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ROLE of 5-HT1A RECEPTORS in the ABILITY of IDAZOXAN and RACLOPRIDE to BLOCK CONDITIONED AVOIDANCE RESPONDING Sarah M

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ROLE of 5-HT1A RECEPTORS in the ABILITY of IDAZOXAN and RACLOPRIDE to BLOCK CONDITIONED AVOIDANCE RESPONDING Sarah M Northern Michigan University NMU Commons All NMU Master's Theses Student Works 2009 ROLE OF 5-HT1A RECEPTORS IN THE ABILITY OF IDAZOXAN AND RACLOPRIDE TO BLOCK CONDITIONED AVOIDANCE RESPONDING Sarah M. Jacobson Northern Michigan University Follow this and additional works at: https://commons.nmu.edu/theses Recommended Citation Jacobson, Sarah M., "ROLE OF 5-HT1A RECEPTORS IN THE ABILITY OF IDAZOXAN AND RACLOPRIDE TO BLOCK CONDITIONED AVOIDANCE RESPONDING" (2009). All NMU Master's Theses. 417. https://commons.nmu.edu/theses/417 This Open Access is brought to you for free and open access by the Student Works at NMU Commons. It has been accepted for inclusion in All NMU Master's Theses by an authorized administrator of NMU Commons. For more information, please contact [email protected],[email protected]. ROLE OF 5-HT1A RECEPTORS IN THE ABILITY OF IDAZOXAN AND RACLOPRIDE TO BLOCK CONDITIONED AVOIDANCE RESPONDING By Sarah M. Jacobson Thesis Submitted to Northern Michigan University In partial fulfillment of the requirements For the degree of MASTER OF SCIENCE Graduate Studies Office 2009 SIGNATURE APPROVAL FORM This thesis by Sarah M. Jacobson is recommended for approval by the student’s thesis committee in the Department of Psychology and by the Dean of Graduate Studies. _______________________________________________________________ Committee Chair: Dr. Adam J. Prus Date _______________________________________________________________ First Reader: Dr. Cynthia A. Prosen Date _______________________________________________________________ Second Reader: Dr. Joseph H. Porter Date _______________________________________________________________ Department Head: Dr. Sheila S. Burns Date _______________________________________________________________ Dean of Graduate Studies: Dr. Cynthia A. Prosen Date OLSON LIBRARY NORTHERN MICHIGAN UNIVERSITY THESIS DATA FORM In order to catalog your thesis properly and enter a record in the OCLC international bibliographic data base, Olson Library must have the following requested information to distinguish you from others with the same or similar names and to provide appropriate subject access for other researchers. NAME: Jacobson, Sarah Marie DATE OF BIRTH: March 5, 1982 ABSTRACT ROLE OF 5-HT1A RECEPTORS IN THE ABILITY OF IDAZOXAN AND RACLOPRIDE TO BLOCK CONDITIONED AVOIDANCE RESPONDING By Sarah M. Jacobson Atypical antipsychotic drugs (APD)s are regarded as more effective and safer than typical APDs for the treatment of schizophrenia. The hypothesis that combined blockade of α2 and D2 receptors produces atypical APD effects has been supported by the ability of the α2 receptor antagonist idazoxan (IDX) combined with a low dose of the D2 receptor antagonist raclopride (RAC) to block conditioned avoidance responding in rats. However, IDX is also a partial agonist at 5-HT1A receptors. The present study sought to clarify the role of 5-HT1A receptors in the effects of IDX combined with RAC, on conditioned avoidance responding in 16 male Sprague Dawley rats using a two-chamber shuttlebox equipped with a tilting grid floor. The α2 adrenoceptor antagonist, yohimbine (YOH), was also tested in combination with RAC. RAC dose-dependently inhibited avoidance responding. IDX and YOH decreased avoidance responding when paired with an ineffective dose of RAC. Pretreatment with the 5-HT1A receptor antagonist WAY100635 failed to significantly alter the avoidance rate of the IDX and RAC combination. The α2 adrenoceptor agonist, guanfacine, restored deficits in responding induced by the RAC+IDX treatment. The 5-HT1A agonist 8-OH-DPAT reduced avoidance responding when paired with the ineffective dose of RAC. Based on these findings, α2 receptor blockade, not 5-HT1A receptor stimulation, appears to mediate the ability of IDX and RAC to block conditioned avoidance responding. i Copyright by Sarah M. Jacobson 2009 ii AKNOWLEDGEMENTS The author would like to thank Dr. Adam Prus for providing intellectual and financial support throughout the course of this study, Dr. Cynthia Prosen for her suggestions and encouragement, and Dr. Joe Porter for providing valuable input during the completion of this research and writing. This document was formatted in accordance with the American Psychological Association style guidelines. iii TABLE OF CONTENTS List of Tables ............................................................................................................. vii List of Figures ............................................................................................................ viii List of Abbreviations ................................................................................................... ix Introduction ....................................................................................................................1 History of Treatment ..........................................................................................2 Dopamine Hypothesis ........................................................................................3 Amphetamine Psychosis ........................................................................3 Antipsychotic Drugs ..............................................................................4 Negative Symptoms and Cognitive Impairments ..................................5 Atypical Antipsychotic Drugs................................................................8 Theories of Antipsychotic Atypicality ...............................................................9 D2/5-HT2A Hypothesis ...........................................................................9 5-HT2A Receptor Involvement .................................................11 5-HT1A Receptor Involvement .................................................12 Adrenoceptors ......................................................................................13 α1 Adrenoceptor Involvement ..................................................13 α2 Adrenoceptor Involvement ..................................................14 α2/D2 Hypothesis ..................................................................................15 Models for Studying Antipsychotic Drugs ......................................................20 Catalepsy Test ......................................................................................20 Paw Test ...............................................................................................21 iv Prepulse Inhibition (PPI) ......................................................................22 Microdialysis........................................................................................23 Conditioned Avoidance Response .......................................................23 Idazoxan and CAR ...............................................................................25 Rationale ......................................................................................................................25 Methods........................................................................................................................26 Animals ............................................................................................................26 Apparatus .........................................................................................................27 Conditioned Avoidance Response ...................................................................28 Training ................................................................................................29 Testing..................................................................................................29 Treatments........................................................................................................30 Data Analysis ...................................................................................................34 Results ..........................................................................................................................35 Training ............................................................................................................35 Testing..............................................................................................................38 Dose-response Curves ..........................................................................38 Raclopride ................................................................................38 Haloperidol ..............................................................................38 Idazoxan ...................................................................................39 Yohimbine................................................................................39 WAY100635 ............................................................................40 Paired Treatments ................................................................................61 v Raclopride + Idazoxan .............................................................61 Raclopride + Yohimbine ..........................................................61 Haloperidol + Idazoxan ...........................................................62 Raclopride + (+)8-OH-DPAT ..................................................62 Three Part Combinations .....................................................................80 Raclopride + Idazoxan + WAY100635 (0.05 mg/kg) .............80 Raclopride + Idazoxan + WAY100635 (0.2 mg/kg) ...............81 Raclopride + Idazoxan + Guanfacine ......................................81 Discussion ....................................................................................................................95
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