Evidence that phospholipid turnover is the signal transducing system coupled to serotonin-S2 receptor sites.

Courcelles, D. de Chaffoy de; Leysen, Josée E.; Clerck, Fred De; Belle, H. Van; Janssen, P A

doi:10.1016/s0021-9258(17)39651-5

Cited by 190 publications

(1 citation statement)

References 41 publications

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“…Thus, it reduces formation of the second messengers DAG and IP 3 (4,57) and results in a consecutive decrease of PKC-dependent phosphorylation of the signal transductor MARCKS. The free inositol depletion by lithium improves the clinical course in patients, not only with bipolar but also with unipolar major depression and abolishes the pathological fluctuation of behavioral alterations in these mental disorder, especially in those patients who had been treated unsuccessfully with other antidepressants before (30,57,62,77). However, the onset of the benefit of lithium administration requires several weeks, similar to tricyclic antidepressants.…”

Section: Impact Of Lithium On Second Messenger Phosphoinositide Signa...mentioning

confidence: 99%

The serotonergic system: Implications for overtraining and exercise‐induced eating disorders

Strüder

2003

European Journal of Sport Science

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Serotonin (5-HT) regulates the most extensive modulatory behavioral system in the brain of vertebrates. 5-HT projections are influenced by extrinsic and intrinsic impulses from different cortical brain areas, which reach Raphe nuclei over feedback loops, containing external and internal body information about planning, evaluation, motivation, or excitation. Serotonergic neurotransmission adjusts neuromodulation with consecutive adequate stimulation of the neuronal network. This depends on appropriate equilibration of presynaptic 5-HT storage and release but also on 5-HT reuptake from synaptic cleft by 5-HT transporters. The associated pre-and postsynaptic 5-HT receptor cooperation, postsynaptic second messenger response, and phosphoinositide signaling mediated by postsynaptic 5-HT 2 receptor subpopulation alter signal transduction in which myristolated alanine rich C kinase substrate is prominently involved in regulation of further central 5-HT areas in the brain and corresponding functional neuronal changes. Even though the central function of 5-HT neurotransmission is dominating in multifold behavioral regulation, peripheral concentration of tryptophan (TRP) and TRP passage across the blood-brain barrier and TRP hydroxylase activity are also important for appropriate 5-HT neurotransmission, as they affect central 5-HT synthesis. The high adaptability of 5-HT neurotransmission is able to compensate neuromodular dysfunctions in the brain by mechanisms that mediate 5-HT biosynthesis, release, reuptake, preand postsynaptic receptor stimulation with the respective second messenger response, and signal transduction to various areas of the brain that are involved in regulation of behavior, mood, memory, learning, and attenuation of obsession. Adequate 5-HT system function supports regulation of intercommunicative neuronal transmission in the brain, which optimizes behavioral neuromodulation during and after transient disturbances of neuromodular behavior caused by stress-induced exertions. Impairment of neuromodulation and neuronal network in the brain with transient dysfunctions or permanent substantial deficits at manifestation of various types of depression results from prevalent impairment of 5-HT neurotransmission and its central interaction with other neurotransmitter systems. It is suggested that in overtrained athletes, central fatigue, mental deficiency, and behavioral alterations with depressive mood are probably caused by a central exhaustive exercise stress that elicits impairment of complex neuromodulation, also afflicting the interaction of central neurotransmitters or hypothalamic neuropeptides and releasing factors. This suggestion is also supported by data on alterations in 5-HT neurotransmission in eating disorders. Key Points:• This review discusses important aspects of peripheral and central regulation of the 5-HT system and their relevance for overtraining and exercise-induced eating disorders. • The serotonergic system has a benefit for regulation of intercommunicative neuronal transmission in th...

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Section: Impact Of Lithium On Second Messenger Phosphoinositide Signa...mentioning

confidence: 99%

The serotonergic system: Implications for overtraining and exercise‐induced eating disorders

Strüder

2003

European Journal of Sport Science

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The pharmacology of ketanserin, the first selective serotonin S₂‐antagonist

Awouters

1985

Drug Development Research

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Awouters, F.: The pharmacology of ketanserin, the first selective serotonin S2-antagonist. Drug Dev. Res. 6:263-300, 1985. The quinazolinedione derivative ketanserin was studied in many known and newly introduced tests to obtain its detailed pharmacological profile. Ketanserin was a potent, orally very effective antagonist of endogenous serotonin (5-HT): 0.15 mglkg (ED50 S.C. and p.0.) protected rats from the gastric lesions induced by the mast cell activator compound 48/80. Many other in vivo observations, such as antagonism of tryptamine-induced cyanosis in rats (ED50 s.c., 0.056 mglkg), inhibition of mescaline-induced head twitches in rats (ED50 s.c., 0.097 mglkg), and inhibition of 5-HT-induced effects in various species, revealed the potent antagonist activity of ketanserin on vasoconstrictor and bronchoconstrictor actions of serotonin. When compared to other compounds with 5-HT-antagonist activity, the pharmacological profile of ketanserin corresponds to that of a potent, peripherally acting serotonin antagonist with weak associated ol-adrenergic blocking and antihistamine activity. In addition, binding experiments and studies on isolated tissues and platelets disclosed the high selectivity of ketanserin's serotonin antagonism. Serotonin S2-receptors of the rat frontal cortex were labeled by low concentrations of ketanserin (Ki = 0.39 nM), and affinity of drugs for S2-receptors highly correlated with their activity against serotonin-induced contractions of blood vessel preparations (e.g., of the rat caudal artery, A2-value of ketanserin: 0.83 nM) and serotonin-induced platelet aggregation. In these experiments, ketanserin was devoid of serotonin !&-binding, of agonist activity on vascular smooth muscle, of inhibition of 5-HT uptake into platelets, and of 5-HT antagonism on gastrointestinal smooth muscle. The absence of all these secondary activities is pharmacologically characteristic for ketanserin when compared to known serotonin-antagonists. On the basis of this profile of pure and selective serotonin S2-antagonism, ketanserin was studied in experimental hypertension and in many spontaneous and induced circulatory dysfunctions. A prolonged antihypertensive effect can be obtained with ketanserin in the absence of distinct compensatory mechanisms. Vascular dysfunction can start at low, sensitizing concentrations of serotonin and be almost completely corrected by ketanserin, despite the involvement of other mediators. Ketanserin is a very effective antagonist of the mixture of vasoactive substances released by aggregating platelets. In experimental thrombosis, sustained ketanserin treatment prevents the impairment of blood flow and the associated organ deficiency. When deviations from normal hemorrheology are long-standing, as in aged spontaneously hypertensive dogs, acute ketanserin administration is distinctly antihypertensive and reduces hemorrheological abnormalities. At the conclusion of these extensive studies, serotonin appears to act at peripheral S2-receptors as the primary pathological mediator...

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The role of the endothelium in arterial thrombosis and the influence of antithrombotic therapy

Bush

Patrick

1986

Drug Development Research

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Bush, L.R. and D. Patrick:The role of the endothelium in arterial thrombosis and antithrombotic therapy. Drug Dev. Res. 7:319-340, 1986.The nonthrombogenicity of vascular endothelium, a single layer of cells separating bloodborne platelets and thrombogenic components of the underlying subendothelium, results from more than its provision of a physical barrier. These cells synthesize and secrete prostacyclin, plasminogen activator, and inhibitors of the coagulation system. They also catabolize proaggregatory agents such as ADP and serotonin (5-HT). Damage to or removal of the endothelium is, of course, a potent thrombogenic stimulus. We have employed an acute canine model of coronary arterial thrombosis, which combines vessel narrowing and intimal injury as stimuli for repetitive, regular occlusive thrombus formation. Of all agents tested by us and others in this model, prostacyclin, selective thromboxane (TXA2) synthetase inhibitors, and 5-HT antagonists consistently inhibit thrombus formation. Available data suggest that the antithrombotic actions of TXA2 synthetase inhibitors result in part from vascular metabolism of platelet-derived endoperoxides, as well as endogenous PG12 production. Serotonin, alone, exerts weak proaggregatory effects. However, it uniquely amplifies the proaggregatory effects of many physiologic proaggregatory mediators. Serotonin2 antagonists are more potent and consistently antithrombotic in this canine model than TXA2 synthetase inhibitors.The discordance between the marked antithrombotic effects of 5-HT antagonists and TXA2 synthetase inhibitors in vivo and their weak antiaggregatory and proaggregatory effects in vitro, respectively, underscores the danger of relying exclusively upon in vitro platelet aggregatory behavior to assess either the potential importance of a mediator or antithrombotic efficacy of a new drug. On the basis of results obtained from our laboratory Received final version December 20, 1985; accepted February 20, 1986. Address reprint requests to Dr. L. R. Bush, W26-208, MSDRL, West Point, PA 19486. 0 1986 Alan R. Liss, Inc. 320Bush and Patrick and others that employ similar in vivo models of thrombosis, we conclude that 1) since platelet aggregation in vivo is stimulated by many physiologic agonists, in vivo and in vitro, models of aggregation and thrombosis should reflect this; 2) the most potent or efficacious proaggregatory agent in vitro may not necessarily be the most important mediator in vivo and vice versa. Future development of antithrombotic agents should continue; aspirin can be improved upon in several respects. Perhaps future antithrombotic agents will be targeted to specific platelet membrane (g1yco)proteins involved in platelet-platelet (aggregation) and platelet-vessel wall (adhesion) interactions.

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Evidence that phospholipid turnover is the signal transducing system coupled to serotonin-S2 receptor sites.

Cited by 190 publications

References 41 publications

The serotonergic system: Implications for overtraining and exercise‐induced eating disorders

The serotonergic system: Implications for overtraining and exercise‐induced eating disorders

The pharmacology of ketanserin, the first selective serotonin S₂‐antagonist

The role of the endothelium in arterial thrombosis and the influence of antithrombotic therapy

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Evidence that phospholipid turnover is the signal transducing system coupled to serotonin-S2 receptor sites.

Cited by 190 publications

References 41 publications

The serotonergic system: Implications for overtraining and exercise‐induced eating disorders

The serotonergic system: Implications for overtraining and exercise‐induced eating disorders

The pharmacology of ketanserin, the first selective serotonin S2‐antagonist

The role of the endothelium in arterial thrombosis and the influence of antithrombotic therapy

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Product

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The pharmacology of ketanserin, the first selective serotonin S₂‐antagonist