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Biomedical subjects

D Sugden

Publications and source records attributed to D Sugden.

103 records · Page 6Linked to original sources
PubMed1983

Psychopharmacological effects of melatonin in mouse and rat.

Some of the psychopharmacological characteristics of melatonin have been defined using a number of established tests of sedative/hypnotic, anticonvulsant and analgesic activity in mice and rats. The effect of melatonin in these tests has been compared to its neurotoxicity and acute toxicity. In the mouse, a low dose of melatonin (20 mg/kg i.p.) potentiated pentobarbitone- and barbitone-induced sleep. Melatonin also potentiated pentobarbitone-induced sleep in the rat. Higher doses (greater than or equal to 200 mg/kg i.p.) antagonized pentylenetetrazole, 3-mercaptopropionic acid and electroshock-induced convulsions in mice and had analgesic activity in both hot-plate and writhing tests. The presence of motor incoordination, indicated by the rotorod test, after administration of these large doses (greater than or equal to 200 mg/kg i.p.) suggests that the anticonvulsant and analgesic activities of melatonin may not represent specific neuropharmacological actions. LD50 values for melatonin in the mouse and rat were determined for different routes of administration. A sedative dose of melatonin (20 mg/kg i.p.) did not alter whole brain 5-hydroxytryptamine or 5-hydroxyindole acetic acid concentrations, suggesting that the hypothesis that the sedative action of melatonin is due to an interaction with serotoninergic neurons may need to be re-examined.

Analgesics↗
PubMed1982

Effects of melatonin on sleep and neurochemistry in the rat.

1 The effects of intraperitoneally administered melatonin on sleep and brain neurochemistry in the rat were studied by use of EEG recording and standard fluorescence techniques. 2 Melatonin, 10 mg/kg, reduced time to sleep onset and time spent awake but increased both slow wave and paradoxical sleep. Qualitatively similar but smaller effects were produced by a dose of 2.5 mg/kg. 3 Neither dose of melatonin altered normal EEG patterns or disrupted normal sleep behaviour. 4 Melatonin, 20 mg/Kg, did not significantly alter concentrations of tryptophan, 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, noradrenaline or dopamine in any part of the brain. 5 it is concluded that the sleep promoting activity of melatonin cannot be related to gross changes in brain indoleamine and catecholamine levels.

Animals↗
PubMed1981

Changes in the rat sleep-wake cycle produced by DL-6-fluorotryptophan, a competitive inhibitor of tryptophan hydroxylase.

DL-6-Fluorotryptophan (6-FT), a competitive inhibitor of tryptophan hydroxylase, produced a transient disruption of sleep in rats chronically implanted with EEG recording electrodes. In the 4 h period following the administration of 6-FT (120 mg/kg) awake time was increased, paradoxical sleep time was decreased and slow-wave sleep remained unchanged. These sleep changes were accompanied by significant reductions in brain 5-HT levels. L-Tryptophan (100 mg/kg) co-administration with 6-FT prevented the major sleep changes whereas L-leucine (100 mg/kg) was without effect. The major sleep changes produced by 6-FT were prevented by the pineal indole melatonin (20 mg/kg) but not by L-5-hydroxytryptophan (5 mg/kg). These neurochemical and drug interaction data raise the possibility that 5-hydroxytryptamine is involved in the control of paradoxical rather than slow-wave sleep in the rat.

Amino Acids↗
PubMed1979

Biotransformation and elimination of digoxin with normal and minimal renal function.

Six subjects with normal renal function (NRF) and 6 patients with minimal renal function (MRF) on 3 times weekly hemodialysis received 150 muCi3H-digoxin-12 alpha orally. Serial urine collections were made for five days or more. Digoxin and metabolites were separated using diethylaminoethyl Sephadex LH-20 column chromatography. Mean cumulative percentages of the ingested radioactivity excreted over five days in NRF and MRF groups were: digoin, 54.5% and 14.7%; bis-digitoxoside of digoxigenin, 2.0% and 0.59%; mono-digitoxoside, 0.8% and 0.19%; digoxigenin, 0.25% and 0.03%; and dihydrodigoxin, 0.3% and 0.03%. Half-lives based on the mean rates of disappearance from urine comparing NRF and MRF groups were: for digoxin 40 hr and 120 hr; for bis-digitoxoside, 11.5 hr and 46 hr; for mono-digitoxoside, 8.5 hr and 12 hr; for digoxigenin, 2 hr and 7.5 hr; and for dihydrodigoxin, 1.2 hr and 7.0 hr. Considering the relationships of the five-day cumulative excretion and half-lives of digoxin and metabolites in the NRF and MRF groups, it appears unlikely that there is a major alteration in the biotransformation of digoxin in advanced renal failure when there appears to be a shift from renal to slower biliary excretion.

Adult↗
PubMedDate not supplied

Activation of protein kinase C potentiates isoprenaline-induced cyclic AMP accumulation in rat pinealocytes.

The pineal gland has proven to be an excellent model for the study of adrenergic control systems. Noradrenaline, released from sympathetic nerve terminals in the pineal gland, regulates a large nocturnal increase in melatonin synthesis by stimulating the activity of arylalkylamine N-acetyltransferase (NAT, EC 2.3.1.87) 30-70-fold. An essential step in both the induction and maintenance of high NAT activity is an increase in intracellular cyclic AMP. Noradrenaline acts via beta-adrenoceptors to increase pineal cyclic AMP by activating adenylate cyclase, and the activation of pineal alpha 1-adrenoceptors potentiates beta-adrenergic stimulation not only of NAT but of both cyclic AMP and cyclic GMP. Here we describe investigations designed to test whether alpha 1-adrenergic potentiation of beta-adrenergic stimulation of pineal cyclic AMP involves protein kinase C. Our results suggest that kinase activation is involved and the data provide the first demonstration of a synergistic interaction between Ca2+-phospholipid-dependent protein kinase (protein kinase C) and neurotransmitter-dependent stimulation of cyclic AMP.

Animals↗
PubMedDate not supplied

Design of subtype selective melatonin receptor agonists and antagonists.

Studies of the physiological actions of melatonin have been hindered by the lack of specific, potent and subtype selective agonists and antagonists. In the present study, we describe the utility of a melanophore cell line from Xenopus laevis for exploring structure-activity relationships among novel melatonin analogues and report a novel MT2-selective agonist (IIK7) and MT2-selective receptor antagonist (K185). IIK7 is a potent melatonin receptor agonist in the melanophore model, and in NIH3T3 cells expressing human mt1 and MT2 receptor subtypes. In radioligand binding experiments IIK7 is 90-fold selective for the MT2 subtype. K185 is devoid of agonist activity, but acts as a competitive melatonin antagonist in melanophores. A low concentration (10(-9) M) antagonizes melatonin inhibition of forskolin stimulation of cyclic AMP in NIH3T3 cells expressing human MT2 receptors, but has no effect in cells expressing mt1 receptors. In binding assays, K185 is 140-fold selective for the MT2 subtype.

1-Methyl-3-isobutylxanthine↗