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Jmo the Role of Neuronal Histamine in Memory 31 /si JMO THE ROLE OF NEURONAL HISTAMINE IN MEMORY PROCESSING DISSERTATION Presented to the Graduate Council of the University of North Texas in Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY By William A. Stutts., B.A. Denton, Texas December, 1995 31 /si JMO THE ROLE OF NEURONAL HISTAMINE IN MEMORY PROCESSING DISSERTATION Presented to the Graduate Council of the University of North Texas in Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY By William A. Stutts., B.A. Denton, Texas December, 1995 Stutts, William A., The role of neuronal histamine in memory processing. Doctor of Philosophy (Psychology), December, 1995, 89 pp., 22 illustrations, references, 32 titles. Neuronal histamine(HA) may play a role in memory processing. This hypothesis is based upon evidence that the action of histamine at central H1 and H2 histamine receptor sites has been shown to modulate memory of rats and mice in adversely-motivated tasks. The purpose of this study was to test this hypothesis more thoroughly in mice using two distinct approaches to neuronal HA manipulation. One approach involved the use of new pharmacological agents which act at the histamine H3 receptor. It has been demonstrated that the selective H3 antagonist thioperamide increases HA release in the brain of mice whereas the H3 agonist imetit decreases HA release via modulation of presynaptic H3 autoreceptors. It was expected that an increase in neuronal HA via the autoreceptor mechanism would result in facilitation of memory processing whereas a decrease in HA release would disrupt memory processing. The second approach involved the manipulation of cerebral HA levels via the specific enzyme inhibiting compounds alpha-flouromethylhistidine (alpha- FMH), a potent neuronal HA depleter and metoprine, a histamine-methyl transferase inhibitor which results in accumulation of neuronal HA. Again, effects of increased HA due to metoprine and decreased HA levels due to alpha- FMH were expected to facilitate and disrupt memory processing respectively. One trial inhibitory (passive) avoidance training was employed in each experiment in order to evaluate the effect of each drug on memory. Each compound was tested for effects on memory consolidation and memory retrieval as well as for the presence of state dependent effects. The pattern of effects obtained with thioperamide suggested facilitation of acquisition or memory storage (consolidation) processes, with no effect on the retrieval phase of memory processing. In accordance with those findings, significant disruption of memory occurred when imetit was present during the consolidation phase of memory processing, but not when presented prior to the retrieval phase. These findings suggest that H3 receptor sites play a significant role in the modulation of memory processes via some mechanism which exclusively affects the acquisition or memory consolidation process, while the retrieval of previously laid down memory traces is unaffected. 11 TABLE OF CONTENTS INTRODUCTION 1 Neuropharmacology of Histamine 1 Role of Histamine in Cognitive Functions 3 Pharmacological Tools 8 Inhibitory (Passive) Avoidance Paradigm 18 Statement of Experimental Problem 19 General Expectations 20 GENERAL METHOD 23 Animals 23 Apparatus and Procedure 23 Locomotor activity 23 Inhibitory Avoidance 24 Shock Sensitivity 25 General Procedure 25 Statistical Analysis 26 PARAMETRIC DATA 27 Effect of Shock Intensity on Retention Performance 27 Method 27 Results and Discussion 28 iii Method 30 Results and discussion 30 EXPERIMENT 3 - EFFECT OF THIOPERAMIDE ON LEARNING AND MEMORY FOR INHIBITORY AVOIDANCE 32 Method 33 Animals 33 Locomotor activity 33 Test for acquisition/memory storage effects 34 Test for retrieval effects 34 Test for state dependency 34 Test for shock sensitivity 35 Results and Discussion 35 Locomotor activity 35 Acquisition/memory storage effects 39 Retrieval Data 40 Shock Sensitivity Data 41 EXPERIMENT 4 - THE EFFECT OF IMETIT ON LEARNING AND MEMORY FOR INHIBITORY AVOIDANCE 44 Method 45 Animals 45 Locomotor activity 45 IV Test for retrieval effect 46 Test for state dependency 46 Test for shock sensitivity 46 Results and Discussion 47 Locomotor activity 47 Acquisition/memory storage effects 51 Retrieval Data 53 Shock Sensitivity Data 54 EXPERIMENT 4 - EFFECT OF METOPR1NE ON LEARNING AND MEMORY FOR INHIBITORY AVOIDANCE 57 Method 58 Animals 58 Locomotor activity 58 Test for acquisition/memory storage effects 59 Test for retrieval effects 59 Test for state dependency 59 Test for shock sensitivity 60 Results and Discussion 60 Locomotor activity 60 Acquisition/memory storage effects 63 Retrieval Data 64 Shock Sensitivity Data 65 EXPERIMENT 6 -EFFECT OF ALPHA-FMH ON LEARNING AND MEMORY FOR INHIBITORY AVOIDANCE 67 Method 68 Animals 68 Locomotor activity 68 Test for acquisition/memory storage effects 69 Test for retrieval effects 69 Test for shock sensitivity 69 Results and Discussion 69 Locomotor activity 69 Acquisition/memory storage effects 73 Retrieval Data 74 Shock Sensitivity Data 75 CHAPTER VIII 77 GENERAL DISCUSSION 77 REFERENCES 86 VI LIST OF ILLUSTRATIONS Fig. 1. Latency to enter the dark compartment on a 24-h retention test for untreated mice a function of shock intensity. Data are expressed as mean raw latency (± SE), corrected latency (retention-training latency ± SE) or median latency) 29 Fig. 2. Latency to enter the dark compartment (+ SE ) as a function of retest interval for mice tested following training at 0.08 or 0.28 mA shock intensities 31 Fig. 3. Horizontal components of locomotor activity (top to bottom; left to right) as a function of dose of thioperamide 37 Fig. 4. Changes in the vertical (left, top to bottom) and stereotypy (right, top to bottom) components of locomotor activity as a function of dose of thioperamide 38 Fig. 5. Latency to enter the dark compartment as a function of pretraining thioperamide dose 39 Fig. 6. The effect of pretesting dose of thioperamide on latency to enter the dark compartment 40 Fig. 7. The effect of thioperamide on shock sensitivity as a function of the percent of time spent on the safe side 41 \11 Fig. 9. Changes in the stereotypy (right, top to bottom) and the vertical (left, top to bottom) components of locomotor activity as a function of dose of imetit.51 Fig. 10. Dose effect curve for imetit showing the effect on ambulation expressed as distance traveled in cm. Over 60 minutes 52 Fig. 11. Latency to enter the dark compartment as a function of pretraining imetit dose 53 Fig. 12. The effect of pretesting dose of imetit on latency to enter the dark compartment 54 Fig. 13. The effect of imetit on shock sensitivity as a function of the percent of time spent on the safe side 55 Fig. 14.Changes in the horizontal components of locomotor activity (top to bottom; left to right) as a function of dose of metoprine 62 Fig. 15. Changes in the stereotypy (right, top to bottom) and the vertical (left, top to bottom) components of locomotor activity as a function of dose of metoprine 63 Fig. 16. Latency to enter the dark compartment as a function of pretraining metoprine dose 64 Fig. 17. The effect of pretesting dose of metoprine on latency to enter the dark compartment 65 Fig. 18. The effect of metoprine on shock sensitivity as a function of the percent of time spent on the safe side 66 VI! 1 Fig. 19.Changes in the horizontal components of locomotor activity (top to bottom; left to right) as a function of dose of alpha-FMH) 72 Fig. 20. Changes in the stereotypy (right, top to bottom) and the vertical (left, top to bottom) components of locomotor activity as a function of alpha-FMH.... 73 Fig. 21. Latency to enter the dark compartment as a function of pretraining A- FMH dose 74 Fig. 22. Effect of pretesting dose of alpha-FMH on latency to enter the dark compartment 75 Fig. 23. The effect of alpha-FMH on shock sensitivity as a function of the percent of time spent on the safe side 76 IX CHAPTER I INTRODUCTION Neuropharmacology of Histamine In the brain, histamine (HA) is synthesized and released by two distinct types of histaminergic cells. Mast cells are believed to control vascular and inflammatory processes via HA release both centrally as well as outside the CNS. These connective tissue cells of the circulatory system are scarce in the brain but their HA content is relatively high and exists as a constant pool being released and slowly rejuvenated . Neurons are the other source of HA which functions as the transmitter of a system resembling other monoaminergic neuronal systems in several respects. HA does not readily cross the blood-brain barrier and therefore, the function of histamine receptors in the CNS is to mediate the actions of the locally synthesized, stored and released amine (Schwartz, Arrang, Garbarg, 1986a). The availability of immunohistochemical techniques have allowed histaminergic cells to be visualized. Most histaminergic neurons arise from various magnocellular mammillary nuclei in the ventral part of the posterior hypothalamus. Their axons constitute long ascending fiber tracts passing through the lateral hypothalamic area and projecting, mainly in an ipsilateral fashion, to all regions of the diencephalon and telencephalon (Schwartz et al, 1986a). The general disposition of the histaminergic system resembles the catecholaminergic and serotonergic systems in the brain in which there are few compact cell groups having a wide distribution of long varicose fibers. The chemical actions of HA are mediated not only by the two well known H1 and H2 receptor sub-classes, but also by the recently discovered H3 receptors with distinct localization and pharmacology. Actions at H1-receptors, responsible for the 'drowsiness' side effects of antihistamines appear to be mediated by breakdown of inositol phosphates which alter intracellular Ca+2 levels. H2-receptors appear to be directly linked with adenylate cyclase and their stimulation results in enhanced electrophysiologically recorded responses to excitatory agents (Schwartz, Arrang, Garbarg, Korner,1986b).
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