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The Investigation of the Antiparkinsonian Effects of Glutamate Receptor Antagonists

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The Investigation of the Antiparkinsonian Effects of Glutamate Receptor Antagonists THE INVESTIGATION OF THE ANTIPARKINSONIAN EFFECTS OF GLUTAMATE RECEPTOR ANTAGONISTS SIMRANJIT KAUR B.Sc (Hons.) M.Sc The School of Pharmacy, University of London, 29/39 Brunswick Square, London WCIN 1 AX A thesis submitted in partial fulfilment of the requirements of the University of London, Faculty of Medicine for the degree of Doctor of Philosophy June 1997 ProQuest Number: 10104733 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10104733 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT 1. This study investigated the locomotor effects of glutamate antagonists in drug-naive and reserpine-treated mice. The NMDA channel blockers, dextromethorphan, memantine, amantadine and phencyclidine (PCP), enhanced the locomotor activity of drug-naive mice. Two clear populations could be differentiated after the administration of 40 mg/kg dextromethorphan, i.e non-responders and responders. We postulated that the responders were able to metabolise dextromethorphan to the more potent dextrorphan. Only high doses of memantine, PCP and ketamine reversed the akinesia induced by reserpine. Due to the induction of motor deficits, these drugs are not a viable option, at present, for use as monotherapy in PD. These drugs may be more beneficial as adjuncts to the dopamine- based therapy of PD. When interactions with the dopamine D, agonist, SKF 38393, the Dg agonist, RU 24213, and the dopamine precursor, L-Dopa, were investigated in reserpine-treated mice, only dextromethorphan interacted positively with SKF 38393, while MK 801, the glutamate release blockers, lamotrigine and clonidine, the glycine site antagonist, (±) HA-966 and the competitive NMDA antagonist, CPP, interacted synergistically with L-Dopa. It is conceivable that subthreshold doses of the NMDA channel blockers are needed to potentiate the response to L-Dopa, as very low doses of MK 801 synergised with L-Dopa while higher doses induced motor deficits, which impeded locomotion. This curvilinear response is a hallmark of the glutamate antagonists, as low doses increase locomotion by possibly acting at the level of the striatum and/or the nucleus accumbens (NAc) and facilitating dopaminergic transmission by enhancing synthesis and/or release of dopamine, while high doses decrease locomotion by inducing motor deficits, which may result from the action of these drugs at sites outside the basal ganglia, such as the motor cortex. 2. Stereotaxic injections of the glutamate antagonists were then administered into the corpus striatum (CS) or the substantia nigra pars reticulata (SNr) of reserpine-treated rats to determine the site of action of these compounds. Only a subgroup of competitive A bstract NMDA receptor antagonists, CPP and CGP 40116, induced behavioural arousal from the CS whereas MK 801, PCP, the competitive NMDA receptor antagonist, AP-5, which was ineffective in the CS, and the AMP A receptor antagonist, NBQX in addition to CPP and CGP 40116 produced activity from the SNr. As there is a narrow window between doses which are beneficial and doses which induce motor deficits, careful titration of doses is necessary to separate out the beneficial effects from the detrimental effects. Our results indicate that both the CS and the SN are involved in the locomotor-stimulant as well as side-effect inducing properties of these drugs. 3. The effects of MK 801 were then determined in the cataleptic rat model of PD. Systemic MK 801 alleviated the catalepsy induced by systemic haloperidol and by intrastriatal or intraaccumbens haloperidol. MK 801 administered into the CS, NAc, SNr, subthalamic nucleus (STN) or the entopeduncular nucleus (EPN), attenuated the catalepsy induced by systemic haloperidol. However, systemic MK 801 was ineffective against the catalepsy induced by intrapallidal or intrathalamic muscimol. These results indicate that catalepsy induced by neuroleptics and the anticataleptic ability of MK 801 can arise from regions apart from the CS. The finding that MK 801 was ineffective against intracerebral muscimol-induced catalepsy supplements evidence for theories advanced by Chesselet and Delfs (1996) and Levy et al. (1997), stating that the hyperactivity of the STN may not depend directly on the hypoactivity of the GP, but instead the cortico-subthalamic glutamatergic pathway may be responsible. AO^O\\11I)GEMENTS I would like to thank my supervisor, Dr. Mike Starr, for his exenplary guidance, boundless enthusiasm and encouragement during the course of this research. I would also like to express my gratitude towards Steve Coppard and his excellent staff for all their help. Thanks also to Dr. Chris Biggs and Andy Fisher for making the laboratory a joy to work in. A special thanks to Hülya Ôzer of the University of Istanbul, Turkey, with whom the work detailed in Chuter Five was jointly undertaken. Thank you to Glaxo-Wellcome, Merz, Synthelabo Recherche, Ciba Geigy, Novo Nordisk, Byk-Gulden and Tocris Neuramin for their gifts of the drugs used in this research. Finally, 1 would like to thank my parents for all their support and encouragement. TABLE OF CXSNTENTS Page Tide 1 Abstract 2 Acknowledgments 4 Table of Contents 5 list of Figines 13 List of TaUes 23 Abbreviations 24 PuUications 27 Qiapter One General Introduction 28 1.1 The aetiology and pathology of Parkinson's disease (PD) 29 1.2 Neurochemistry of PD 31 1.2.1 Dopamine in PD 31 1.2.1.1 Dopamine receptors 32 1.2.1.2 Dopamine agonists 32 1.2.2 Other neurotransmitters in PD 34 1.2.3 Glutamate in PD 36 1.2.3.1 Glutamate receptors and their localisation 36 1.2.3.1.1 Molecular structure 37 1.2.3.2 Glutamate antagonists 38 1.3 Animal models of PD 42 1.3.1 MPTP lesions 42 1.3.2 6-Hydroxy-dopamme (6-OHDA) lesions 43 1.3.3 Anphetamines 44 1.3.4 Reseipine-induced akinesia 44 1.3.5 Neuroleptic-induced catalepsy 45 1.4 Glutamate-dopamine interactions in the basal ganglia 46 1.5 Glutamate-dopamine interactions in the context of PD 50 1.6 Current therapy of PD 51 1.6.1 L-Dopa 51 1.6.2 Direct-acting dopamine agonists 52 1.6.3 Selegiline 53 1.6.4 Anticholinergics 53 1.6.5 Amantadine 54 1.7 Novel therapies of PD 54 1.8 The antiparkinsonian effects of glutamate antagonists 55 1.8.1 As monotherapy 55 1.8.2 As adjuncts to dopamine agonists or L-Dopa 57 1.9 Aims of this research 59 Charter Two IVbteiials and Methods 61 2.1 Locomotor activity in the mouse 62 2.1.1 Animals 62 2.1.2 Drug-naive mice 62 2.1.3 Induction of akinesia and administration of glutamate antagonists 64 2.1.4 Interaction studies with a dopamine D^ agonist, SKF 38393 64 2.1.5 Interaction studies with a dopamine Dj agonist, RU 24213 64 2.1.6 Interaction studies with a dopamine precursor, L-Dopa 65 2.1.7 Statistical analysis 65 2.1.8 Drugs 65 2.2 Locomotor activity in the rat 66 2.2.1 Animals 66 2.2.2 Stereotaxic surgery and cannulae implantation 67 2.2.3 Induction of akinesia and dmg administration 67 2.2.4 Statistical analysis 68 2.2.5 Drugs 68 2.3 Catalepsy in the rat 69 2.3.1 Animals 69 2.3.2 Stereotaxic surgery and the intracerebral administration of agents 70 2.3.3 Induction and measurement of catalepsy 70 2.3.4 Systemic administration of haloperidol and MK 801 71 2.3.5 The effect of MK 801 on haloperidol-induced catalepsy in the 71 corpus striatum (CS) 2.3.6 The effect of NBQX on the anticataleptic activity of MK 801 71 2.3.7 The effect of MK 801 on haloperidol-induced catalepsy in the 71 nucleus accumbens (NAc) 2.3.8 Anticataleptic activity of MK 801 administered into the substantia 72 nigra pars reticulata (SNr), the entopeduncular nucleus (EPN) or the subthalamic nucleus (STN) 2.3.9 The effect of bicucuUine administered into the SNr 72 2.3.10 The effect of MK 801 on catalepsy induced by intracerebral 72 muscimol 2.3.11 Statistical analysis 72 2.3.12 Drugs 72 2.4 Histology 71 Ch^iter Three Locomotor effects of systemic glutamate antagonists in 75 dmg-naive and monoamme-depleted mice 3.1 Introduction 76 3.2 Results 77 3.2.1 Control treatments 77 3.2.1.1 Vehicle in drug-naive mice 77 3.2.1.2 Vehicle in monoamine-depleted mice 78 8 3.2.1.3 SKF 38393 in monoamine-depleted mice 78 3.2.1.4 RU 24213 in monoamine-depleted mice 78 3.2.1.5 L-Dopa in monoamine-depleted mice 79 3.2.2 The NMDA receptor-linked ion channel blockers 79 3.2.2.1 Amantadine 79 3.2.2.1.1 In drug-naive mice 79 3.2.2.2 Memantine 81 3.2.2.2.1 In dmg-naive mice 81 3.2.2.2.2 In monoamine-depleted mice 81 3.2.2.2.3 In conjunction with SKF 38393 82 3.2.2.2.4 In conjunction with RU 24213 82 3.2.2.2.5 In conjunction with L-Dopa 82 3.2.2.3 Dextromethorphan 84 3.2.2.3.1 In dmg-naive mice 84 3.2.2.3.2 In monoamine-depleted mice 85 3.2.2.3.3 In conjunction with SKF 38393 85 3.2.2.3.4 In conjunction with RU 24213 85 3.223.5 In conjunction with L-Dopa 86 3.2.2.4 Phencyclidine (PCP) 86 3.2.2.4.1 In dmg-naive mice 86 3.2.2.4.2 In monoamine-depleted mice 87 3.22.4.3 In conjunction with SKF 38393 87 3.2.2.4.4 In conjunction with RU 24213 88 3.2.2.4.5 In conjunction with L-Dopa 88 3.2.2.5 Ketamine 91 3.2.2.5.1 In drug-naive mice 91 3.2.2.S.2 In monoamine-depleted mice
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