The cardiac ryanodine receptor (RyR2) is a Ca2+ ion channel found in the sarcoplasmic reticulum (SR), an intracellular membranous Ca2+ storage system. It is well known that a destabilization of RyR2 can lead to a Ca2+ flux out of the SR, which results in an overload of intracellular Ca2+; this can also lead to arrhythmias and heart failure. The catecholamines play a large role in the regulation of RyR2; stimulation of the Beta-adrenergic receptor on the cell membrane can lead to a hyperphosphorylation of RyR2, making it more leaky to Ca2+. We have previously shown that strong electron donors will inhibit RyR2. It is hypothesized that the catecholamines, sharing a similar structure with other proven inhibitors of RyR2, will also inhibit RyR2. Here we confirm this hypothesis and show for the first time that the catecholamines, isoproterenol and epinephrine, act as strong electron donors and inhibit RyR2 activity at the single channel level. This data suggests that the catecholamines can influence RyR2 activity at two levels. This offers promising insight into the potential development of a new class of drugs to treat heart failure and arrhythmia; ones that can both prevent the hyperphosphorylation of RyR2 by blocking the Beta;-adrenergic receptor, but can also directly inhibit the release of Ca2+ from RyR2.

Removal of the pineal gland from partially parathyroidectomized rats produces stereotyped violent seizures. Inasmuch as the neurotransmitter norepinephrine (NE) has been implicated in this experimental paradigm, the purpose of this study was to investigate the effect of specific alterations in catecholamine function on convulsions produced by pinealectomy (PinX). Additionally, the role of various pineal substances, sex differences and the caging paradigm in the convulsive response was studied. Male and female rats (grouped five per cage) were found to respond similarly to the convulsive stimulus of parathyroidectomy followed by PinX. Neither implants of melatonin nor ventricular injections of arginine vasotocin in isolated and grouped rats, respectively, produced consistent changes in convulsions from PinX. The method of caging the rats after PinX, however, dramatically influenced seizures. Isolated rats (one per cage) convulsed significantly later after PinX and did so less often than grouped (five per cage) controls. NE neurotransmission appears to play a strong role in influencing PinX-induced seizures. Augmenting NE function with desipramine suppressed seizures. Convulsions were enhanced by the (beta)-receptor antagonist timolol, while neonatal injections of the catecholamine neurotoxin 6-OHDA potentiated seizures so markedly that many rats died from just one convulsion. NE levels were significantly reduced in the telencephalons and increased in the brain stems of sham-pinealectomized rats which had also received neonatal 6-OHDA; telencephalic levels of DA were elevated by 6-OHDA. Both the proconvulsant effects of 6-OHDA and the alterations it produced in central catecholamine levels were prevented, for the most part, by pretreatment with DMI. Altering both NE and DA function with L-dihydroxyphenylalanine, (alpha)-methyl-p-tyrosine, FLA-63 or reserpine did not significantly affect PinX-induced seizures in isolated rats. NE appears to play a strong role in modulating PinX-induced seizures; however, a deficit in NE function per se does not seem to be the fundamental cause of the seizures since sham-pinealectomized rats having lowered NE and/or DA function did not convulse.

In many behavioral paradigms, repeated exposures to a particular stimulus or event results in lower immediate early gene (IEG) expression. First, it was investigated if a similar reduction in IEG expression in the brain areas controlling male sexual behaviors would be observed after repeated copulation experiences in male Japanese quail. The results showed that IEG expression, as assessed by egr-1 immunoreactivity, did not increase in the POM, the BST, or the PAG after a copulation episode in highly sexually experienced subjects. One possibility was that the pattern of initial elevation of neuronal activity during the early trials of sexual interactions and the lack of increase in IEG expression later was associated with the novelty of sexual stimuli. While early exposures to certain stimuli constitute a new learning experience, the significance of such exposures would be lower as the level of experience increases. It was hypothesized that the introduction of a novel stimulus would increase the IEG expression in the POM, the BST and the PAG of experienced subjects. To evaluate this prediction, subjects were tested to see if they learn to respond to females decorated with distinct novel artificial cues after repeated exposures. The results showed that control subjects that did not have sexual experiences with decorated females discriminate against such females and directed their responses to normal females. Trained subjects did not show such preferences and responded to both types of females. In the next experiment, contrary to the prediction, no increase in IEG expression was observed after the introduction of the novel stimulus. This might be due to lower sexual motivation in subjects exposed to novel females. Effects of sexual experience were also tested in the catecholaminergic system. It was hypothesized that TH innervation in the POM and the BST would increase as a result of sexual experience. IEG expression in the catecholaminergic areas was predicted to be lower after repeated sexual experiences. The results showed no effect of experience in either tyrosine hydroxylase (TH) innervation, nor TH-egr-1 colocalization. These findings suggest that experience-related changes in male sexual behavior may be mediated by a different neurotransmitter system. / text

Includes bibliographical references (leaves 183-207) A local intradermal technique using colchicine to estimate cell division rate in wool follicles is refined and used throughout the thesis. Statistical methods used to analyse data obtained with this method are described and discussed. The implications of the findings are of great significance to research into the influence of physiological changes on wool production, and suggest experiments should be conducted under controlled environmental conditions, with a minimum of stress imposed on the animals.

Includes bibliographical references (leaves 183-207) / ix, 207 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / A local intradermal technique using colchicine to estimate cell division rate in wool follicles is refined and used throughout the thesis. Statistical methods used to analyse data obtained with this method are described and discussed. The implications of the findings are of great significance to research into the influence of physiological changes on wool production, and suggest experiments should be conducted under controlled environmental conditions, with a minimum of stress imposed on the animals. / Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Sciences, 1992