Depletion of norepinephrine

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

Schechter MD, Rosecrans JA (1972) Nicotine as a discriminative cue in rats depleted of norepinephrine or 5-hydroxytryptamine, Psychopharmacologia 24 417 29 Schreiber R, Brocco M, MiUan Ml (1994) Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the atypical antipsychotics, clozapine and risperidone, Eur J Pharmacol 264 99-102... 

Reserpine also interferes with the neuronal storage of a variety of central transmitter amines such that significant depletion of norepinephrine, dopamine, and 5-hydroxytryptamine (serotonin) occurs. This central transmitter depletion is responsible for the sedation and other CNS side effects associated with reserpine therapy. The depletion of brain amines also may contribute to the antihypertensive effects of reserpine. 

Fuld P, Katzman R, Davies P, et al Intrusions as a sign of Alzheimer dementia chemical and pathological verification. Ann Neurol 11 155-159, 1982 Fuller RW, Hemiick-Luecke SK Antagonism by tomoxetine of the depletion of norepinephrine and epinephrine in rat brain by ocmethyl-m-tyrosine. Res Commun Chem Pathol Pharmacol 41 169-172, 1983 Fuster JM The Prefrontal Cortex Anatomy, Physiology and Neuropsychology of the Frontal Lobe. New York, Raven, 1989... 

Reserpine blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines, probably by interfering with an uptake mechanism that depends on Mg2+ and ATP (Figure 6-4, carrier E). This effect occurs throughout the body, resulting in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons. Chromaffin granules of the adrenal... 

Correct answer = D. Reserpine blocks the uptake of norepinephrine into intracellular storage vesicles, resulting in depletion of norepinephrine and gradual decline in blood pressure. Phenylephrine is a pure vasoconstrictor and raises systolic and diastolic blood pressures. Dopamine raises systolic and diastolic blood pressures by stimulating the heart and (at high doses) causing vasoconstriction. Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation. Norepinephrine has a pressor effect. 

KuUcami VA, Jha S, Vaidya VA (2002) Depletion of norepinephrine decreases the proliferation, hut does not influence the survival and differentiation, of granule cell progenitors in the adult rat hippocampus. Eur J Neurosci 16 2008-2012. 

Possibly the best evidence suggesting involvement of norepinephrine and serotonin in major depressive disorder devolved from depletion studies (Delgado et al., 1990). In these stndies, patients who have responded to treatment for depression are given procedures, which deplete brain levels of serotonin or norepinephrine. Serotonin levels are decreased by nse of a low monoamine diet, followed by a drink which inclndes all the amino acids except the serotonin precnrsor tryptophan. Norepinephrine levels are depleted by administration of alpha-methylparatyrosine. In patients who had responded to treatment with a serotonergic antidepressant, depletion of serotonin cansed a prompt and dramatic, but brief reoccurrence of the symptoms of major depression. In patients who had responded to treatment with a noradrenergic antidepressant, depletion of norepinephrine caused a relapse into depression. The converse was not true in other words, serotonin depletion did not canse relapse in patients who responded to noradrenergic antidepressants, and vice versa. 

When animals are exposed to inescapable shock, they exhibit consistent behavioral reactions—initially hypervigilance or arousal and ultimately a profound state of withdrawal and "depression." In addition, such animals eventually show a significant depletion of norepinephrine, likely accompanied by changes in NE receptor sensitivity in parts of the brain. Alterations of receptor sensitivity may leave the animals in a state of chronic hyperarousal. In essence, their nervous systems may be permanently altered such that traumatized animals and people alike are relatively unable to dampen or inhibit excessive emotional arousal. Antidepressants that affect norepinephrine appear to alter receptor sensitivity, both in humans and animals. Serotonergic antidepressants may also indirectly inhibit hypersensitive NE cells (Nagy et al. 1993), and thus can play a role in treating hyperarousal in PTSD patients. 

Disulfiram and Fusaric Acid. Administration of these dopamine-/3-hydroxylase inhibitors produces an increase in REM sleep several hours after the drug administration. This is caused by depletion of norepinephrine brain levels. 

Injection of 5,7-dihydroxytryptamine in the rat induced a reduction of tryptophan hydroxylase in all regions of the brain. It also caused depletion of norepinephrine, but did not deplete dopamine. The pretreatment of laboratory animals with desmethylimipramine (desipramine) blocked the neurotoxic reaction to the norepinephrine reuptake system, but did not protect the serotonergic reuptake system. (Lovenburg 1978). 

Guanethidine (e.g., Esimel) Sequestered into adrenergic nerve endings. Initially releases norepinephrine (increase BP and HR). Then depletes norepinephrine from terminal and interferes with release. Reflex tachycardia is then impossible because of depletion of norepinephrine. Severe hypertension when other agents fail. Rarely used. Initial increase in neart rate and blood pressure (due to release of norepinephrine). Resting and orthostatic hypotension. Bradycardia, decreased cardiac output, dyspnea in COPD patients, severe nasal congestion. No depression (poor CNS penetration)... 

Demethyldtalopram the main metabolite of dtalopram is a four times less potent 5-HT uptake inhibitor in vitro than its parent compound [table 10]. Its potency is similar to that of fluoxetine and femoxetine but its selectivity index is significantly higher 105 versus 55 and 49 respectively [75]. Both dtalopram and its main metaboUte retain their selectivity in in vivo experiments antagonizing the depletion of serotonin induced by H 75/12 (a-Et-30H-4Me-phenethylamine) but not the depletion of norepinephrine induced by H 77/77 (a-Me-30H-4Me-phenethylamine) [31,76,77]. 

In an effort to identify those tetrahydroisoquinolines which will inhibit the action of COMT, but will not act as false neurotransmitters, a series of tetrahydroisoquinolines were evaluated as substrates and inhibitors of this enzyme, and were also tested for their ability to stimulate norepinephrine release from mouse hearts in vivo. Methyl substituents at C-2 and C-4 of 6,7-dihydroxytetrahydroisoquinolines had little effect in regard to COMT, but did eliminate the norepinephrine depleting activity. The interesting exception was 6,7-dihydroxy-2,2-dimethyltetrahydroisoquinolinium iodide which was an active depleter of norepinephrine from mouse hearts. ... 

Guanadrel (u-28288D, VII), equipotent to guanethldlne in the clinic, appears to offer more stable blood pressure control during the day with less frequent diarrhea Studies on guancydine (vill) continued to support the mechanism of a direct vascular effect with partial depletion of norepinephrine stores observed only after high chronic dosing under certain conditions ... 

Their mechanism of lowering tissue levels of norepinephrine is not related to an interference of the uptake, storage or release of catecholamines. The administration of 05-MI results in a depletion of norepinephrine in various tissues of animals and a reduction in the synthesis of catecholamines by 70 percent in man. Although only the 1-isomer of OS-MI is active as a tyrosine hydroxylase inhibitor, the d-form potentiates the action of OS-MT, a phenomenon which has been postulated to occur as a result of an effect on membrane permeability. a-MI has served as a valuable experimental tool wherever the involvement of catecholamines has... 

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