Previous studies in this laboratory have demonstrated that low doses of some selective $ sigma$ ligands such as DTG act as "agonists" by potentiating the neuronal response of rat CA$ sb3$ dorsal hippocampus pyramidal neurons to NMDA. Other $ sigma$ ligands such as haloperidol act as "antagonists" by reversing this potentiation. At doses in between 1-1000 $ mu$g/kg, i.v., several selective $ sigma$ ligands and antidepressant $ sigma$ ligands present a bell-shaped dose-response curve, which effect cannot be explained by a rapid desensitization. These $ sigma$ ligands that behave as "agonists" at low doses act as "antagonists" at the dose of 1000 $ mu$g/kg, i.v. / To date, two subtypes of $ sigma$ receptors ($ sigma sb1$ and $ sigma sb2$) are acknowledged. However, data presented in this thesis have shown that pertussis pretreatment abolished the potentiation induced by JO-1784 but not that induced by (+)pentazocine. Moreover, the injection of colchicine in the dentate gyrus abolished the potentiation induced by JO-1784, but not that of (+)pentazocine. These data suggest that the subtype of $ sigma sb1$ receptor on which J0-1784 is acting is related to a G-protein and is located presynaptically whereas the subtype of $ sigma sb1$, receptor on which (+)pentazocine is acting is not related to a G-protein and is located postsynaptically. / Because progesterone possesses high affinity at the $ sigma$ receptors, we have determined the effects of neuroactive steroids on NMDA-induced excitation. Low doses of DHEA potentiated the NMDA response selectively and dose-dependently. Progesterone had no effect by itself but reversed, at low doses, the potentiation of the NMDA response induced by DHEA as well as those induced by selective $ sigma$ ligands. The degree of the potentiation induced by 1 $ mu$g/kg, i.v. of DTG is significantly greater in ovariectorized rats than in control rats. Moreover, in late pregnancy, ten-fold higher dose of DTG is required to obtain a selective potentiation of the NMDA response. Conversely, the potentiation of the NMDA response induced by DTG is greater at day 5 post-partum than in control rats. / The data presented in this thesis suggest that: (1) more than two subtypes of $ sigma$ receptors exist in the mammalian brain; (2) neuroactive steroids such as progesterone and DHEA modulate the NMDA response via $ sigma$ receptors.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.41983 |
| Date | January 1996 |
| Creators | Bergeron, Richard, 1961- |
| Contributors | Montigny, Claude de (advisor), Debonnel, Guy (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Neurology and Neurosurgery.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001558990, proquestno: NQ29891, Theses scanned by UMI/ProQuest. |
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