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The effect of chronic antidepressant administration on β-adrenoceptor function of the rat pineal
British Journal of Pharmacology, 1983
The 1-adrenoceptor agonist, isoprenaline (1.5-3.0 mg kg-intravenously), produced a doserelated increase in rat pineal melatonin content. This increase was prevented by pretreatment with the selective PI-adrenoceptor antagonist, atenolol (2mgkg 1), but not by the P2-adrenoceptor antagonist, butoxamine (2 mg kg-1). The P2-adrenoceptor agonist, terbutaline (5.0mg kg-1), produced a moderate increase in pineal melatonin content. 2 Repeated daily administration of desmethylimipramine (10mg kgfor 10 days) and maprotiline (10mg kgfor 10 days), antidepressants predominantly inhibiting noradrenaline (NA) uptake, reduced the isoprenaline-induced increase in pineal melatonin content. Amitriptyline (20 mg kg-I for 14 days), a drug which inhibits both NA and 5-hydroxytryptamine (5-HT) uptake, had a similar effect. The P-adrenoceptor agonist, clenbuterol (5 mg kgfor 14 days), also attenuated the increase in pineal melatonin produced by isoprenaline. 3 In contrast, chronic administration of the selective 5-HT uptake inhibitor, fluoxetine (10mg kgfor 10 days), or the antidepressants, iprindole and mianserin (both 20mg kg1 for 14 days), which do not inhibit monoamine uptake, failed to reduce the increase in pineal melatonin following isoprenaline. Repeated electroconvulsive shock was similarly without effect. 4 Ten hours after the final dose of desmethylimipramine (10mg kg-1) once daily for 10 days there was no change in the usual dark phase increase in pineal melatonin. 5 The data suggest that repeated administration of certain antidepressant drugs results in reduced pineal P-adrenoceptor sensitivity. However the lack of change in the dark phase increase in pineal melatonin following repeated desmethylimipramine, implies that the reduced B-adrenoceptor sensitivity may be part of an adaptive process which maintains normal pineal function. Therefore the decrease in 1-adrenoceptor number in the brain reported after chronic antidepressant administration may not be associated with a change in overall synaptic function. the pineal P-adrenoceptors have characteristics of the Pl-subtype (Zatz, Kebabian, Romero, Lefkowitz & Axelrod, 1976; Backstrom, 1977) and in addition that the administration of desmethylimipramine (DM1) produces similar effects on pineal P
Melatonin and Depression: A Translational Perspective From Animal Models to Clinical Studies
Frontiers in Psychiatry, 2021
Daily rhythm of melatonin synchronizes the body to the light/dark environmental cycle. Several hypotheses have been raised to understand the intersections between melatonin and depression, in which changes in rest-activity and sleep patterns are prominent. This review describes key experimental and clinical evidence that link melatonin with the etiopathology and symptomatology of depressive states, its role in the follow up of therapeutic response to antidepressants, as well as the clinical evidence of melatonin as MDD treatment. Melatonin, as an internal temporal cue contributing to circadian organization and best studied in the context of circadian misalignment, is also implicated in neuroplasticity. The monoaminergic systems that underly MDD and melatonin production overlap. In addition, the urinary metabolite 6-sulfatoxymelatonin (aMT6) has been proposed as biomarker for antidepressant responders, by revealing whether the blockage of noradrenaline uptake has taken place within 24 h from the first antidepressant dose. Even though animal models show benefits from melatonin supplementation on depressive-like behavior, clinical evidence is inconsistent vis-à-vis prophylactic or therapeutic benefits of melatonin or melatonin agonists in depression. We argue that the study of melatonin in MDD or other psychiatric disorders must take into account the specificities of melatonin as an integrating molecule, inextricably linked to entrainment, metabolism, immunity, neurotransmission, and cell homeostasis.
Noradrenergic Function and Clinical Outcome in Antidepressant Pharmacotherapy
Neuropsychopharmacology, 2001
Controversy remains regarding the role of noradrenergic systems in determining clinical response to antidepressant pharmacotherapy. Pineal gland production of melatonin can serve as a physiologic index of noradrenergic function. The aim of this study was to examine the effects of antidepressant treatment on 24-hour urinary excretion of the principle metabolite of melatonin, 6-sulfatoxymelatonin in treatment responders and nonresponders. Twenty-four outpatients meeting DSM-III-R criteria for Major Depression received treatment with either fluvoxamine or imipramine for 6 weeks while participating in a placebocontrolled double-blind clinical trial. Twenty-four hour excretion of 6-sulfatoxymelatonin was measured at baseline and at the conclusion of the treatment trial. Changes in urinary excretion of 6-sulfatoxymelatonin distinguished antidepressant responders from nonresponders, with a significant increase observed in the former group and a significant decrease in the latter. The degree of clinical response was correlated with the change in 6-sulfatoxymelatonin excretion. These results suggest that enhanced noradrenergic function may play an important role in determining clinical response to antidepressant pharmacotherapy.
Nocturnal urinary excretion of 6-hydroxymelatonin sulfate in prepubertal major depressive disorder
Biological Psychiatry, 1992
Levels of the melatonin metabolite, 6-hydroxymelatonin sulfate, were measured in overnight urine from 31 prepubertai children with major depressive disorder and 15 normal control children with very. low family loading for affective disorder. The two groups did not differ with regard to their nocturnal excretion of this compound, nor was any depressive subgroup identified whose 6-hydroxymelatonin sulfate excretion differed from that of the control group. Previous studies of pineal function in depression are reviewed and discussed in the context of the present investigation.
European Journal of Pharmacology, 2010
Melatonin was previously shown to produce an antidepressant-like effect in the tail suspension test. In this work the mechanisms underlying its antidepressant-like effect were further studied by investigating the involvement of the dopaminergic system in its antidepressant-like effect in the tail suspension test. The effect of melatonin (1 mg/kg, i.p.) was prevented by the pretreatment of mice with haloperidol (0.2 mg/kg, i. p., a nonselective dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a selective dopamine D1 receptor antagonist), and sulpiride (50 mg/kg, i.p., a selective dopamine D2 receptor antagonist). The i.p. administration of melatonin (0.01 mg/kg) or fluoxetine (1 mg/kg, a serotonin reuptake inhibitor) in combination with SFK38393 (0.1 mg/kg, s.c., a dopamine D1 receptor agonist) reduced the immobility time in the tail suspension test as compared with either drug alone. Moreover, the pretreatment with melatonin (0.01 mg/kg, i.p.) produced a synergistic effect with apomorphine (0.5 μg/kg, i.p., a dopamine D2 receptor agonist), but the pretreatment with fluoxetine (1 mg/kg, i.p.) was ineffective to potentiate the effect of apomorphine. Dopamine receptor antagonists or agonists alone or in combination with melatonin did not affect locomotor activity. These results indicate that the antidepressant-like effect of melatonin in the tail suspension test is likely mediated by an interaction with the dopaminergic system, through an activation of dopamine D1 and D2 receptors. Our data confirm the previous notion on the role exerted by melatonin in depression, suggesting that it might be further investigated as an alternative for the management of depression associated with anhedonia.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2018
We studied the effects of the multi-modal antidepressant, vortioxetine and the SSRI, paroxetine on pineal melatonin and monoamine synthesis in a sub-chronic tryptophan (TRP) depletion model of depression based on a low TRP diet. Female Sprague-Dawley rats were randomised to groups a) control, b) low TRP diet, c) low TRP diet + paroxetine and d) low TRP diet + vortioxetine. Vortioxetine was administered via the diet (0.76 mg/kg of food weight) and paroxetine via drinking water (10 mg/kg/day) for 14 days. Both drugs resulted in SERT occupancies > 90%. Vortioxetine significantly reversed TRP depletion-induced reductions of pineal melatonin and serotonin (5-HT) and significantly increased pineal noradrenaline NA. Paroxetine did none of these things. Other studies suggest pineal melatonin synthesis may involve N-methyl-D-aspartate (NMDA) receptors and glutamatergic modulation. Here observed changes may be mediated via vortioxetine's strong 5-HT reuptake blocking action together with possible additional effects on glutamate neurotransmission in the pineal via NMDA receptor-modulation and possibly with added impetus from increased NA output.
Melatonin and Monoaminergic System – Behavioural Aspects
Romanian Journal of Neurology, 2016
Melatonin, the hormone synthesized mainly by the pineal gland, is a key member of the complex monoaminergic signaling system, and a circadian regulator with pleiotropic functions. This ubiquitary lipophilic and hydrophilic molecule acts both at cellular and subcellular level, exerting anti-inflammatory, anti-oxidative and anti-apoptotic activities, extremely important in the nervous system, given its high vulnerability to oxidative injury. Melatonin deprivation and the consecutive chronodisruption are associated with multiple behavioural abnormalities, psychiatric disorders and neurodegenerative diseases. The present review summarizes the available information concerning the link between melatonin, monoaminergic neurotransmission and the pathophysiological bases of these conditions.