Norepinephrine Involvement in the Intermittent Swim Stress-Induced Deficit in Spatial Learning and Memory

Learning and memory impairments are often caused by stress disorders including depression. The present study investigated the involvement of norepinephrine in the swim stress-induced deficits of spatial learning and memory. Exposure to intermittent swim stress (ISS) followed by learning and memory tests in the Morris water maze (MWM) were used to investigate this relationship. The ISS paradigm consists of intermittent exposure to cold water, producing stress responses in rats. Reboxetine, a norepinephrine selective reuptake inhibitor (NSRI), was employed to investigate whether this compound reverses the ISS-induced deficit. In other words, rats exposed to the ISS, were hypothesized to experience impaired learning and subsequent deficits in memory while rats treated with reboxetine that are also exposed to stress will not experience these deficits. In order to provide further evidence that reboxetine reverses the affect of the ISS on spatial learning and memory, a 24-hour post-stress assessment in the MWM in one single massed session of 18 trials (9 blocks of 2 trials each) on the day following the ISS was performed. This provided verification that ISS-induced deficits in spatial learning and memory are sensitive to the effects of reboxetine thereby implicating that norepinephrine is a crucial contributor to this phenomenon. It was hypothesized that if norepinephrine is involved in depressive behaviors caused by stress, then reboxetine will attenuate any deficits produced by the ISS paradigm in the learning and memory trials performed in the MWM

Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy.

BackgroundIron deficiency (ID) results in ventricular hypertrophy, believed to involve sympathetic stimulation. We hypothesized that with ID 1) intravenous norepinephrine would alter heart rate (HR) and contractility, 2) abdominal aorta would be larger and more distensible, and 3) the beta-blocker propanolol would reduce hypertrophy.Methods1) 30 CD rats were fed an ID or replete diet for 1 week or 1 month. Norepinephrine was infused via jugular vein; pressure was monitored at carotid artery. Saline infusions were used as a control. The pressure trace was analyzed for HR, contractility, systolic and diastolic pressures. 2) Abdominal aorta catheters inflated the aorta, while digital microscopic images were recorded at stepwise pressures to measure arterial diameter and distensibility. 3) An additional 10 rats (5 ID, 5 control) were given a daily injection of propanolol or saline. After 1 month, the hearts were excised and weighed.ResultsEnhanced contractility, but not HR, was associated with ID hypertrophic hearts. Systolic and diastolic blood pressures were consistent with an increase in arterial diameter associated with ID. Aortic diameter at 100 mmHg and distensibility were increased with ID. Propanolol was associated with an increase in heart to body mass ratio.ConclusionsID cardiac hypertrophy results in an increased inotropic, but not chronotropic response to the sympathetic neurotransmitter, norepinephrine. Increased aortic diameter is consistent with a flow-dependent vascular remodeling; increased distensibility may reflect decreased vascular collagen content. The failure of propanolol to prevent hypertrophy suggests that ID hypertrophy is not mediated via beta-adrenergic neurotransmission

The Postural Tachycardia Syndrome (POTS): Pathophysiology, Diagnosis & Management

Postural tachycardia syndrome (POTS), characterized by orthostatic tachycardia in the absence of orthostatic hypotension, has been the focus of increasing clinical interest over the last 15 years 1. Patients with POTS complain of symptoms of tachycardia, exercise intolerance, lightheadedness, extreme fatigue, headache and mental clouding. Patients with POTS demonstrate a heart rate increase of ≥30 bpm with prolonged standing (5-30 minutes), often have high levels of upright plasma norepinephrine (reflecting sympathetic nervous system activation), and many patients have a low blood volume. POTS can be associated with a high degree of functional disability. Therapies aimed at correcting the hypovolemia and the autonomic imbalance may help relieve the severity of the symptoms. This review outlines the present understanding of the pathophysiology, diagnosis, and management of POTS

Organic Cation Transporter 3: A Cellular Mechanism Underlying Rapid, Non-Genomic Glucocorticoid Regulation of Monoaminergic Neurotransmission, Physiology, and Behavior

Corticosteroid hormones act at intracellular glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) to alter gene expression, leading to diverse physiological and behavioral responses. In addition to these classical genomic effects, corticosteroid hormones also exert rapid actions on physiology and behavior through a variety of non-genomic mechanisms, some of which involve GR or MR, and others of which are independent of these receptors. One such GR-independent mechanism involves corticosteroid-induced inhibition of monoamine transport mediated by “uptake2” transporters, including organic cation transporter 3 (OCT3), a low-affinity, high-capacity transporter for norepinephrine, epinephrine, dopamine, serotonin and histamine. Corticosterone directly and acutely inhibits OCT3-mediated transport. This review describes the studies that initially characterized uptake2 processes in peripheral tissues, and outlines studies that demonstrated OCT3 expression and corticosterone-sensitive monoamine transport in the brain. Evidence is presented supporting the hypothesis that corticosterone can exert rapid, GR-independent actions on neuronal physiology and behavior by inhibiting OCT3-mediated monoamine clearance. Implications of this mechanism for glucocorticoid-monoamine interactions in the context-dependent regulation of behavior are discussed

Chromosome movement in lysed mitotic cells is inhibited by vanadate.

Mitotic PtK1 cells, lysed at anaphase into a carbowax 20 M Brij 58 solution, continue to move chromosomes toward the spindle poles and to move the spindle poles apart at 50% in vivo rates for 10 min. Chromosome movements can be blocked by adding metabolic inhibitors to the lysis medium and inhibition of movement can be reversed by adding ATP to the medium. Vanadate at micromolar levels reversibly inhibits dynein ATPase activity and movement of demembranated flagella and cilia. It does not affect glycerinated myofibril contraction or myosin ATPase activty at less than millimolar concentrations. Vanadate at 10--100 micron reversibly inhibits anaphase movement of chromosomes and spindle elongation. After lysis in vanadate, spindles lose their fusiform appearance and become more barrel shaped. In vitro microtubule polymerization is insensitive to vanadate

Blockade of alpha 2-adrenergic receptors in prelimbic cortex: impact on cocaine self-administration in adult spontaneously hypertensive rats following adolescent atomoxetine treatment

RATIONALE: Research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder demonstrated that chronic methylphenidate treatment during adolescence increased cocaine self-administration established during adulthood under a progressive ratio (PR) schedule. Compared to vehicle, chronic atomoxetine treatment during adolescence failed to increase cocaine self-administration under a PR schedule in adult SHR. OBJECTIVES: We determined if enhanced noradrenergic transmission at α2-adrenergic receptors within prefrontal cortex contributes to this neutral effect of adolescent atomoxetine treatment in adult SHR. METHODS: Following treatment from postnatal days 28–55 with atomoxetine (0.3 mg/kg) or vehicle, adult male SHR and control rats from Wistar-Kyoto (WKY) and Wistar (WIS) strains were trained to self-administer 0.3 mg/kg cocaine. Self-administration performance was evaluated under a PR schedule of cocaine delivery following infusion of the α2-adrenergic receptor antagonist idazoxan (0 and 10–56 μg/side) directly into prelimbic cortex. RESULTS: Adult SHR attained higher PR break points and had greater numbers of active lever responses and infusions than WKY and WIS. Idazoxan dose-dependently increased PR break points and active lever responses in SHR following adolescent atomoxetine vs. vehicle treatment. Behavioral changes were negligible after idazoxan pretreatment in SHR following adolescent vehicle or in WKY and WIS following adolescent atomoxetine or vehicle. CONCLUSIONS: α2-Adrenergic receptor blockade in prelimbic cortex of SHR masked the expected neutral effect of adolescent atomoxetine on adult cocaine self-administration behavior. Moreover, greater efficacy of acute idazoxan challenge in adult SHR after adolescent atomoxetine relative to vehicle is consistent with the idea that chronic atomoxetine may downregulate presynaptic α2A-adrenergic autoreceptors in SHR.National Institutes of Health grant DA011716. (DA011716 - National Institutes of Health)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693724/Published versio

Iodine-123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography

Preliminary investigation of the radioiodinated (S,S)-reboxetine analogue, 123I-INER, in baboons showed this tracer to have promise for imaging the noradrenaline transporter (NAT) using single photon emission computed tomography (SPECT). More recently, the radioiodinated (R,S)-stereoisomer of 123I-INER, 123I-NKJ64, has been synthesized and preliminary evaluation in rats has been reported. This article reports the brain distribution and pharmacokinetic properties of 123I-NKJ64 in baboons and compares results with 123I-INER data in the same species. SPECT studies were conducted in two ovariectomized adult female baboons using two different protocols: (1) bolus of 123I-INER or 123I-NKJ64; and (2) bolus plus constant infusion of 123I-NKJ64 with reboxetine (2.0 mg/kg) administration at equilibrium. Following bolus injection, both radiotracers rapidly and avidly entered the baboon brain. The regional brain accumulation of 123I-NKJ64 did not match the known distribution of NAT in baboon brain, contrasting with previous results obtained in rats. Conversely, the regional distribution of 123I-INER was consistent with known distribution of NAT in baboon brain. No displacement of 123I-NKJ64 was observed following administration of reboxetine. This contrasts with previous data obtained for 123I-INER, where 60% of specific binding was displaced by a lower dose of reboxetine. These data suggest that 123I-NKJ64 may lack affinity and selectivity for NAT in baboon brain and 123I-INER is the most promising iodinated reboxetine analogue developed to date for in vivo imaging of NAT in brain using SPECT. This study highlights the importance of species differences during radiotracer development and the stereochemical configuration of analogues of reboxetine in vivo. Synapse, 2012. -® 2012 Wiley Periodicals, In

The Effect of Vincristine Sulphate on the Axoplasmic Flow of Proteins in Cultured Sympathetic Neurons

The effect of vincristine sulphate on the axoplasmic flow of labelled proteins in neurites of chick embryo sympathetic neurons growing in tissue culture was studied by autoradiography. In control neurons most of the 3H-proteins synthesized during a 90-min pulse with a 3H-amino acid were localized in cell bodies. There was a diminishing gradient of labelled proteins in the neurites which was highest in portions adjacent to the cell bodies and lowest at the periphery. During a physiological chase there was a gradual increase in the amount of label in the neurites, so that after a 15-h chase even the most peripheral portions were well labelled. This indicates that a portion of the labelled proteins synthesized in the cell bodies are transported peripherally into the neurites. The centrifugal movement of labelled proteins in neurites was markedly decreased when cells were grown in medium containing 10 µg/ml vincristine sulphate. After a 15-h chase in the presence of drug only a small amount of label was in the peripheral portion of the neurites. Treatment with vincristine did not decrease the rate of amino acid incorporation or alter the rate of protein turnover during the course of the experiment. Thus an explanation of the results based on an altered rate of total cell protein synthesis or degradation is unlikely. The capacity of sympathetic neurons to take up and concentrate exogenous [3H]norepinephrine in their neurites was only slightly reduced by vincristine. This indicates that at least some cellular activities requiring metabolic energy are relatively unaffected by the interruption in axoplasmic flow caused by vincristine and that the mechanism by which vincristine interferes with axoplasmic flow does not involve general cellular toxicity. The major morphological differences between control and vincristine-treated neurons were the absence of microtubules and the presence of crystal-like structures within the cells. The relationship between the effect of vincristine on the axoplasmic flow of proteins and the arrangement of the microtubule system is discussed