INFORMATION TO USERS This manuscript MS been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, sorne thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction la dependent upon the quality of the copy submitted. Broken or indistinct prim. coIored or poor quality illustrations and photographs, print bleedlhrough, substandard margins. and improper alignment can adversely affect reproduction. ln the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicat8 the deletion. Cversize materials (e.g., maps, drawings. charts) are reproduced by sectioning the original, beginning at the upper Ieft-hand corner and continuing from left to right in equal sections with small overlaps. Photographs incluclect in the original manuscript have been reproduced xerographically in this copy. Higher quality 8- x 9'" black and white photographie pnnts are available for any photographs or illustrations appearing in this copy for an additional charge. Contad UMI directly to order. Bell & Howell Information and Leaming 300 North Zeeb Road, Ann Arbor, MI 48108-1346 USA 800-521-0600 ELECTROPHYSIOLOGICAL STUDIES IN RAT DORSAL BIPPOCAMPUS: MODULATION OF THE NEURONAL RESPONSE TO N-METHYL-D-ASPAIlTATE DY SELECTIVE SIGMA. AND SIGMAz LIGANDS BY Sophie Couture Student number: 9549733 JuIy 1998 A thesis submitted to the Faculty ofGraduate Studies and Research in partial fulfilment ofthe degree of Master in Science Sophie COUTURE. 1998 McGill University Department of neurology and neurosurgery MontréaJ7 Québec National Library Bibliothèque nationale 1+1 of Canada du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Street 395. rue Wellington Ottawa ON K1 A 0N4 0IIawa ON K1A 0N4 Canada Canada The author has granted a non­ L'auteur a accordé une licence non exclusive licence aUowing the exclusive permettant à la National Library ofCanada to Bibliothèque nationale du Canada de reproduce, loan, distribute or seU reproduire, prêter, distribuer ou copies ofthis thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/film, de reproduction sur papier ou sur format électronique. The author retains ownersbip ofthe L'auteur conserve la propriété du copyright in tbis thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts from it Ni la thèse ni des extraits substantiels may he printed or otherwise de ceUe·ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son penmSSlon. autorisation. 0-612-50743-2 Canad~ ACKNOWLEDGEMENTS • These experiments were carried oui: in the Neurobiological Psychiatrie Unit at McGill under the supervision of Dr. Guy Debonnel. The research was conducted to fu1f1l the requirements of a Ma~ter in Science. 1 wish to thank Dr. Debonnel for his expert advice and his support and guidance throughout my studies. 1would also like to thank the members of the selection committee. namely Or. de Montigny. Dr. Debonnel and Dr. Blier for accepting rny candidacy as a graduate student and. providing me with such a stimulating environment. 1 am also grateful to Claude Bouchard. Normand Lavoie and Yves Simard for always being available for technical assistance and advice. A special "thanks" to aIl staff members and fellow graduate students for their continuous support and encouragement during my studies at McGill University. Finally, 1 would like to covey a very special thank you to my friend and fiance. Patrice for his encouragement and patients and, my parents for their understanding and continuous support. • Manuscripts and authorship Guidelilles for Thesis Preparation • Faculty ofGraduate Studies and Research~ McGill University The review of the literature and the studies presented in this Master thesis concem the modulation of the neuronal response by selective sigma ligands. Two experimental series are presented in tbis thesis. One article has been published, the second one has been submitted. 1have conducted all the experimental work, analyzed the data, drew the figures and written the papers. In regards to the second article~ the technician Nonnand Lavoie also contributed to a minor extent in the obtention ofexperimental datas. It is the policy ofthe Faculty at McGill University to allow the students to include as chapters "original publications" concerning the thesis research project. The faculty regulations Can he summarized as follows: Candidates have the option~ subject to the approval of their Department. of including. as part oftheir thesis. copies ofthe text ofa paper(s) submitted for publication. or the clearly-duplicated text of published paper(s), provided that these copies are bound as an integral part of the thesis. [fthis option is chosen. connecting texis, providing 10gicaJ bridges between the different papers. are mandatory. • II The thesis must still conform to aIl other requirements of the "Guidelines Conceming Thesis • Preparation" and should he in a literary form that is more than a mere collection of manuscripts published or to he published. The thesis must include, as separate chapters or sections: (1) a table of contents, (2) a general abstract in English and French, (3) an introduction which clearly states the rationaie and objectives of the study. (4) a comprehensive review of the background literature to the subject of the thesis, when this review is appropriate, (5) a final overall conclusion and/or summary. Additional rnaterial (procedural and design data, as weIl as descriptions of equipments used) must he provided where appropriate and in sufficient detail Ce.g. in appendices) to allow a clear and precise judgemem to be made of the importance and originality of the research reported in the thesis. • III LIST OF PUBLICATIONS • Published Abstracts 1. Debonnel G, and Couture S (1997) Modulation of the neuronal response to N-Methyl-D- Aspartate by selective O 2 ligands, Neuroscience Meeting. New Orleans. 2. Couture S, and Debonnel G (1997) Sensitivity ofselective 0 ligands to the opiate antagonist naloxone, Neuroscience Meeting, New Orleans. 3. Couture S, and Debonnel G (1996) Modulation of the neuronal response to N-Methyl-D- Aspartate by selective O 2 Ligands. ACNP abstract. 4. Couture S, and Debonnel G (1996) Modulation of the neuronal response to N-Methyl-D- Aspartate by selective O 2 Ligands, Research Day, Dept. of Psychiatry. Mcgill University. 5. Couture S. and Debonnel G (1997) Sensitivity ofselective (J ligands to the opiate antagonist naloxone, Research Day, Dept.ofNeurology, McGill University. 6. Couture S, and Debonnel G (l997) Sensitivity of selective (J ligands to the opiate antagonist naloxone, Research Day, Dept. of Psychiatry. 7. Couture S, and Debonnel G (1997) Implication of (J ligands as potential anticonvulsants or proconvulsants, Symposium on Epilepsy, Laurentides. Published Articles 1. Couture S, and Debonnel G (1998) Modulation of the neuronal response to N-Methyl-D- aspartate by selective (J2Iigands, SYNAPSE, 29:62-71. • IV ., Couture S, Lavoie N, and Debonnel G (1998) Suppression of {+)-pentazocine effects by • naloxone (submitted, SYNAPSE). • v ABSTRACT • 1t has now been accepted for severa! years, that (] receptors exist as at least two distinct entities denoted a 1 and O 2, We have previously shown in our laboratory that several selective (] 1 ligands potentiate the neuronal response to NMDA in the dorsal hippocampus of rat. The non selective 0/01 ligand, DTG, aIso potentiates the neuronal response. However. when il is administered at doses between 3 and 40 Jlglkg, the increase of NMDA-induced activation tums in to an epileptoid activity. Data presented in tbis thesis suggest that similarly to (] 1 ligands, selective 02 ligands such as Lu 28-179. Lu 29-252 and BD 1008 dose-dependently potentiate the NMDA response. Interestingly, the effects of these drugs are not reversed by the non selective (] /02 antagonist haloperidoI. by the neurosteroid progesterone nor by the selective (J 1 antagonist NE-l00. The (] 2 ligand CB-64D a1so potentiates. dose-dependently. the NMDA response, its effect. however is reversed by haloperidol and by the neurosteroid progesterone. AlI O 2 ligands failed to generate any epileptoid activity on their own but, with the subsequent administration of a (11 agonist (10-1784). an epileptoid activity was induced. This epileptoid activity was not observed following the subsequent administration of the al agonist (+)-pentazocine. The a receptor is believed to be a non opioid receptor insensitive to naloxone. However. recently, a protein has been identified that resembles the cr opioid receptor originally proposed by Martin and colleagues in 1976. Therefore to answer this discrepancy, we verified the spectrum of (] ligands for which the potentiation of the NMDA response is mediated by the naloxone-sensitive (] receptor. The potentiation ofthe NMDA response induced by (+)-pentazocine. but not 10-1784. BD- • • 737 and L. 687-384. was suppressed by naloxone. The data presented in tbis thesis suggest that: (1) similarly to CJ 1 ligands. CJ 2 agonists potentiate the NMDA response; (2) the coactivation ofone type of CJ 1 and O 2 receptors appears to he necessary to induce epileptoid activity; (3) haloperidol may not act as a O 2 antagonist; (4) and (+)-pentazocine might act on two types of 01 receptor: one which is haloperidol sensitive and an other, which is naIoxone sensitive but different than the opiate receptors. • 2 ABRÉGÉ • On reconnaît maintenant l'existence d'au moins deux sous types de récepteurs 0: les récepteurs 0 1 et cr1. Plusieurs études de notre laboratoire ont démontré que de nombreux ligands a ( potentialisent la réponse neuronale au NMDA dans l'hippocampe dorsal du rat. n a également été démontré que le DTG~ un ligand non sélectif a ( /oz, potentialise aussi la réponse neuronale au NMDA mais que~ lorsque il est administré à des doses comprises entre 3 et 40 flglkg, il induit une activité épiIepto·.oe.