The experiments reported in this thesis studied the mechanisms of expression of overexpectation of conditioned fear, as measured by freezing. In Stage I, rats were conditioned to fear a tone and a flashing light conditioned stimulus (CS) through pairings with a 0.5 mA, 1 s shock. In Stage II, overexpectation was trained by the reinforcement of a compound of these CSs with a shock of the same magnitude. Two compound ?? shock pairings produced an overexpectation effect, as measured by freezing to presentations of the tone alone, while further Stage II training caused over-training of overexpectation. Expression of the overexpectation effect produced by two compound ?? shock pairings could be prevented by pre-test injection of the benzodiazepine partial inverse agonist FG7142. This effect was dose-dependent and not due to state-dependent memory. Control experiments suggested that it was also not due to any general effect of FG7142 on the Pavlovian freezing response. Freezing to a tone that had been conditioned, but not subjected to any decremental training procedures, was unaffected by administration of FG7142 before either the conditioning or test session. FG7142 also did not affect freezing to a tone that had been subjected to an associative blocking procedure. The hypothesis that overexpectation of conditioned fear may be context-dependent was also tested. However, renewal was not observed. Rats that received Stage II training in a context distinct from the Stage I training context showed equivalent expression of overexpectation regardless of whether testing was conducted in the Stage I or Stage II training context. These results are consistent with the hypothesis that overexpectation, like extinction, leads to the imposition of a GABAA receptor-mediated mask on the fear CR. Moreover, they suggest that this masking of fear is the specific consequence of negative predictive error.

Les nanotubes de carbone (NTC) sont difficilement détectables dans les matrices biologiques. Ceci rend l'étude de leur toxicité et de leur biodistribution plus difficile. Lors de ce travail, nous avons étudié, dans un premier temps, l'effet de l'albumine sérique de veau (BSA) sur la dispersion des NTC puis dans un second temps, la toxicité, la biodistribution ainsi que la clairance d'un NTC multi-feuillet (MWCNT) chez le rat en utilisant le nickel, une impureté métallique présente dans le nanotube étudié. Après une unique instillation intratrachéale de 100 μg de MWCNT, nos résultats ne montrent ni inflammation, ni lésions pulmonaires, ni modifications des paramètres physiologiques pulmonaires. De plus, l'absence de passage de la barrière alvéolo-capillaire et la mise en place d'un long mécanisme de clairance ont été observées dans le poumon. Afin de mieux comprendre ce mécanisme et à l'aide de la microscopie electronique et de la spectroscopie infrarouge, nous avons montré que les MWCNT sont chimiquement modifiés et sont clivés dans le poumon. Ces résultats, ainsi que l'étude de la phagocytose des MWCNT et de l'apoptose des macrophages alvéolaires, ont permis d'émettre l'hypothèse d'un mécanisme de clairance selon laquelle l'élimination des MWCNT dans le poumon serait liée à la phagocytose, l'apoptose, la dégradation de MWCNT par les macrophages alvéolaires puis la phagocytose de cellules apoptotiques.

Les tests couramment utilisés pour évaluer le déficit sensori-moteur induit par une lésion du cerveau chez le rat posent problèmes en termes de sensibilité, d'objectivité et de quantification. Nous avons émis l'hypothèse selon laquelle l'analyse 3D de la cinématique de la locomotion constitue un paradigme expérimental approprié pour quantifier un tel déficit. Aussi, la locomotion a été étudiée lors d'une course sur tapis roulant (25 cm/s) muni ou pas d'obstacles (deux obstacles de 3cm de haut et 1,2 cm de large) à l'aide du système optoélectronique VICON. Le mouvement des quatre pattes a été simultanément enregistré avant et après induction d'une lésion unilatérale soit du striatum (mort d'origine métabolique des neurones striataux) soit du cortex cérébral (infarctus du cortex moteur) chez le rat adulte. Le laboratoire a précédemment montré que ces deux modèles de lésion conduisaient à une anomalie plus ou moins durable de la traversée d'une poutre étroite et surélevée, test classiquement utilisé pour évaluer la locomotion du rat. La première étude décrit pour la première fois la stratégie utilisée par le rat pour franchir un obstacle. Elle révèle que le franchissement s'accompagne d'une rupture complète du pattern locomoteur de base et que l'élévation des ceintures contribue de façon notable au passage de chacune des pattes au- dessus de l'obstacle. La seconde étude montre que la lésion du striatum s'accompagne d'un déficit locomoteur durable lors des deux modalités de course, l'anomalie portant sélectivement sur les pattes contralatérales à la lésion. Plus précisément, ces pattes présentent une flexion exagérée pendant la phase d'appui dont la durée est augmentée. Par ailleurs, lorsque que la patte antérieure opposée à la lésion conduit la manœuvre de franchissement, elle prend fréquemment appui sur l'obstacle suite à une initiation trop précoce de son élévation. Dans ce cas, la patte postérieure homolatérale franchit ou non correctement l'obstacle. L'ensemble de ces résultats suggère l'implication du striatum dans la programmation des mouvements guidés par la vue. La dernière expérience montre qu'aucune des modalités de locomotion n'est affectée par la lésion corticale, suggérant que le faisceau corticospinal n'est indispensable ni à la locomotion ni à son adaptation à l'environnement. En conclusion, notre travail montre que nos modalités d'enregistrement de la locomotion sont appropriées pour quantifier le déficit fonctionnel induit par une lésion du striatum, mais pas celui induit par une lésion du cortex moteur. Il serait intéressant de répéter les expériences lors d'une course volontaire, de manière à s'affranchir de la stimulation sensitive générée par le déroulement du tapis sous les pattes et d'étudier la réversibilité du déficit en cas de lésion partielle du striatum.

Vascular reactivity to vasopressin and phenylephrine is potentiated by constrictor prostanoids (CP) in normotensive female (F) but not male (M) rat aorta and CP function is estrogen-dependent. This study investigated the effects of estrogen on CP function and arterial blood pressure (MAP) during development of aortic coarctation-induced hypertension (HT). M and F rats, (15-18 wks.) in four groups: normotensive (NT), hypertensive (HT), ovariectomized (OVX), and OVX estrogen-replaced (OE), underwent abdominal aortic coarctation or sham surgery (NT). At 14 days, SQ 29,548 (SQ, Thromboxane A2 (TXA2) receptor antagonist) was given i.v. to the groups. In another experiment, rats received Ridogrel (TXA2 receptor antagonist+TXA2 synthase (TXS) inhibitor) or vehicle (methyl cellulose) daily, for 14 days. Thoracic aortae were analyzed for morphology, incubated in Kreb’s Henseleit Buffer (KHB) ± angiotensin II (ANG II), or underwent continuous pulsatile flow and pressure experiments (PFP) with KHB ± ANG II. Perfusate was analyzed for thromboxane B2 (TXB2) and prostaglandin F1α (PGF1α). RT-PCR and immunohistochemistry were performed for TXS. MAP was higher in F-HT than in M-HT after 14 days. SQ infusion reduced MAP substantially more in F-HT and OE-HT than in others. Ridogrel prevented increases in MAP in F/OE-HT rats, but not M/OVX-HT. Basal release of TXB2 and PGF1α increased to a greater extent in F-HT than in M-HT relative to their controls. ANG II-stimulated TXB2 and PGF1α release increased to a greater extent in F-HT than in M-HT. With or without ANG II, TXB2 production in HT during PFP increased with estrogen. PGF1α increased during PFP with estrogen, however not with ANG II. Pressurization resulted in less diameter change in F and OE-HT than in OVX-HT. Elastin increased with HT (inhibited by Ridogrel) in all but M. Collagen increased in HT with estrogen (inhibited by Ridogrel). Neither OVX-HT nor Ridogrel had any effect on morphology. Estrogen increased TXS with HT. Estrogen enhanced vascular CP and MAP in F-HT by increased expression of TXS and collagen density in the vasculature indicating that in aortic coarctation-induced HT, CP are upregulated by estrogen. Specific forms of HT in human beings may involve estrogen-induced vascular CP upregulation.

Rat hepatocytes have previously been reported to possess prostaglandin E₂ receptors of the EP₃-type (EP₃-receptors) that inhibit glucagonstimulated glycogenolysis by decreasing cAMP. Here, the isolation of a functional EP₃ϐ receptor cDNA clone from a rat hepatocyte cDNA library is reported. This clone can be translated into a 362-amino-acid protein, that displays over 95% homology to the EP₃ϐ receptor from mouse mastocytoma. The amino- and carboxy-terminal region of the protein are least conserved. Transiently transfected HEK 293 cells expressed a single binding site for PGE₂ with an apparent Kd of 15 nM. PGE₂ > PGF₂α > PGD₂ competed for [³H]PGE₂ binding sites as did the EP₃ receptor agonists M&B 28767 = sulprostone > misoprostol but not the EP₁ receptor antagonist SC 19220. In stably transfected CHO cells M&B 28767 > sulprostone = PGE₂ > misoprostol > PGF₂α inhibited the forskolin-elicited cAMP formation. Thus, the characteristics of the EP₃ϐ receptor of rat hepatocytes closely resemble those of the EP₃ϐ receptor of mouse mastocytoma.

No description available.

Our study investigated the potential for a combination of diabetes and nicotine treatment to affect blood pressure in the rat. We used streptozotocin injection and oral nicotine feeding as models of type-1 diabetes and smoking respectively. Blood pressure was assessed using the indirect tail-cuff technique. In an attempt to further characterize our experimental model, we also observed body weight, plasma glucose and the contractility of aortic segments in various treatment groups. Our data was expressed as mean ± SEM, and significance was regarded as P < 0.05. We found that a combination of streptozotocin and nicotine treatment resulted in a significant elevation of systolic blood pressure compared with either treatment alone, or control. Furthermore, assessment of aortic contractility showed alteration of reactivity to both phenylephrine and sodium nitroprusside as a result of the combination treatment. We also observed a trend for our combination treatment to exacerbate the elevation of plasma glucose level seen in streptozotocin induced diabetic rat models. This study serves as an experimental basis to underline the importance of cessation of tobacco use for individuals with diabetes mellitus.

Background: Intracellular glucocorticoid receptors (GRs) mediate the regulation of lung development, including alveolarization, by glucocorticoids (GCs). One potential approach to determining the role of GC-GR signalling in alveolar formation would be by pharmacologic blockade. Hypothesis: CP472555, a novel GR antagonist with negligible anti-PR activity, is a suitable tool for the study of GC-GR regulation of rat alveolarization. Design/Methods: CP472555 doses needed to block GR were estimated in vitro in fetal rat lung primary cultures. Postnatally, a variety of doses were administered intraperitoneally over a range of days. Results: During postnatal days (PN)0-PN10, when GC levels are low, CP472555 induced changes consistent with GR agonist activity. While GC levels increase after PN11, animals exposed to CP472555 from PN11-PN21 exhibit changes consistent with anti-GR antagonist activity. Conclusion: CP472555 causes a degree of GR blockade sufficient to permit further pharmacological investigation of the role of endogenous GC-GR signalling at the end of alveolarization.

The naked mole-rat (Heterocephalus glaber) demonstrates a strict social and reproductive hierarchy. Oxytocin (OXT) is a peptide hormone that acts both peripherally and centrally in the regulation of a number of sexual and social behaviours. The main area of central production of this peptide is the paraventricular nucleus of the hypothalamus (PVN). The present study characterized differences that exist in OXT neurons in this region. Breeders and subordinates from established colonies were sacrificed and brains were processed for OXT-immunoreactivity. Four further groups of paired animals underwent various social and hormonal manipulations (opposite-sex paired, same sex-paired, opposite-sex/gonadectomised paired, opposite-sex/vasectomized paired) and were also used for analysis. Results showed that subordinate naked mole-rats had significantly more OXT-immunoreactive neurons in the PVN than either breeders or paired animals that had been gonadectomised. However, no differences were found on measures of OXT cell volume. Possible functional significance of these differences is discussed.

Background: Intracellular glucocorticoid receptors (GRs) mediate the regulation of lung development, including alveolarization, by glucocorticoids (GCs). One potential approach to determining the role of GC-GR signalling in alveolar formation would be by pharmacologic blockade. Hypothesis: CP472555, a novel GR antagonist with negligible anti-PR activity, is a suitable tool for the study of GC-GR regulation of rat alveolarization. Design/Methods: CP472555 doses needed to block GR were estimated in vitro in fetal rat lung primary cultures. Postnatally, a variety of doses were administered intraperitoneally over a range of days. Results: During postnatal days (PN)0-PN10, when GC levels are low, CP472555 induced changes consistent with GR agonist activity. While GC levels increase after PN11, animals exposed to CP472555 from PN11-PN21 exhibit changes consistent with anti-GR antagonist activity. Conclusion: CP472555 causes a degree of GR blockade sufficient to permit further pharmacological investigation of the role of endogenous GC-GR signalling at the end of alveolarization.