DOPAMINE D1-LIKE, D2 AND D3 RECEPTOR SUBTYPES IN CATALEPSY SENSITIZATION AND CONDITIONING IN RATS: IMPLICATIONS FOR MOTOR FUNCTION, MOTIVATION AND LEARNING by Tomek Jan Banasikowski A thesis submitted to the Centre for Neuroscience Studies In conformity with the requirements for the degree of Doctor of Philosophy Queen’s University Kingston, Ontario, Canada July, 2012 Copyright © Tomek J. Banasikowski, 2012 Abstract The behavioral effects of drugs that act on the brain’s dopamine (DA) system change with repeated exposure to the drug. Antipsychotic drugs, that block DA receptors, produce progressively greater effects on behavior with repeated testing. For example, rats repeatedly treated with a low dose of the D2 receptor-preferring antagonist haloperidol do not initially exhibit catalepsy, a response quantified by time spent on a horizontal bar without active movement. However, with repeated drug-environment pairings animals show a reduction in exploration and increases in catalepsy. The current thesis examined the drug-environment relationship in catalepsy sensitization, and how different DA receptor subtypes control this phenomenon. Treatment with a D2, but not D3 or D1-like receptor-preferring antagonist produced catalepsy sensitization. Catalepsy sensitization developed in one test environment did not transfer to another environment. Similarly, rats with a history of haloperidol treatments outside of the test environment (unpaired group) did not exhibit significant catalepsy when given haloperidol for the first time prior to catalepsy testing. Previous exposure to the catalepsy test environment led to a more rapid development of catalepsy sensitization. Thus, drug-environment interaction is critical for the development and expression of catalepsy sensitization. Rats previously given haloperidol and tested with saline in the drug paired environment exhibited conditioned catalepsy. The acquisition of conditioned catalepsy is dependent on D1- like receptors, while its expression is dependent on D3 receptors. Conditioned catalepsy showed gradual day-to-day extinction with repeated saline treatment in the previously haloperidol-paired environment. Following extinction, the response to haloperidol in previously sensitized rats shifted from environment-specific to environment-independent suggesting that a putative ii haloperidol drug cue alone can elicit conditioned catalepsy. In summary, treatment with a D2, but not D1-like or D3 receptor-preferring antagonist in a particular test environment produces catalepsy sensitization, while acquisition of conditioned catalepsy is dependent on D1-like receptors, and its expression is dependent on D3 receptors. Importantly, the acquisition and expression of sensitization to haloperidol is conditional on the presence of drug-associated environmental stimuli. Our findings provide further insight into the current understanding of learning processes involved in the action of antipsychotic drugs and the dissociable effects of D1-like, D2 and D3 receptors controlling this phenomenon. iii Co-Authorship In all cases, I (Tomek J. Banasikowski) designed the experiments, collected and analyzed data and wrote the manuscripts. Richard J. Beninger contributed to data analysis and manuscript preparation. Chapter 2 has been published in its entirety online, and can be cited as: Banasikowski TJ, Beninger RJ (2012). Haloperidol conditioned catalepsy in rats: a possible role for D1-like receptors. The International Journal of Neuropsychopharmacology, 1-10, DOI: http://dx.doi.org/10.1017/S1461145711001696 (published online: 18 November 2011). Chapter 3 has been published in its entirety online, and can be cited as: Banasikowski TJ, Beninger RJ (2012). Reduced expression of haloperidol conditioned catalepsy in rats by the dopamine D3 receptor antagonists nafadotride and NGB 2904. European Neuropsychopharmacology, 1-8, DOI: http://dx.doi.org/10.1016/j.euroneuro.2012.02.004, (published online: 10 March 2012). Chapter 4 is to be submitted for publication: Banasikowski TJ, Beninger RJ (2012). Drug-environment interaction controls the acquisition and expression of haloperidol catalepsy sensitization and conditioning. (To be submitted July 2012). iv Know rather that we must turn to nature itself, to the observation of the body in health and disease, to learn the truth. Hippocrates v Table of Contents Abstract ............................................................................................................................................ ii Co-Authorship................................................................................................................................. iv List of Figures ................................................................................................................................. ix List of Abbreviations……………………………………………………………………………....x Chapter 1 General Introduction........................................................................................................ 1 1.1 Dopamine Neuron Anatomy .................................................................................................. 2 1.2 Dopamine Neuron Physiology ............................................................................................... 4 1.3 Dopamine Receptor Subtypes ................................................................................................ 5 1.4 Dopamine and Motor Function .............................................................................................. 7 1.5 Dopamine and Motivation ..................................................................................................... 9 1.6 Dopamine and Stimulus-Reward Learning .......................................................................... 14 1.7 Dopamine and Behavioral Sensitization .............................................................................. 18 1.8 Hypothesis............................................................................................................................ 21 1.9 References ............................................................................................................................ 23 Chapter 2 Haloperidol Conditioned Catalepsy in Rats: A Possible Role for D1-like Receptors ... 37 2.1 Abstract ................................................................................................................................ 38 2.2 Introduction .......................................................................................................................... 39 2.3 Materials and Methods ......................................................................................................... 41 2.3.1 Subjects ......................................................................................................................... 41 2.3.2 Drugs ............................................................................................................................. 41 2.3.3 Behavioral Testing ........................................................................................................ 41 2.3.4 Experimental Design ..................................................................................................... 42 2.3.5 Statistics ........................................................................................................................ 44 2.4 Results .................................................................................................................................. 44 2.4.1 Experiment 1: Haloperidol Catalepsy ........................................................................... 44 2.4.2 Experiment 2: SCH 23390 Catalepsy ........................................................................... 47 2.4.3 Experiment 3: Haloperidol + SCH 23390 Catalepsy .................................................... 47 2.5 Discussion ............................................................................................................................ 48 2.6 References ............................................................................................................................ 59 Chapter 3 Reduced Expression of Haloperidol Conditioned Catalepsy in Rats by the Dopamine D3 Receptor Antagonists Nafadotride and NGB 2904 ........................................................................ 67 3.1 Abstract ................................................................................................................................ 68 vi 3.2 Introduction .......................................................................................................................... 69 3.3 Materials and Methods ......................................................................................................... 71 3.3.1 Subjects ......................................................................................................................... 71 3.3.2 Drugs ............................................................................................................................. 71 3.3.3 Behavioral Testing ........................................................................................................ 72 3.3.4 Experimental Design ..................................................................................................... 72 3.3.5 Statistics ........................................................................................................................ 75 3.4 Results .................................................................................................................................