Noradrenaline turnover

Noradrenalin turnover is decreased with antidepressant treatment. This is a compensatory effect of elevated intra-synaptic noradrenalin causing feedback inhibition of tyrosine hydroxylase. This effect has been consistently observed with noradrenergic-specific antidepressants, as expected, but has also been reported with serotonergic-specific... 

Engberg, G., and Eriksson, E. (1991) Effects of a-2-adrenoceptor agonists on locus coeruleus firing rate and brain noradrenaline turnover in EEDQ-treated rats. Naunyn Schmiedebergs Arch Pharmacol 343 472-477. 

Narita, M., Suzuki, T., Misawa, M., Nagase, H., Nabeshima, A., Ashizawa, T., Ozawa, H., Saito, T., Takahata, N. Role of central ATP-sensitive potassium channels in the analgesic effect and spinal noradrenaline turnover-enhancing effect of intracerebroventricularly injected morphine in mice, Brain Research 1992, 596, 209-214. 

Catecholamine turnover rates were reported to be unchanged except in one study where whole brain noradrenaline turnover was found to be increased (Goiter and Michaelson, 1975). It should be noted that turnover studies utilize the inhibition of an enzyme of transmitter synthesis (usually tyrosine hydroxylase) and measurement of accumulation of catecholaminergic intermediates. If lead were to cause an alteration at the level of the synthesizing enzymes then these methods would be unlikely to detect any lead effect. 

The anticonvulsant properties of the drug would appear to be due to its ability to inhibit fast sodium channels, which may be unrelated to its psychotropic effects. Like lithium, it has been shown to decrease the release of noradrenaline and reduce noradrenaline-induced adenylate cyclase activity unlike lithium, it seems to have little effect on tryptophan or 5-HT levels in patients at therapeutically relevant concentrations. It also reduces dopamine turnover in manic patients and increases acetylcholine... 

Male New Zealand White rabbits (2200 g) were exposed to 750 ppm [3.25 g/m ] ethylbenzene for 12 h per day for seven days. Twelve or 24 h following the final day of exposure, the rabbits were killed and their brains dissected. Ethylbenzene depleted both striatal and tubero-infundibular dopamine levels (Mutti et al, 1988). In male Sprague-Dawley rats exposed to 2000 ppm [8.70 g/m ] ethylbenzene for 6 h per day for three consecutive days and killed 16-18 h following the last exposure, ethylbenzene increased dopamine and noradrenaline levels and turnover in the hypothalamus and the median eminence. Ethylbenzene exposure also reduced the secretion of prolactin and increased dopamine turnover within the dopamine-cholecystokinin-8 immunoreactive nerve terminals of the nucleus accumbens (Andersson et al, 1981). 

Histamine H3-receptors have been reported to regulate not only the release and turnover of histamine via autoreceptors on histaminerglc nerve endings [1-3], but also the releases of noradrenaline, dopamine, serotonin, and acetylcholine via heteroreceptors on non-histaminerglc axon terminals [22-26], Thioperamide increased the release of these neurotransmitters, while... 

In relation to the monoaminergic systems we observed that clobenpropit increased turnover rate of noradrenaline only in some brain regions (17), although histamine H3 heteroreceptors modulate the releases of noradrenaline, dopamine, and serotonin [23-26]. Thus, it appears that the contribution of histamine H3 hetero receptors on the modulation of monoaminergic neurotransmitters may be minor, just being similar to the cholinergic system. 

There are indications that early exposure to lead decreases acetylcholine release and turnover (ref. 101). In addition, neonatal administration of lead has been shown to increase the number of GABAergic receptors at the age of 60-70 days (ref. 14). Effects of early lead exposure on dopamine and noradrenaline levels may also exist (ref. 102). 

Andersson K, Fuxe K, Eneroth P, Isaksson O, Nyberg F, Roos P (1983) Rat growth hormone and hypothalamic catecholamine nerve terminal systems. Evidence for rapid and discrete reductions in dopamine and noradrenaline levels and turnover in the median eminence of the hypophysectomized male rat. Eur J Pharmacol 95 271-275. 

Catecholamines. The quantitative determination of dopamine and noradrenaline in tissue samples of 0.1-10 mg at levels in the order of 0.5 pmol has been described [84]. These methods are based on extraction, formation of the pentafluorpropionyl derivatives, and the use of the homologues, a-methyidopamine and a-methylnoradrenaline as internal standards in SIM. Higher sensitivity than obtainable with fluorimetric or enzymic assays is reported [462J. Applications have been to amine determination in specific regions of rat brain [84] and to measurement of heart ventricle concentrations [463]. A combination of assays of this type with the use of synthesis inhibitors or radioisotope labelled precursors allows direct estimation of brain amine turnover in animals. 

Evidence accumulated in 1978 for a catecholamine receptor supersensitivity theory of depression. 8 The therapeutic action of antidepressants may be due to delayed post-synaptic changes in receptor sensitivity, rather than to acute events like uptake. Various drugs, including TCA, mianserin, viloxazine and iprindol, as well as electroconvulsive therapy (ECT), but not selective 5-HT uptake inhibitors, caused central alpha-adrenoceptor subsensitivity in rats as measured by noradrenaline (NA)-associated adenylate cyclase or by receptor binding. In vivo, the effects were associated with chronic but not acute treatment, paralleling the clinical effects. MAOI may cause similar effects on chronic but not acute treatment. , 24-27 Brain NA turnover in rats was decreased by chronic desipramine and other TCA, but unaffected by iprindol and increased by mianserin.3,28... 

It has been known for some time that TH protein expression is oxygen sensitive and shows a graded response to the duration of hypoxic exposure in the rat medulla. A short 3-day exposure resulted in a 26— 50% increase in TH depending on the subpopulation of medullary nuclei examined. In contrast, 14 days of hypoxic exposure resulted in 31-41% increases in TH, after which the level of TH returned to baseline (Schmitt et ak, 1993). While oxygen sensors in the medulla appear to regulate the level of TH without input from the carotid body, the hypoxia-induced increase in turnover rate of noradrenaline (NE) requires input from the carotid body (Soulier et ak, 1992). 

Mianserin and maprotiline are tetracyclic antidepressants, which have actions similar to those of the tricyclie antidepressants. However, while the tetracyclics are more sedating, their antimusearinic effects are less marked. Maprotiline inhibits the leuptake of noradrenaline (norepinephrine) and has weak affinity for eentral adrenergic (aj) receptors. Mianserin does not prevent the peripheral reuptake of noradrenaline it blocks presynaptic adrenergic (a2) receptors and increases the turnover of hrain noradrenaline. It is also an antagonist of serotonin receptors in some parts of the brain. 

Investigations along these lines are then confronted with another problem, namely that the relative activity, in comparison with a standard compound such as imipramine (1), may differ essentially in the various animal models aimed at detecting one and the same property, such as noradrenaline re-uptake. Additional pharmacological properties of the studied compound may affect the various test models in different manners. Also basic properties of the test systems, e.g. the turnover rate of the biogenic amine involved in various strains of animals, may determine the results critically. These latter circumstances may be the cause of different results being obtained in different laboratories. For that reason, a short critical appraisal of the most commonly used methods seems appropriate. 

Bennett, G. W., Marsden, C. A., Sharp, T., and Stolz, J. F., 1981a, Concomitant determination of endogenous release of dopamine, noradrenaline, 5-hydroxytryptamine, and thyrotrophin-releasing hormone (TRH) from rat brain slices and synaptosomes, in Central Neurotransmitter Turnover (C. J. Pycock and P. V. Taberner, eds.), pp. 183-189, Croom-Helm, London. 

Another aspect of catecholaminergic turnover that has been studied is the measurement of the metabolites of dopamine (homovanillic acid, HVA) and noradrenaline (vanillylmandelic acid, VMA). Silbergeld and Chisholm (1976) reported that HVA was increased by 33% in brain and 265% in urine, and VMA was increased by 48% in brain and 216% in urine in mice given 5g Pb/1 (2625 ppm Pb) from birth. It is likely that increased urinary... 

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