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Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

Norepinephrine (NE) is one of three catecholamine neurotransmitters in the brain and has been studied extensively in relation to the biology of suicide as well as psychiatric disorders that significantly increase the risk of suicide. NE became a candidate for the pathology of depression in the 1950s, but not because of a discovery of altered concentrations of NE in depressed patients or suicide victims. Instead, NE was one of the neurotransmitters along with dopamine and serotonin that was directly affected by newly discovered antidepressant drugs. Since that time, NE has been one of the most studied neurotransmitters with regard to depression biology and suicide, second only to serotonin. However, interest in the role of NE in suicide and depression has dwindled considerably over the past 10 years. In fact, interest in monoamines appears to be waning overall, possibly driven by a push by the National Institutes of Health for paradigm shifts in understanding psychiatric disease biology. The move away from interest in the monoamines is also being driven by high-throughput technologies such as microarrays, which divert investigators from traditional disease candidates to novel proteins and pathways. Despite the current trends, evidence that points to dysfunction in the central noradrenergic system in depression and suicide is very strong and it remains quite possible that deficits in NE signaling may lie at the very root of psychiatric disorders that contribute to suicide. This chapter reviews the neurobiology and functional output of the brain noradrenergic system in relation to the potential involvement of NE in depression and suicide.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2002. / Bibliography: leaves 131-146.

This abstract sent to supervisor 5/4/12 Tyrosine hydroxylase is the enzyme which controls the ratelimiting step in the synthesis of noradrenaline. In order to discover whether the activity of tyrosine hydroxylase might serve as an indicator of noradrenergic function in the brain, two preparations for the direct measurement of TH activity in rat brain regions by a tritium-release method were employed: synaptosomal suspensions prepared from pinchedoff nerve terminals, and partially solubilised enzyme preparations prepared from frozen homogenates or synaptosomal suspensions and assayed at saturating concentrations of cofactor and tyrosine. There was evidence of an increase in tyrosine hydroxylase activity in hippocampal synaptosomes of rats killed immediately after a mild electrical footshock. Activation of synaptosomal enzyme activity was also found after single doses of clonidine and parachloroamphetamine, and after repeated handling; and single doses of morphine and of yohimbine appeared to lower tyrosine hydroxylase activity. Repeated administration of drugs such as clonidine, desipramine and 2-deoxyglucose, however, did not affect tyrosine hydroxylation rate. A preliminary finding , suggesting differences in synaptosomal tyrosine hydroxylase activity related to experience with different reinforcement schedules (continuous reward vs. partial reward) in a runway experiment, was not substantiated in later experiments; nor was there any difference between the synaptosomal tyrosine hydroxylase activity of naive controls and rats given repeated daily shocks for a week. The saturated TH assay performed on solubilised enzyme was, as predicted, unresponsive to the short term stimulation effects detected with the synaptosomal assay. However, other changes, such as a reduced maximal hydroxylation rate after repeated desipramine administration, and an increased rate several weeks after a course of electrical stimulation of the septal area, were established with the saturated assay. Although the changes in stimulated rats were associated with increased behavioural tolerance to stress, e.g. resistance to extinction of a running response in a runway, other experiments in which the behavioural stress-tolerance was induced by behavioural methods alone showed no accompanying changes in TH activity. Measures of synaptosomal and saturated soluble TH activity appear to constitute independent indicators of noradrenergic function. It seems that synaptosomal tyrosine hydroxylase activity is not, as anticipated, controlled by the firing rate of locus coeruleus neurones; but it may be subject to local regulation in noradrenergic terminals. The results are discussed in the context of theoretical aspects of the regulation of noradrenaline synthesis in the brain, and the mechanisms underlying physiological responses to stress and behavioural tolerance to stress.

Norepinephrine (NE) is one of three catecholamine neurotransmitters in the brain and has been studied extensively in relation to the biology of suicide as well as psychiatric disorders that significantly increase the risk of suicide. NE became a candidate for the pathology of depression in the 1950s, but not because of a discovery of altered concentrations of NE in depressed patients or suicide victims. Instead, NE was one of the neurotransmitters along with dopamine and serotonin that was directly affected by newly discovered antidepressant drugs. Since that time, NE has been one of the most studied neurotransmitters with regard to depression biology and suicide, second only to serotonin. However, interest in the role of NE in suicide and depression has dwindled considerably over the past 10 years. In fact, interest in monoamines appears to be waning overall, possibly driven by a push by the National Institutes of Health for paradigm shifts in understanding psychiatric disease biology. The move away from interest in the monoamines is also being driven by high-throughput technologies such as microarrays, which divert investigators from traditional disease candidates to novel proteins and pathways. Despite the current trends, evidence that points to dysfunction in the central noradrenergic system in depression and suicide is very strong and it remains quite possible that deficits in NE signaling may lie at the very root of psychiatric disorders that contribute to suicide. This chapter reviews the neurobiology and functional output of the brain noradrenergic system in relation to the potential involvement of NE in depression and suicide.

To study the influence of the central noradrenergic system on antinociceptive effects mediated by the CB1-receptor agonist methanandamide, intact rats were contrasted with rats in which noradrenergic nerves were largely destroyed shortly after birth with the neurotoxin DSP-4 [N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (50 mg/kg sc × 2, P1 and P3); zimelidine (10 mg/kg sc, 30 min pretreatment, selective serotonin reuptake inhibitor). When rats attained 10 weeks of age, monoamine and their metabolite concentrations were determined in the frontal cortex, thalamus, and spinal cord by an HPLC/ED method. Antinociceptive effects after methanandamide (10 mg/kg ip) apply were evaluated by a battery of tests. In addition, immunohistochemistry and densitometric analysis of the cannabinoid CB1 receptor in the rat brain was performed. DSP-4 lesioning was associated with a reduction in norepinephrine content of the frontal cortex (>90 %) and spinal cord (>80 %) with no changes in the thalamus. Neonatal DSP-4 treatment produced a significant reduction in the antinociceptive effect of methanandamide in the tail-immersion test, hot-plate test and writhing tests. In the paw pressure and formalin hind paw tests results were ambiguous. These findings indicate that the noradrenergic system exerts a prominent influence on analgesia acting via the cannabinoid system in brain, without directly altering CB1 receptor density in the brain.

To study the influence of the central noradrenergic system on antinociceptive effects mediated by the CB1-receptor agonist methanandamide, intact rats were contrasted with rats in which noradrenergic nerves were largely destroyed shortly after birth with the neurotoxin DSP-4 [N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (50 mg/kg sc × 2, P1 and P3); zimelidine (10 mg/kg sc, 30 min pretreatment, selective serotonin reuptake inhibitor). When rats attained 10 weeks of age, monoamine and their metabolite concentrations were determined in the frontal cortex, thalamus, and spinal cord by an HPLC/ED method. Antinociceptive effects after methanandamide (10 mg/kg ip) apply were evaluated by a battery of tests. In addition, immunohistochemistry and densitometric analysis of the cannabinoid CB1 receptor in the rat brain was performed. DSP-4 lesioning was associated with a reduction in norepinephrine content of the frontal cortex (>90 %) and spinal cord (>80 %) with no changes in the thalamus. Neonatal DSP-4 treatment produced a significant reduction in the antinociceptive effect of methanandamide in the tail-immersion test, hot-plate test and writhing tests. In the paw pressure and formalin hind paw tests results were ambiguous. These findings indicate that the noradrenergic system exerts a prominent influence on analgesia acting via the cannabinoid system in brain, without directly altering CB1 receptor density in the brain.

Thesis (Ph. D.)--Ohio State University, 2008.

The norepinephrine transporter (NET) plays a pivotal role in terminating noradrenergic signaling and conserving norepinephrine (NE) through the process of re-uptake. Recent evidence suggests a close association between NE release and regulation of NET function. The present study evaluated the relationship between release and uptake, and the cellular mechanisms that govern these processes. KCl stimulation of PC12 cells robustly increased [ H]NE uptake via the NET and simultaneously increased [ H]NE release. KCl-stimulated increases in uptake and release were dependent on Ca . Treatment of cells with phorbol-12-myristate-13-acetate (PMA) or okadaic acid decreased [ H]NE uptake but did not block KCl-stimulated increases in [ H]NE uptake. In contrast, PMA increased [ H]NE release and augmented KCl-stimulated release, while okadaic acid had no effects on release. Inhibition of Ca -activated signaling cascades with KN93 (a Ca calmodulin-dependent kinase inhibitor), or ML7 and ML9 (myosin light chain kinase inhibitors), reduced [ H]NE uptake and blocked KCl-stimulated increases in uptake. In contrast, KN93, ML7 and ML9 had no effect on KCl-stimulated [ H]NE release. KCl-stimulated increases in [ H]NE uptake were independent of transporter trafficking to the plasma membrane. While increases in both NE release and uptake mediated by KCl stimulation require Ca , different intracellular mechanisms mediate these two events.