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The Anxiomimetic Properties of Pentylenetetrazol in the Rat

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The Anxiomimetic Properties of Pentylenetetrazol in the Rat University of Rhode Island DigitalCommons@URI Open Access Dissertations 1980 THE ANXIOMIMETIC PROPERTIES OF PENTYLENETETRAZOL IN THE RAT Gary Terence Shearman University of Rhode Island Follow this and additional works at: https://digitalcommons.uri.edu/oa_diss Recommended Citation Shearman, Gary Terence, "THE ANXIOMIMETIC PROPERTIES OF PENTYLENETETRAZOL IN THE RAT" (1980). Open Access Dissertations. Paper 165. https://digitalcommons.uri.edu/oa_diss/165 This Dissertation is brought to you for free and open access by DigitalCommons@URI. It has been accepted for inclusion in Open Access Dissertations by an authorized administrator of DigitalCommons@URI. For more information, please contact [email protected]. THE ANXIOMIMETIC PROPERTIES OF PENTYLENETETRAZOL IN THE RAT BY GARY TERENCE SHEARMAN A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN PHARMACEUTICAL SCIENCES (PHARMACOLOGY AND TOXICOLOGY) UNIVERSITY OF RHODE ISLAND 19 80 DOCTOR OF PHILOSOPHY DISSERT.A.TION OF GARY TERENCE SHEAffiil.AN Approved: Dissertation Cormnittee \\ Major Professor ~~-L_-_._dd__· _... _______ _ -~ar- Dean of the Graduate School UNIVERSITY OF RHODE ISLAND 1980 ABSTRACT Investigation of the biological basis of anxiety is ham­ pered by the lack of an appropriate animal model for research purposes. There are no known drugs that cause anxiety in laboratory animals. Pentylenetetrazol (PTZ) produces intense anxiety in human volunteers (Rodin, 1958; Rodin and Calhoun, 1970). Therefore, it was the major objective of this disser- tation to test the hypothesis that the discriminative stimu­ lus produced by PTZ in the rat was related to its anxiogenic action in man. It was also an objective to suggest the neuro- chemical basis for the discriminative stimulus property of PTZ through appropriate drug interactions. In an operant pro­ cedure of lever pressing on a FR 10 schedule of food rein­ forcement, male hooded rats were trained to respond with a lever on one side of a food cup 15 min following a 20 mg/kg PTZ injection and to respond with a lever on the alternate side 15 min following a 1 ml/kg saline injection. All of the rats learned this discrimination reliably in a mean of 30 training sessions. The discriminative stimulus produced by PTZ was dose- and time-dependent. The anxiogenic stimulants cocaine, R05-3663 and strychnine generalized to the PTZ dis­ criminative stimulus whereas yohimbine partially generalized. The discriminative stimulus produced by cocaine, R05-3663 and yohimbine was antagonized by the anxiolytic drug, diazepam. The discriminative stimulus produced by cocaine was not antag­ onized by haloperidol. The non-anxiogenic psychomotor stimu­ lants ~-amphetamine, methylphenidate or caffeine did not gen­ eralize to ~he PTZ discriminative stimulus. Bemegride was the only convulsant drug tested that generalized to the PTZ discriminative stimulus. Picrotoxin and 3-mercaptopropionic partially, but not significantly, generalized to the PTZ dis­ criminative stimulus but bicuculline, garnma-hydroxybutyrate or nicotine did not generalize. The PTZ discriminative stim­ ulus was dose-dependently antagonized by benzodiazepine-type, barbiturate-type, propanediol carbamate-type anxiolytics as well as valproic acid. Tolerance did not develop to antago­ nism of the PTZ of discriminative stimulus by diazepam or chlordiazepoxide. The discriminative stiIT'ulus produced by PTZ was not antagonized by an anticonvulsant or other central nervous system depressants that are not anxiolytics. There was a significant correlation between the potency of drugs effective in antagonizing the PTZ discriminative stimulus and their effective doses in a conflict test of anxiety as well as their clinically effective doses. The GABA antago­ nist ROS-3663 generalized to the PTZ discriminative stimulus whereas picrotoxin and 3-mercaptopropionic acid partially generalized. The PTZ discriminative stimulus was antagonized by the GABA mimetic, valproic acid. The glycine antagonist, strychnine, generalized to the PTZ discriminative stimulus. Neither acetylcholine nor serotonin agonists or antagonists generalized to or antagonized the PTZ discriminative stimulus. The catecholamine agonist, cocaine, generalized to the PTZ discri~inative stimulus whereas yohimbine and apomorphine par­ tially generalized. However, neither a-amphetamine nor methyl­ phenidate generalized to the PTZ discriminative stimulus and catecholamine receptor antagonists did not antagonize the PTZ discriminative stimulus. Generalization to the PTZ discrimi- native stimulus by anxiogenic drugs and lack of generalization by non-anxiogenic psychomotor stimulants or convulsants as well as antagonism of the PTZ discriminative stimulus by anxi­ olytics but not non-anxiolytic anticonvulsant or depressants supports the hypothesis that the discriminative stimulus pro­ duced by PTZ in the rat is related to its anxiogenic action in man. Generalization to the PTZ discriminative stimulus by GABA antagonists and antagonism by GABA agonists but lack of generalization to or antagonism by drugs affecting other neu­ rotransmitter systems suggests that the PTZ discriminative stimulus might be ·mediated through decreased GABA neuronal ac­ tivity. ACKNOWLEDGEMENTS It gives me great pleasure to dedicate this dissertation to my family who provided the encouragement and emotional support needed for completion of my graduate career. I will be forever grateful to Dr. Harbans Lal who acted as my ad- visor and provided me with the best graduate training. I am very grateful for the understanding and friendship of Dr. Paul Carroll. Many thanks are extended to Drs. Alvin Swonger, Nelson Smith, Domenic Valentinor John DeFeo and Robert Hill for their significant contribution to my graduate education. Special thanks to Drs. Nicholas Odrey and W. D. Lawing who provided assistance with statistical analyses. Typographic assistance of Mrs. Edith Williams is deeply appreciated. v TABLE OF CONTENTS PAGE ABSTRACT ..... ii ACKNOWLEDGEMENTS .. v TABLE OF CONTENTS . Vl LIST OF TABLES .• ix LIST OF FIGURES . x INTRODUCTION l LITERATURE REVINN . 3 A. BEHAVIORAL ACTIONS OF PENTYLENETETRAZOL 3 Introduction. .. 3 Facilitation of Learning. 3 Impairment of Learning. ..... 5 Possible Chemical Basis of PTZ-Induced Retrograde Amnesia .......... 9 PTZ Induced Amnesia as a Tool to Screen Anti-Petit Mal Drugs. .. 11 Conclusion ................. 11 B. NEUROCHEMICAL ACTIONS OF PENTYLENETETRAZOL. 12 Introduction. ..... 12 Effect of PTZ on Acetylcholine ....... 12 Acetylcholine Levels. .. 12 Acetylcholine Release . 13 Acetylcholesterase. .. 15 Choline Uptake. ..... 16 Effect of PTZ on GABA . 17 GABA Levels . 17 GABA Release. 18 GAD/GABA-T . 19 Uptake. 19 Effectiveness of GABA and GABA-mimetic Drugs Against PTZ . • . 19 Effectiveness of PTZ Against GABA . 21 Effect of PTZ on Monoamine Metabolism . 23 vi PAGE Effect of Monoamine Manipulation on PTZ Seizure Threshold. 26 Conclusion . 31 .METHODS. 32 Subjects . 32 Apparatus. 32 PTZ-Saline Discrimination Trainin~ . 33 Discrimination Testing . 36 A. Generalization Testing . 36 B. Antagonism Testing . 37 C. Antagonism Testing with Diazepam and Chlordiazepoxide After Their Chronic Administration . 37 D. Test for Antagonism of the Discriminative Stimuli Produced by Cocaine, Yohirnbine and R05-3663 in Rats Trained to Dis- criminate Between PTZ and Saline . 38 E. Test for Diazepam and Haloperidol Antagonism of the Discriminative Stimulus Produced by Cocaine in Rats Trained to Discriminate Between PTZ and Saline . 38 Drugs. 39 Statistical Analyses . 41 RESULTS. 43 Acquisition of the PTZ-Saline Discrimination 43 Effect of Varying PTZ Pretreatment-Time on Lever Selection. 46 Generalization Testing . 48 1. Anxiogenic CNS Stimulants. 48 2. Non-Anxiogenic CNS Stimulants. 51 3. Convulsants. 53 4. Cholinergic Drugs. 56 5. Drugs Affecting Monoaminergic Activity . 58 6. Opiate Agonist and Antagonists . 60 Antagonism Testing . 68 1. Effect of Benzodiazepines, Meprobamate and Barbiturates . 68 2. Effect of Non-Anxiolytic Anticonvulsant Drugs. 74 3. Effect of Some GABAmimetic Drugs . 76 4. Other CNS Depressants. 80 5. Effect of Caffeine: A Phosphodiesterase Inhibitor. 81 6. Effect of Drugs Affecting Catecholaminergic Transmission • 81 7. Effect of Drugs Affecting Serotonergic Transmission . 84 8. Effect of Anticholinergics • 86 vii PAGE Lack of Tolerance Development to Benzodiazepines in Antagonism of the PTZ Discriminative Stimulus . 9. 7 Tests for Diazepam and Haloperidol Antagonism of the Discriminative Stimuli Produced by: 1. Cocaine. .. 98 2. ROS-3663 . .. 100 3. Yohimbine. 101 DISCUSSION . 104 Acquisition of PTZ-Saline Discrimination . Anxiogenic Property of PTZ as a Discriminative 104 Stimulus . 105 1. Time Course of PTZ Discrimination. .. 105 2. Generalization with Other Anxiogenics ... 106 3. Blockade of the P7Z Discriminative Stimulus by Anxiolytics ... 109 Neurochemical Correlates of the Anxiogenic Discriminative Stimulus Property of PTZ ..... 118 1. Gamma-aminobutyric acid (GABA) 119 2 . Glycine. ... 125 3. Phosphodiesterase Inhibition . 127 4 . Acetylcholine. 128 5. Serotonin. 129 6. Catecholamines . 131 7. Endorphins . 134 8. Endogenous Benzodiazepine Receptor Ligand(s). .. 135 SUMMARY AND CONCLUSIONS. 138 BIBLIOGRAPHY . 143 viii LIST OF 'rABLES TABLE PAGE 1 Response emitted with the incorrect lever prior to lever selection during acquisition of the Pentylenetetrazol (2Q mg/kg) - Saline Discrimination. · 45 2 Effect of varying pentylenetetrazol treatment time on lever selection
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