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Effects of the Nmda Receptor Antagonist Mk-801 on the Timing and Temporal Processing of Short-Intervals in Rats

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Effects of the Nmda Receptor Antagonist Mk-801 on the Timing and Temporal Processing of Short-Intervals in Rats EFFECTS OF THE NMDA RECEPTOR ANTAGONIST MK-801 ON THE TIMING AND TEMPORAL PROCESSING OF SHORT-INTERVALS IN RATS Jonathan P. Miller A Dissertation Submitted to the Graduate College of Bowling Green State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY December 2005 Committee: Kevin C. H. Pang, Advisor J. Devin McAuley, Co-Chair Michael E. Geusz Daniel D. Wiegmann Graduate Faculty Representative ii ABSTRACT Kevin C. H. Pang, Advisor J. Devin McAuley, Co-Chair The present series of studies examined effects of MK-801, an NMDA antagonist, on short-interval timing in rats. The first study used two experiments to examine timing performance using the peak-interval (PI) and PI-gap procedures during chronic exposure of MK- 801. The first of these experiments investigated the effects of three MK-801 doses (0.025 mg/kg, 0.05 mg/kg, & 0.2 mg/kg) administered for 10 sessions; the second experiment examined a single dose (0.2 mg/kg) administered for 15 sessions. MK-801 interfered with short interval timing by producing an over-estimation of time and a non-scalar increase in variability. Additionally, MK-801 increased response rate, suggesting a decrease in response inhibition. The influence of MK-801 on the formation of temporal memories was examined by switching the temporal criterion (Meck, 1988; Meck, Komeily-Zadeh, & Church, 1984). Spontaneous alternation and water maze tasks were determined whether the dose of MK-801 (0.05 mg/kg) also influenced spatial memory. Results suggested that MK-801 did not alter temporal learning and that this dose (0.05 mg/kg) had no effect on spontaneous alternation and water maze. MK- 801 did increase the rate of responding, demonstrating that the drug had positive effects. However, the dose may have been insufficient to alter both spatial and temporal learning. Therefore, more work needs to be done with high concentrations of MK-801 before concluding that NMDA receptor antagonists have no influence on the learning of temporal durations. Finally, modeling simulations were used to qualitatively fit the MK-801 data using Scalar Expectancy Theory (SET) in order to better understand the effects of MK-801 on timing and iii temporal processing. Modeling results suggest MK-801 has a wide ranging effect on the mechanisms of timing and temporal processing. Based on the simulations, the best fit to the data was obtained when five of the eight parameters were altered. Clock speed was slowed, while variability of clock speed, memory transformation, threshold, and base-rate of responding values were all increased. In summary, no definitive conclusions can be made about MK-801 effects on temporal learning. However there are two clear effects on timing and temporal processing, MK- 801 causes an over-estimation of time and an increased rate of responding. iv I dedicate this project to my friends and family (both living and deceased) who have all had a great impact in making me the person that I am today. Thank you for your understanding and tolerance during all my years of schooling. v ACKNOWLEDGMENTS I would like to thank the members of my committee for their valuable feedback and help in conducting these experiments. I also thank Liz Hartmann for her help in constructing all of the operant boxes, Kelly Wright, Trisha Straight, Steve Borawski, and Leslie Gulvas for their help in conducting the experiments, and the members of the BGSU Timing Research group for providing a sounding board for many ideas. In addition, we would like to thank Dr. Peter Balsam for his suggestion to explore a state-dependent learning explanation for our data, which was used in the design of Experiment 2 in Chapter 2. This study is supported by PHS grant AG20560 and the generous donations of Mrs. Dorothy Price. vi TABLE OF CONTENTS Page CHAPTER 1. INTRODUCTION .................................................................................................2 CHAPTER 2. EFFECTS OF THE NMDA RECEPTOR ANTAGONIST MK-801 ON SHORT-INTERVAL TIMING IN RATS ....................................................................................7 Experiment 1...................................................................................................................11 Method ................................................................................................................11 Animals ...................................................................................................11 Apparatus................................................................................................11 Drug ........................................................................................................12 Procedure................................................................................................13 Data Analysis..........................................................................................14 Results.................................................................................................................16 Peak-Interval Procedure.........................................................................16 Peak-Interval Gap Procedure.................................................................20 Discussion...........................................................................................................20 Experiment 2...................................................................................................................24 Method ................................................................................................................25 Animals ...................................................................................................25 Apparatus................................................................................................25 Drug ........................................................................................................25 Procedure................................................................................................25 Data Analysis..........................................................................................26 vii Results.................................................................................................................26 Discussion...........................................................................................................30 General Discussion .........................................................................................................31 CHAPTER 3. EFFECTS OF MK-801 ON LEARNING NEW TEMPORAL MEMORIES FOR SHORT-INTERVAL TIMING IN RATS .........................................................................37 Method ............................................................................................................................40 Animals ...............................................................................................................40 Drug ....................................................................................................................41 Peak-Interval Procedure.....................................................................................41 Apparatus................................................................................................41 Procedure................................................................................................42 Data Analysis..........................................................................................43 Spontaneous Alternation.....................................................................................46 Apparatus................................................................................................46 Procedure................................................................................................47 Data Analysis..........................................................................................47 Morris Water Maze.............................................................................................48 Apparatus................................................................................................48 Procedure................................................................................................48 Data Analysis..........................................................................................49 Results.............................................................................................................................49 Peak-Interval Procedure.....................................................................................49 Analysis by Session .................................................................................49 viii Analysis by Trial .....................................................................................54 Spontaneous Alternation.....................................................................................62 Water Maze .........................................................................................................63 Escape Latency .......................................................................................63 Time in Target Quadrant & Platform Crossings....................................65 Discussion.......................................................................................................................65 CHAPTER 4. QUALITATIVE MODELING OF MK-801 DATA USING SCALAR EXPECTANCY THEORY.........................................................................................................70 Method ............................................................................................................................72
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