Cannabis (known in its common forms as Cannabis sativa or Cannabis indica) is the most widely used illicit drug in the world and has been used for thousands of years for medicinal, religious and hedonistic purposes. In the last half of the 20th century the therapeutic uses of cannabis were largely ignored as most Western governments prohibited the use of the drug. Prohibition has come about largely as a result of the view that cannabis is a dangerous drug that poses major risks to both mental and physical health. However, this view is being increasingly challenged in recent years with a major popular movement towards decriminalization of cannabis occurring in some Western countries and a resurgence of interest in the medicinal properties of cannabis. Since Mechoulam and colleagues first isolated delta 9-tetrahydrocannabinol (delta 9-THC) as the main psychoactive constituent of cannabis, considerable advances have been made in the pharmacology of cannabis and cannabis-like drugs (cannabinoids). Central and peripheral cannabinoid receptors have been isolated and two endogenous ligands have been discovered. In addition, two cannabinoid receptor antagonists have been developed. However, our knowledge of the behavioural, neural and emotional effects of cannabis and the cannabinoids has often lagged behind our understanding of basic cannabinoid pharmacology. The present thesis attempts to further the understanding of the behavioural, neural and emotional effects of cannabinoids, using laboratory rats as subjects. A synthetic analogue of delta 9-THC (CP 55,940), is used as the primary pharmacological tool. The thesis offers a broad perspective with three major areas of investigation. These are: 1) the effects of CP 55,940 on anxiety-related behaviour (Chapters 2 and 3); 2) the effects of CP 55,940 on patterns of brain activation as indicated by c-fos expression (Chapter 4) and; 3) the addictive potential of CP 55,940 and its capacity to produce sensitization to the effects of other drugs such as cocaine (Chapters 5 and 6). A recurring theme throughout the thesis is that genetic factors may partially determine the behavioural, neural and emotional response to cannabinoids. To this end, the thesis compares Lewis and Wistar trains of rat in a wide variety of assays. Previous research has isolated Lewis rats as an "addiction-prone" and a "cannabinoid-preferring" strain, as they are more sensitive to the rewarding effects of various drugs of abuse including cannabinoids. Conversely, cannabinoids appear to have aversive effects in Wistar rats. A long-standing puzzle in cannabinoid research has been the question of why rats do not self-administer cannabis or cannabinoids. One likely reason is that cannabinoids have predominately aversive effects in rats. It is proposed here that these aversive effects arise because cannabinoids are anxiogenic agents in most rat strains. However some evidence indicates that the Lewis strain of rat are the only strain to find cannabinoids rewarding. It is hypothesised that Lewis rats may be more susceptible to the rewarding effects of cannabinoids because they are less susceptible to the anxiogenic effects of these compounds. In Chapters 2 and 3 the anxiogenic effects of the synthetic cannabinoid agonist CP 55,940 were compared in Lewis and Wistar rats in several different animal models of anxiety. In Chapter 2, the predatory odour avoidance, open area avoidance and conditioned ultrasonic vocalization (USV) models were utilised. In the predatory odour avoidance model, rats were exposed to cat odour in a rectangular arena and given the opportunity to hide in a small box. Both Lewis and Wistar rats displayed high levels of hiding during odour exposure. In Wistar but not Lewis rats, 50 �g/kg of CP 55,940 (i.p.) enhanced this avoidance response. Unfortunately, Lewis rats showed exceptionally high avoidance of the cat odour making it difficult to discern the effects of CP 55,940. To avoid this problem a second experiment was conducted, where rats were tested in the same arena as in the first experiment but with no cat odour present. Again in Wistar, but not Lewis rats, 25 and 50 �g/kg of CP 55,940 (i.p.) increased the avoidance of the open space. In the third experiment, Lewis and Wistar rats were placed in a chamber in which they had previously received footshock. Wistar but not Lewis rats re-exposed under the influence of 10, 25 or 50 �g/kg CP 55,940 (i.p.) emitted significantly more USVs than vehicle-treated rats. Thus, CP 55,940 clearly increased anxiety-related behaviour in Wistar rats but not Lewis rats, supporting the notion of a genetic predisposition towards cannabinoid-induced anxiety. In Chapter 3 the generality of the findings made in Chapter 2 were tested by utilising two further animal models of anxiety, the social interaction and light-dark emergence tests. From the results of Chapter 2, it could be claimed that Lewis rats were merely subsensitive to the effects of CP 55,940. Therefore a higher dose range (0, 25, 50 and 75 �g/kg i.p.) of CP 55,940 was employed in Chapter 3. In addition, the rotarod test was used to assess whether CP 55,940 has ataxic effects at these doses. In the first experiment, two unfamiliar rats were placed in a large arena and the time the rats spent socially interacting was recorded. CP 55,940 significantly reduced the total time rats spent socially interacting in Lewis (25 and 75 �g/kg) and Wistar rats (50 and 75 �g/kg). However, CP 55,940 has a significantly greater effect in Wistar rats compared to Lewis rats. In the second experiment, rats were placed in a small box within a large open arena and the latency to emerge from this box was measured. CP 55,940 increased emergence latency (at 75 �g/kg) and mean time per entry into the box (at 25 and 75 �g/kg) in Wistar but not Lewis rats. Furthermore, CP 55,940 caused a greater decrease in time spent in the open arena (at 25 and 75 �g/kg) and frequency of emergence (at 75 �g/kg) in Wistar rats in comparison to Lewis rats. In the third experiment, CP 55,940 (at 25, 50 and 75 �g/kg) caused mild incoordination only in Lewis rats as measured by the rotarod test. This finding argues against the assertion that the CP 55,940-induced anxiety-like behaviours in Wistar rats are merely a result of motoric impairment. Furthermore, it illustrates that Lewis rats are not generally subsensitive to the effects of CP 55,940. That is, when compared to other rat strains, Lewis rats may be more or less sensitive to the effects of CP 55,940 depending on what behaviour is being assessed. From the results of Chapters 2 and 3 it can be seen that Lewis rats are less sensitive to the anxiogenic effects of CP 55,940 than Wistar rats. In Chapter 4 it was hypothesised that in Lewis rats the effects of CP 55,940 on neural substrates of reward far outweigh the effects the compound has on neural substrates mediating anxiety. To examine this issue, the effects of CP 55,940 at a moderate (50 �g/kg i.p.) and high (250 �g/kg i.p.) dose were observed on c-fos expression (a measure of neural activation) and behaviour in Lewis and Wistar rats. CP 55,940 dose-dependently inhibited locomotor activity and reduced body temperature with Lewis rats being significantly less affected than Wistar rats. The 250 �g/kg dose caused significant catalepsy in both strains with a significantly greater effect in Wistar rats. These strain differences in the effects of CP 55,940 on body temperature and motor behaviour clearly correlated with c-fos expression in various regions and subregions. In general, Lewis rats showed significantly less Fos-labeled cells in comparison to Wistar rats. These strain differences in the effects of CP 55,940 on c-fos expression appeared unique to cannabinoids, as cocaine (15 mg/kg i.p.) had equivalent effects on c-fos expression in Lewis and Wistar rats. CP 55,940 promoted c-fos expression in areas not previously assessed, such as the median preoptic nucleus (MnPO), medial preoptic nucleus (MPO), anterior hypothalamic area (AH), islands of Calleja (ICjM), periaqueductal gray (PAG) and the pedunculopontine tegmental nucleus (PPTg). The strain differences uncovered in Chapters 2 and 3 correlated well with strain differences in the effects of CP 55,940 on c-fos expression in areas implicated in cannabinoid-induced anxiety, such as the central nucleus of the amygdala, bed nucleus of the stria terminalis, paraventricular nucleus of the hypothalamus and PAG. However, the effects of CP 55,940 on c-fos expression in a neural circuit which may underlie reward, which includes the shell of the nucleus accumbens (NAS) and PPTg, were also less in Lewis rats in comparison to Wistar rats. Future investigations must address whether the reduced effects of CP 55,940 on the Lewis rat are due to pharmacokinetics or pharmacodynamics. In addition, future studies must reconcile the pattern of c-fos expression observed here with prior reports of the Lewis rat being a unique "cannabinoid-preferring" strain. In Chapter 4, CP 55,940 administration promoted c-fos expression in areas of the brain thought to play a critical role in behavioural sensitization such as the ventral tegmental area and NAS. This is interesting because it is possible that c-fos is involved in promoting neuroadaptations that underlie drug addiction. To examine this idea, Chapter 5 investigated a behavioural assay of the long-term neural adaptations that may occur with the chronic administration of cannabis, namely, behavioural sensitization. This chapter also examined an animal model of the "gateway hypothesis", that is, the hypothesis that prior exposure to cannabis increases an individuals vulnerability to using other drugs. This animal model is known as cross-sensitization. First it was shown that Lewis, but not Wistar rats, given cocaine (15 mg/kg i.p.) every second day over a two week period displayed a progressively greater locomotor response to the drug over days indicating behavioural sensitization. When CP 55,940 (0, 10, 25 or 50 �g/kg i.p.) was administered under a similar regime, no such sensitization was observed in either strain. Rather, the two highest doses of CP 55,940 (25 and 50 �g/kg) caused locomotor suppression that lasted throughout administration. When Lewis or Wistar rats pre-exposed ten times to CP 55,940 were challenged with cocaine (15 mg/kg), no exaggerated locomotor response to cocaine was evident relative to non pre-exposed rats. When these rats were subsequently re-tested with CP 55,940, it continued to produce a dose-dependent suppression of locomotor activity. Finally, when CP 55,940 (50 �g/kg) was co-administered with cocaine in Lewis rats, it significantly reduced the locomotor hyperactivity produced by the drug but did not block the development of behavioural sensitization to cocaine. These results show that CP 55,940 does not sensitize locomotor activity with repeated administration in the same way as cocaine, and that pre-exposure or concurrent exposure to CP 55,940 does not enhance sensitivity to the subsequent behavioural effects of cocaine. Therefore, unlike Chapters 2, 3 and 4 where strain differences were observed in CP 55,940?induced anxiety, hypothermia, catalepsy, c-fos expression and ataxia, there were no strain differences with respect to behavioural sensitization. Landmark studies by Gardner and colleagues showed that Lewis rats are particularly susceptible, in comparison to other rat strains, to the rewarding effects of delta 9-THC on: 1) medial forebrain bundle (MFB) self-stimulation behaviour and; 2) dopamine (DA) efflux in the NAS. However, in Chapter 4 Lewis rats were less susceptible than Wistar rats to CP 55,940-induced c-fos expression in the NAS. Further, Lewis rats showed no behavioural sensitization to the chronic administration of CP 55,940. In light of these findings, Chapter 6 assessed whether CP 55,940 does have a rewarding effect on MFB self-stimulation behaviour in Lewis rats. Lewis rats were trained to self-stimulate the MFB using a rate?frequency paradigm and then administered CP 55,940 (0, 10, 25 and 50 �g/kg i.p.). CP 55,940 had no effect on MFB self-stimulation behaviour as assessed by the M50, the stimulation frequency at which half-maximal response rates were obtained. This result calls into question previous assertions that Lewis rats are a "cannabis-preferring" strain of rat. Previous studies utilising the cannabinoid CB1 receptor antagonist, SR 141716, have shown that the endogenous cannabinoid system may have some involvement in the rewarding effects of cocaine, morphine, sucrose and alcohol. Thus, Chapter 6 also assessed the effects of SR 141716 (0, 1, 3, 10 and 20 mg/kg i.p.) on MFB stimulation in Lewis rats. The role of DA in MFB stimulation reward has already been established, so for comparison purposes the effects of the DA D1 receptor antagonist SCH 23390 (0.06 mg/kg i.p.) was also assessed. Only a very high dose of SR 141716 (20 mg/kg) caused a significant inhibition of the rewarding efficacy of the stimulation with all other doses (1, 3, and 10 mg/kg) being ineffective in modulating the rewarding impact of brain stimulation. This was seen as an increase in M50. By comparison, a relatively low dose (0.06 mg/kg) of SCH 23390 caused a large increase in M50. These results indicate a relatively modest influence of the endogenous cannabinoid system on reward-relevant neurotransmission in the self-stimulation paradigm. Chapter 7 concludes the thesis and discusses the implications of the results obtained. The main findings of the current thesis are: 1) that the suggested "addiction-prone" Lewis strain of rat is less susceptible to cannabinoid-induced anxiety in comparison to Wistar rats; 2) Lewis rats show less cannabinoid-induced c-fos expression in comparison to Wistar rats (including in brain regions implicated in cannabinoid-induced anxiety and reward); 3) cannabinoid-induced c-fos expression exists in a number of brain regions never previously assessed such as the MPO, ICjM and PPTg; 4) behavioural sensitization does not occur with the repeated administration of CP 55,940; 5) cannabinoid pre-exposure or co-administration does not increase the sensitivity of the locomotor-activating effects of cocaine; 6) the endogenous cannabinoid system, at most, only has a minor influence on the neural substrate of brain stimulation reward and; 7) that there are previously unreported strain differences in cannabinoid-induced hypothermia, catalepsy and ataxia. These results add to our understanding of the effects of the behavioural, emotional and neural effects of cannabinoids and the endogenous cannabinoid system.

The aim of this thesis was to investigate neuronal cellular mechanisms that may underlie the behavioural characteristics of the spontaneously hypertensive rat strain (SHR). The SHR was developed by selective breeding for elevated blood pressure and is also described as having increased levels of locomotor behaviour compared to its normotensive control strain, the Wistar-Kyoto. This hyperactivity and other behaviours, including altered sensitivity to reinforcement, have been used to model aspects of behaviour displayed in attention deficit hyperactivity disorder. In vivo intracellular recording of striatal spiny projection neuron activity in urethaneanaesthetised animals from three genetically related strains: the SHR, Wistar-Kyoto and standard Wistar, was employed to measure basic cellular properties and cellular mechanisms of reward-related learning. This population of neurons was chosen because alterations in their activity can influence behaviour and they are known to show cellular changes (synaptic plasticity) that are associated with learning. Cellular properties were measured in 71 neurons. Comparison between strains revealed a significant difference in action potential amplitude and duration between the SHR and Wistar-Kyoto strains. Interestingly, when measured at a later time, in a different sample of rats, the SUR action potential amplitude and duration were significantly different from the earlier sample. A change in the membrane potential repolarisation rate following action potential firing also occurred over this time. Twenty-nine of these neurons were also used in a study investigating the neuronal responses to a low dose of amphetamine (0.5 mg/kg). Changes were observed in some cellular properties following intraperitoneal administration of amphetamine. Synaptic plasticity at the corticostriatal synapses is sensitive to the timing of dopamine release in relation to cortical input. In anaesthetised preparations the spiny projection neuron membrane potential fluctuates between hyperpolarised (DOWN) and depolarised (UP) states, which reflect the level of cortical input. During the present study the responses of nine neurons to the induction of cortical spreading depression were observed to investigate the suitability of this method for use during synaptic plasticity experiments. Spiny projection neurons showed unpredictable responses to cortical spreading depression, therefore this method was not used further. Corticostriatal synaptic plasticity was induced in sixteen spiny projection neurons from two strains: SHR and Wistar. High frequency stimulation of the dopamine neurons in the substantia nigra, during the DOWN-state, did not induce any significant changes in corticostriatal synaptic efficacy. This was also true when high frequency stimulation of dopamine neurons was applied during the UP-state in neurons from the SHR strain. This thesis represents the first in vivo intracellular study of neuronal physiology in the SHR and Wistar-Kyoto rat strains. Results revealed action potential differences between these two behaviourally distinct rat strains. Synaptic mechanisms thought to underlie reward-related learning were not different between the SHR and Wistar strains, although the observed levels of plasticity were inconsistent with previous literature.

Leptin is primarily an adipose-derived hormone that acts in the hypothalamus to regulate body fat levels by suppressing appetite and increasing metabolic rate. Pregnancy is characterised by increased food intake and fat mass to meet the metabolic demands of this physiological state. Leptin concentrations also increase during pregnancy, but this does not prevent the pregnancy-induced hyperphagia, suggesting a state of leptin resistance. The aims of this thesis were to measure hypothalamic leptin responsiveness during pregnancy and to investigate the potential mechanisms underlying pregnancy-induced leptin resistance. The satiety response to intracerebroventricular (i.c.v) leptin was measured in fasted non-pregnant (diestrous), early pregnant (day 7), and mid-pregnant (day 14) rats. Serial blood samples collected from another group of rats demonstrated that despite initial elevated plasma leptin concentrations in pregnant rats, fasting significantly decreased leptin concentrations so that pregnant and non-pregnant groups had similar, low leptin concentrations. Leptin treatment significantly reduced food intake in non-pregnant and early pregnant rats but not in mid-pregnant rats. In addition, there was no post-fasting hyperphagic response in the pregnant rats. These results indicate that pregnant rats become resistant to the satiety action of leptin. To investigate the mechanisms underlying pregnancy-induced leptin resistance, leptin-induced activation of hypothalamic leptin-target neurons was examined. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was measured in non- pregnant and mid-pregnant rats following i.c.v. administration of leptin. Western blot and immunohistochemistry analysis indicated that leptin-induced STAT3 phosphorylation was significantly reduced in the ventromedial nucleus of the hypothalamus (VMH) during pregnancy. A suppression in the amount of leptin-induced STAT3 activation was observed in the arcuate nucleus during pregnancy, yet there was no overall change in the number of leptin responsive neurons compared to non-pregnant rats. This raises the possibility of a decrease in the degree of responsiveness of arcuate nucleus neurons to leptin during pregnancy. Using double-labelled immuno-histochemistry for alpha-melanocyte stimulating hormone (α-MSH) and leptin-induced pSTAT3 it was demonstrated that pro-opiomelanocortin (POMC) neurons remain responsive to leptin during pregnancy. In the VMH, consistent with the reduced pSTAT3, pregnancy also induced a 2-fold reduction in mRNA for the long form of the leptin receptor (Ob-Rb), the only isoform with full signal transduction capabilities. Expression of mRNA for one of the short forms of the leptin receptor (Ob-Ra) in the choroid plexus was decreased in early and late pregnancy, suggesting that reduced leptin transport into the brain may contribute to pregnancy-induced leptin resistance. CSF/plasma leptin concentration ratios did not differ between pregnant and non-pregnant rats however, suggesting unimpaired leptin transport during pregnancy. These results indicate that pregnancy is a state of hypothalamic leptin resistance and is associated with impaired activation of the leptin-induced JAK/STAT3 signalling pathway in the VMH and arcuate nucleus, and reduced expression of Ob-Rb mRNA in the VMH. This state of leptin resistance represents an important adaptation of the maternal brain allowing increased food intake and fat mass so that the maternal body can meet the metabolic demands of pregnancy and prepare for the subsequent demands of lactation.

Under normal circumstances, prolactin regulates its own release via a short-loop negative feedback mechanism in which prolactin, secreted from lactotrophs situated within the anterior pituitary gland, stimulates dopaminergic neurons in the hypothalamus to release dopamine into portal blood circulation. Dopamine, in turn, inhibits lactotroph activity. A change in this regulation of prolactin secretion is seen during late pregnancy where tuberoinfundibular dopaminergic (TIDA) neurons no longer respond to elevated levels of placental lactogen (PL), a lactogen structurally and functionally similar to prolactin, allowing a prolonged elevation of prolactin secretion and the induction of an antepartum prolactin surge (Andrews et al., 2001). The mechanisms behind this loss of responsiveness have not yet been determined. Prolactin acts by binding to its receptor on TIDA neurons and activating the signal transducer and activator of transcription 5b (STAT5b). During lactation, prolactin-induced activation of STAT5b is suppressed. This reduction in STAT5b signalling is consistent with a loss in TIDA responsiveness and is correlated with an increase in suppressor of cytokine signalling (SOCS) messenger ribonucleic acid (mRNA) expression within the arcuate nucleus. As SOCS proteins are known to disrupt prolactin signalling by interfering with STAT signalling in other systems, it is likely that the change in TIDA responsiveness to prolactin or PL during late pregnancy occurs at least partially in response to an increase in SOCS proteins at this time. Although prolactin can induce SOCS mRNA expression within the arcuate nucleus, the level of SOCS mRNA expression observed on day 20 of pregnancy is significantly lower to that observed on day 22. As PL is elevated on day 20 of pregnancy, some other factor or a combination of factors unique to the final 2 days of pregnancy induces the change in prolactin signalling. Late pregnancy is associated with elevated levels of estrogen while progesterone significantly declines. The aim of this study was to test the hypothesis that a fall in progesterone in the presence of elevated levels of estrogen during late pregnancy induces the increase in SOCS levels within TIDA neurons. This then results in a disruption of prolactin signalling, a decline in dopamine production and release, and the induction of the antepartum prolactin surge. To determine if ovarian steroid hormones can act directly on TIDA neurons during late pregnancy, expression of progesterone receptors (PR) and estrogen receptors (ER) within TIDA neurons were examined during pregnancy and lactation. Using double-labelled immunohistochemistry, expression of both steroid receptors within arcuate dopaminergic neurons during pregnancy and lactation was confirmed. This is consistent with the hypothesis that changing levels of steroid hormones might directly regulate TIDA activity. Furthermore, as the level of steroid receptor expression within TIDA neurons did not change significantly during pregnancy and lactation, it is likely that changing levels of serum estrogen and progesterone may affect these neurons at this time. To investigate the potential effects of steroid hormones on prolactin-induced and non prolactin-induced expression of SOCS mRNA, ovariectomised rats were treated with bromocriptine to suppress endogenous prolactin, and were then treated with a regime of chronic progesterone and/or estrogen in the presence and absence of an induced prolactin surge. SOCS mRNA expression within the arcuate nucleus was measured using real time quantitative RT-PCR. It was found that both estrogen and prolactin independently induced SOCS mRNA expression within the arcuate nucleus, but high levels of progesterone inhibited this effect. This supported the hypothesis that a change in SOCS mRNA expression within TIDA neurons might occur following the changes in steroid hormone levels observed during late pregnancy. To specifically investigate the role of estrogen and progesterone in regulating SOCS expression during late pregnancy, an animal model was designed to experimentally alter estrogen and progesterone levels during late pregnancy, and then SOCS mRNA expression was examined. In this model, advancing the late pregnant decline in progesterone resulted in a significant advance in the timing of the antepartum prolactin surge and parturition, while delaying the decline in progesterone abolished the antepartum prolactin surge and delayed parturition. Furthermore, within this model, elevated levels of SOCS mRNA expression were always observed following the withdrawal of progesterone. This suggested that following the decline in progesterone during late pregnancy, elevated levels of estrogen (or PL) are able to induce SOCS mRNA expression within the arcuate nucleus. Given that SOCS proteins disrupt cytokine signalling in other systems, the induction of SOCS proteins during late pregnancy would then presumably mediate the change in TIDA responsiveness to prolactin. To determine whether it was possible to change prolactin responses without affecting parturition, it was hoped to specifically alter progesterone and estrogen signalling in the brain. This was done by centrally administering progesterone to maintain progesterone levels during late pregnancy, and the ER antagonist ICI-182,780 (ICI) to block central estrogen levels. To determine the effectiveness of intracerebroventricular (icv) administration of ICI, two central estrogen mediated endpoints were evaluated: estrogen negative feedback on gonadotrophin releasing hormone (GnRH) pulse frequency (as measured by the frequency luteinizing hormone (LH) pulses) and the induction of PR within hypothalamic nuclei. Also, to confirm that central administration of ICI did not have a peripheral effect, estrogen induced uterine proliferation was measured. Although central ICI administration at the maximum possible dose affected estrogen-induced GnRH pulse frequency and partially reduced estrogen-induced PR expression within arcuate dopaminergic neurons, ICI did not affect the antepartum prolactin surge. Furthermore, cental administration of progesterone did not abolish the antepartum prolactin surge. This suggested that central administration of ICI and progesterone as a tool for researching central actions of ovarian steroids is likely to be limited to certain central endpoints, and was not suitable as a model to study central steroid effects on prolactin regulation. Overall, the progression of the findings in this study led to the formulation of a key hypothesis: that during late pregnancy, elevated levels of estrogen and the withdrawal of progesterone allows for the prolactin-induced increase of SOCS proteins within TIDA neurons. Elevated levels of SOCS proteins may then disrupt normal prolactin signalling, mediated via the JAK/STAT pathway. This results in reduced dopamine synthesis and release and, the subsequent induction of the antepartum prolactin surge.

Includes summary / Includes bibliography / [586] leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Dept. of Anatomy and Histology, 1988

Three leaves of erratum inserted inside front cover. / Bibliography: leaves 178-210. / x, 210 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The mature oophorectomised rat is a well-recognised model of post menopausal bone loss, and has been used in this thesis to study the effects of estradiol on bone cells in vivo. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1995

Thesis (M.D.) -- University of Texas Southwestern Medical Center at Dallas, 2007. / Vita. Bibliography: pp. 42-45.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--School of Pharmacy. University of Missouri--Kansas City, 2006. / "A dissertation in pharmaceutical sciences and pharmacology." Advisor: Srikumaran Melethil. Typescript. Vita. Title from "catalog record" of the print edition Description based on contents viewed Dec. 20, 2007. Includes bibliographical references (leaves 159-192). Online version of the print edition.

The presence of an increased accumulation of intraabdominal fat (IAF) has been linked to dyslipidemia, hyperinsulinemia, and hyperglycemia, which precede the development of type 2 diabetes and coronary artery disease (CAD). It has been shown that IAF begins depostition during childhood. Human studies suggest that regular endurance exercise, that does not necessarily produce an increase in aerobic capacity, can effectively reduce IAF accumulation during these early years. In contrast to human research, studies using animal models of human disease typically employ extremely large volumes of exercise with the intent to maximize aerobic capacity. The present study examined whether half the amount of endurance training, that was previously reported to induce cardiac hypertrophy and approximately double the aerobic capacity of skeletal muscle in rats, would reduce the growth-related accumulation of IAF in growing female rats. Twenty-two 4-week-old female Sprague-Dawley rats were randomly assigned to a running experimental or a non-running control group. The runners exercised on a treadmill 5 days/week for 60 min/day at a speed of 27m/min and up a 15% grade for 10 weeks. After 10 weeks, the parametrial, omental and mesenteric IAF depots and the heart were excised and weighed. Compared with non-runners, the runners had a significantly lower mean parametrial fat mass (2.22 g vs. 3.13 g, p=0.05) and a higher mean heart weight (0.97 g vs. 0.90 g, p=0.05) at the end of 10 weeks. In addition, the lower mean parametrial fat mass in the runners vs. the non-runners (2.19 g vs. 3.19 g, p=0.02) remained significant even after adjusting for the greater heart weights of the runners. One-half the amount of exercise, that was previously reported to induce cardiac hypertrophy and approximately double the aerobic capacity of skeletal muscle in rats, yielded an 8% greater heart weight and a 29% lower parametrial IAF mass, on average, in growing female rats. In addition, the effects of treadmill running on reducing parametrial fat accumulation were independent of the effects of running on increasing heart weight. Thus, future studies examining the effects of exercise on IAF and other health-related metabolic outcomes in rats may consider using lower-dose endurance training protocols that are not designed to maximize improvements in aerobic capacity. / Graduation date: 2002