University of the Pacific Scholarly Commons University of the Pacific Theses and Dissertations Graduate School 1983 A proposed mechanism for the thermotropic effects of pipradrol in the rabbit Stephen Franklyn Small University of the Pacific Follow this and additional works at: https://scholarlycommons.pacific.edu/uop_etds Part of the Medicine and Health Sciences Commons Recommended Citation Small, Stephen Franklyn. (1983). A proposed mechanism for the thermotropic effects of pipradrol in the rabbit. University of the Pacific, Thesis. https://scholarlycommons.pacific.edu/uop_etds/2089 This Thesis is brought to you for free and open access by the Graduate School at Scholarly Commons. It has been accepted for inclusion in University of the Pacific Theses and Dissertations by an authorized administrator of Scholarly Commons. For more information, please contact [email protected]. - A PROPOSED MECHANISM FOR THE THERMOTROPIC EFFECTS OF PIPRADROL IN THE RABBIT A Thesis Presented to the Faculty of the Graduate School University of the Pacific In Partial Fulfillment of the Requirements of the Degree Master of Science - by Stephen Franklyn Small April 1983 ~ LIBRARY ~ ~ ' I ' ~, · SEP 2 31983 i' ~ ' ~ UNIVERS ITY OF THE PACIF.IO i ''''''''''''''' ''~'~'- 409919 ~ This thesis, written and submitted by - Stephen Franklyn Small is approved for r ecommendation to the Graduate Council, University of the Pacific. Department Chairman or Dean: - - :_-- Thesis Com/Ee: .!Uit'!::!J. Co-Chai rman 1J_durch . Co-Chairman - - ~'lvt /f - - -- Dated: I I - ACKNOWLEDGMENTS The author wishes to express his sincere appreciation - - to : -~- Dr. Marvin H. Malone, whose patience, sense of humor and generous gift of time and knowledge has made the com- pletion of this thesis possible. Dr. Raymond M. Quock for his inspiration and guida nce in initiating this study. Dr. Katherine Knapp, Dr. James Blankenship and Dr. David Fries for their interest in this study. -· The School of Pharmacy for the privilege of using their facilities. Fellow graduate students Mike Namba and John Byrne for their encouragement, assistance and friendship. Charles Green and the staff at Green Brothers Pharmacy for their support in the final phase of this study. Sandy Turner for her technical assistance and the - Turner family for their friendship and support. -~= My wife Sandi, and children, Genoa and Lisa, and my parents for their continuous support, love and encourage- ment throughout the course of this study. ii TABLE OF CONTENTS Page LIST OF TABLES . v LIST OF FIGURES vi INTRODUCTION. 1 Clinical Considerations. 4 Temperature Regulation . 6 Statement of the Problem 9 MATERIALS AND METHODS 13 RESULTS . 17 Effects of Pipradrol in Rabbits Pretreated with Dopamine Receptor Blockers . 18 Effects of Pipradrol in Rabbits Pretreated with Alpha-Adrenergic Receptor Blockers . 18 Effects of Pipradrol in Rabbits Pretreated with Serotonin Receptor Blockers ...... 20 Effects of Pipradrol in Rabbits Pretreated with Histamine Receptor of Blockers . 20 Effects of Pipradrol in Rabbits Pretreated with Cholinergic Receptor Blockers. 21 Effects of Pipradrol in Rabbits Pretreated with a Beta-Adrenergic Receptor Blocker . 21 Effects of Pipradrol in Rabbits Pretreated with a Central Nervous System Depressant. 21 Effects of Clonidine in Rabbits Pretr eated with HEAT . 22 Effects of Apomorphine in Rabbits Pretreated with Pimozide . 22 Effects of Successive Treatments of Pipradrol. 22 iii - TABLE OF CONTENTS - (continued) Page DISCUSSION. 65 CONCLUSIONS 76 REFERENCES. 78 APPENDIX A: CALCULATION OF AREA UNDER THE CURVE 84 APPENDIX B: PROGRAM AND ILLUSTRATIVE CALCULA- TIONS. 85 '- ! - iv - --- LIST OF TABLES Table Page I . Colonic Temperature Effects of Pipradrol in Rabbits Pretreated with Various Known Receptor Blockers .. 23 II. Colonic Temperature Effects of Pipradrol in Rabbits Pretreated by Intracelebro­ ventricular Administration of HEAT 27 I I I. Effects of Various Drugs and Pretreatments on the Colonic Body Temperature of Rabbits 29 IV. Evaluation of the Area-Under-the-Curve Data for the Colonic Temperature Effects of Pipradrol in Rabbits Pretreated with Various Known Receptor Blockers. 31 ·- v. Evaluation of the Area-Under-the-Curve Data for the Colonic Temperature Effects of Pipradrol in Rabbits Pretreated by the Intracerebroventricular Administration of HEAT . 33 VI. Evaluation of the Area-Under-the-Curve Data for the Effects of Various Drugs and Pretreatments on the Colonic Body Tempera- ture of Rabbits. 34 v LIST OF FIGURES Figure Page 1. The Dose Res ponse of the Colonic Bo d y Temperature in Rabbits Given Pipradrol. 35 2. Colonic Temperature Effects of Pipradrol in Rabbits Pretreated with Chlo rpromazine 3 7 -- (-30 minutes). 3. Colonic Te mp e rature Effects of P i pradro l in Rabbits Pre treat e d with Haloperidol - - (-30 minutes) . 39 4. The Colonic Te mp e rature Effects of Pipradol and Apomorpine in Rabbits Pre treat e d with Pimozide (-60 minutes) . 41 5. Colonic Te mp e r ature Effects of P ipradrol in Ra bbits Pre treated with Phenoxyben zamine (-60 minutes). 43 6. Colonic Temperature Effects of P ipradrol i n Rabbits Pretreated with HEAT (-30 minutes) 45 7 . Colonic Te mp e r ature Effects of Pipradro l in Ra bbits Pretreated with HEAT (-15 minutes) 47 8 . Colonic Te mpera ture Effects of Pipradrol in Rabbits Pretr eated with Cinanserin (-60 minutes). 49 9 . Colonic Te mp e rature Effects of Pipradrol in Rabbits Pretr eat ed with Cyproheptadine ( - 30 minutes). 51 10. Colonic Temper ature Effect s of Pipradrol in Rabbits Pretreated with Diphenhydramine (-30 minutes). 53 11. Colonic Te mp e rature Effects of Pipradrol in Rabbits Pretreated with Atropine ( - 30 minutes). 55 vi LIST OF FIGURES (continued) Figure Page 12. Colonic Temperature Effects of Pipradrol in Rabbits Pr-treated with Propranolol (-30 minutes). 57 13. Colonic Temperature Effects in Pipradrol in Rabbits Pretreated with Pentobarbital (-30 minutes). 59 14. Colonic Temperature Effects of Clonidine in Rabbits Pretreated with HEAT (-30 minutes). 61 15. The Effect of Successive Treatments of Pipradrol on the Colonic Body Tempera­ ture of Rabbits. 63 16. Comparative Evaluation of Area-Under-The­ Curve Data for the Colonic Body Tempera­ ture Effect of Intravenous Pipradrol in Rabbits Pretreated with Various Known Re­ ceptor Blockers. 67 17. A Proposed Model for Thermoregulation Involving NE (Norepinephrine), Alpha­ Adrenergic Receptors, Nicotinic Acetyl­ choline Receptors and Muscarinic Acetyl­ choline Receptors. 70 vii INTRODUCTION Pipradrol HCl was developed in the early 1950s by the Wm. S. Merre ll Co., Cincinnati, Ohio, as a n ew chemical­ type s timula nt. Designate d by the company as MDR-108, it was shown to induce c h anges in the activity of laboratory animals, specifically an acce l e ration of reaction time to environmental s timuli. Small doses were admi nister e d to pigs, mice, guinea pigs, rats a nd rabbits and wer e observed to induce extr e mely r apid but highly coordinated movements such as lickin g , c h ewing , eating, drinking and scratch ing . These observa tions c losely resembled those seen by the administration of amph e t amine ( 1) . Pipradrol HCL i s alpha-(pipe ridyl)ben zh ydr o l hydr o­ c hloride. The hydrochl o ride salt is a white o do rless powder with a slightly bitter taste. One part dissolves in about 60 parts of hot wate r. Pipradrol is a lso k nown by trade n a mes s u c h as Alertol, Gadexyl, Ceptidrol, Meratonic a nd -1- 2 Metra tran ( 2). OH ~ 0 -?-0 I~ Pipradrol Amphetamine Considering the similarity between the action of pip- radrol and amphetamine on laboratory animals, it was ques- tioned as to whether or not the stereochemical e na ntiomers of pipradrol would also have differe nt pharmacological actions . Therefore, Portoghese and co-workers (3) con- ducted studi es on rat l ocomotor activity using enantiomers of pipradrol synthesized from (R)- a nd (S)- pipecolic acid. I t was found t h at all of the central stimulant activity was due to t h e (R)- pipradrol enantiomer while the more active enantiomer of amphetamine possessed the opposite con figura- tion . Because o f these steric differences in activity, it was suggested that these compounds may be acting on dif- ferent receptors in the central nervous system. The administration of lethal doses of pipradrol intra- venous ly to mice, rats , guinea pigs and rabbits caused 3 tremors and convulsions with death occurring during the con- vulsive stage due to respiratory failure. Lethal doses given orally to dogs caused an increase in motor activity (circling and rolling) with the animals becoming less co- ordinated but rarely experiencing convulsions . Death occur- red suddenly during the hyperactivity stage. Early observations in dogs given pipradrol showed it to differ behaviorally from amphetamine in that the animals did not become irritable and remained amenable to handling whereas animals treated with amphetamines were easily ag- gravated (1). With these observations, pipradrol became classified pharmacologically as a psychomotor stimulant. Psychomotor stimulants are known to increase locomotor activity and to induce stereotyped behavior (4). Loco- motor activity in rats can be measured by means of a photo- cell cage utilizing two parallel photocell beams directed across the long axis of the cage. The number of inter- ruptions of the photocell beam indicates the degree of activity of the test animals. Stereotypic behavior in rats is usually manifested by continuous sniffing, licking or biting , grinding of the jaws, grooming, rearing and occasionally by backward locomotion (5) . Sahakian et al. (6) postulated that these two behaviors might be mediated by different mechanisms. Psychomotor stimulation can also facilitate operant performance such as that reinforced by electrical stimulation 4 - of the brain (7-9). Therefore, it has been suggested that = the increase in behavioral activity produced by psycho­ motor stimulants results from an increase in the value of the rewarding stimuli. This effect may be mediated by the potentiation of a brain reinforcement mechanism (10) .