed D2/D3 compounds may be due to D2 or D3 actions alone or in combination. Studies in mice that lack the D2 receptor will permit a clearer analysis of the role of the D3 receptor in such effects. The proposed self-administration will: (1) examine the reinforcing effects of cocaine in mice lacking the dopamine transporter or to the D1 or D2 receptor, and (2) use these mice to specify more precisely the receptor mechanisms involved in the modification of cocaine self-administration by non-selective dopaminergic compounds. An important feature of this proposal is that self-administration studies in parental inbred strains and studies of responding maintained by a non-drug reinforcer will be conducted to provide a comprehensive basis for interpreting results of self-administration studies in knockout mice. In addition, studies in male and female mice will allow assessment of gender differences in genetic and pharmacological influences on cocaine self-administration. Overall, this research will increase our understanding of the roles of specific dopaminergic proteins in cocaine's abuse-related effects and help to identify the most appropriate targets for medications development. Moreover, integrating gene-targeting strategies with pharmacological and drug self-administration techniques will provide a framework for future studies using yet more advanced genetic technology to identify molecular mechanisms of cocaine's abuse-related effects.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
Application #
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Lynch, Minda
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mc Lean Hospital (Belmont, MA)
United States
Zip Code
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
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
Thomsen, Morgane; Caine, S Barak (2011) False positive in the intravenous drug self-administration test in C57BL/6J mice. Behav Pharmacol 22:239-47
Thomsen, Morgane; Ralph, Rebecca J; Caine, S Barak (2011) Psychomotor stimulation by dopamine D?-like but not D?-like agonists in most mouse strains. Exp Clin Psychopharmacol 19:342-60
Thomsen, Morgane; Caine, S Barak (2011) Psychomotor stimulant effects of cocaine in rats and 15 mouse strains. Exp Clin Psychopharmacol 19:321-41
Thomsen, Morgane; Conn, P Jeffrey; Lindsley, Craig et al. (2010) Attenuation of cocaine's reinforcing and discriminative stimulus effects via muscarinic M1 acetylcholine receptor stimulation. J Pharmacol Exp Ther 332:959-69
Thomsen, Morgane; Han, Dawn D; Gu, Howard H et al. (2009) Lack of cocaine self-administration in mice expressing a cocaine-insensitive dopamine transporter. J Pharmacol Exp Ther 331:204-11
Thomsen, Morgane; Hall, F Scott; Uhl, George R et al. (2009) Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice. J Neurosci 29:1087-92

Showing the most recent 10 out of 23 publications