Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insights into neural mechanisms through which central serotonin (5-HT) systems influence brain function may be gained by examining the contributions of individual 5-HT receptor subtypes. Significant attention has focused on the 5-HT(2C) receptor subtype, which is abundantly expressed throughout the central nervous system and displays high-affinity interactions with a wide variety of psychiatric medications. Both pharmacological and genetic approaches to the analysis of 5-HT(2C) receptor function reveal that it contributes substantially to the serotonergic regulation of a wide variety of behavioral and physiological processes. For example, significant inhibitory effects of 5-HT(2C) receptor stimulation have been observed in both limbic and striatal dopamine pathways. These may contribute to the effects of experimental 5-HT(2C) receptor manipulations on responses to psychostimulant, atypical antipsychotic and antidepressant drugs. Further evidence for a role of these receptors in affect regulation arises from recent findings that alterations in 5-HT(2C) mRNA editing are observed in the brains of suicide victims with a history of depression and in animals exposed to antidepressant drug treatment. Finally, we will review a growing body of evidence indicating a role of 5-HT(2C) receptors in the serotonergic regulation of energy balance. Pharmacological and genetic studies reveal these receptors to influence feeding, glucose homeostasis and the energy efficiency of physical activity.
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PMID:Contributions of 5-HT(2C) receptors to multiple actions of central serotonin systems. 1504 29

Abnormalities in serotonin (5-HT) receptors and 5-HT receptor-mediated signal transduction systems have been widely reported in mood disorders. This study was intended to evaluate 5-HT(2A) receptor-coupled activation of phosphatidylinositol (PI) hydrolysis in subtypes of depression. Samples for fibroblast culture were obtained from patients with major depression with or without melancholia, and normal controls. Dose response curves were determined for 5-HT-induced PI hydrolysis. PI response was determined for bradykinin and l-alpha-lysophosphatidic acid (LPA), alternative Gq-coupled receptor agonists. [125I]LSD binding for 5-HT(2A) also was conducted. Finally, Western blot analysis was performed for phospholipase Cbeta1 (PLCbeta1) and Galpha(q/11) proteins. The maximum PI response observed with 5-HT was significantly lower in melancholics but not nonmelancholic patients relative to controls. Activation of PI hydrolysis by bradykinin and LPA was not reduced in melancholic vs melancholics and controls; responses to both agonists actually were increased in the melancholic group. [125I]LSD binding, PLCbeta1, and Galpha(q/11) protein levels did not differ between groups. The data raise the possibility that the reduced 5-HT(2A) receptor-induced PI hydrolysis is intrinsic to the receptor itself or its coupling to Gq protein, and is not related to altered availability of the 5-HT(2A) receptor, Gq or PLC.
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PMID:Decreased serotonin 5-HT2A receptor-stimulated phosphoinositide signaling in fibroblasts from melancholic depressed patients. 1518 84

Dorsal root-evoked stimulation of sensory afferents in the hemisected in vitro rat spinal cord produces reflex output, recorded on the ventral roots. Transient spinal 5-HT(2C) receptor activation induces a long-lasting facilitation of these reflexes (LLFR) by largely unknown mechanisms. Two Sprague-Dawley substrains were used to characterize network properties involved in this serotonin (5-HT) receptor-mediated reflex plasticity. Serotonin more easily produced LLFR in one substrain and a long-lasting depression of reflexes (LLDR) in the other. Interestingly, LLFR and LLDR were bidirectionally interconvertible using 5-HT(2A/2C) and 5-HT(1A) receptor agonists, respectively, regardless of substrain. LLFR was predominantly Abeta afferent fiber mediated, consistent with prominent 5-HT(2C) receptor expression in the Abeta fiber projection territories (deeper spinal laminae). Reflex facilitation involved an unmasking of polysynaptic pathways and an increased receptive field size. LLFR emerged even when reflexes were evoked three to five times/h, indicating an activity independent induction. Both the NMDA and AMPA/kainate receptor-mediated components of the reflex could be facilitated, and facilitation was dependent on 5-HT receptor activation alone, not on coincident reflex activation in the presence of 5-HT. Selective blockade of GABA(A) and/or glycine receptors also did not prevent reflex amplification and so are not required for LLFR. Indeed, a more robust response was seen after blockade of spinal inhibition, indicating that inhibitory processes serve to limit reflex amplification. Overall we demonstrate that the serotonergic system has the capacity to induce long-lasting bidirectional changes in reflex strength in a manner that is nonassociative and independent of evoked activity or activation of ionotropic excitatory and inhibitory receptors.
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PMID:Serotonin 5-HT2 receptors induce a long-lasting facilitation of spinal reflexes independent of ionotropic receptor activity. 1603 39

Migraine is a complex patholophysiology in which both central and peripheral components of the trigeminal pain pathway probably play a significant role, both in the symptoms and signs of the attack and in the mechanisms of action of antimigraine compounds, such as triptans, which constitute the most important therapy for aborting migraine pain and possess several mechanisms on 5-HT receptor-mediated actions. The experimental neurogenic inflammation model represents a simple procedure to obtain preliminary information on well characterized receptortargeted drugs. The apparent paradox observed with certain drugs that are shown to be effective in this model but not in clinical trials offers the opportunity to better manipulate structure-activity to obtain the best pharmacological profile using an array of experimental models. The observation that nitric oxide donors induce migraine-like pain in migraineours and that nitric oxide plays a pivotal role in the control of several functions in the central nervous system, has prompted the use of such molecules for better understanding the pathophysiology of migraine attacks. A link between central and peripheral components of the trigeminal pain pathway is provided by the observation that cortical spreading depression in the rat activates trigeminovascular afferents and induces a series of cortical meningeal and brainstem events consistent with the development of headache. Studies in humans support the hypothesis that cortical spreading depression underlies migraine.aura. Therefore, tt is possible that visual, motor or sensory aura might be responsible for the generation of the pain through the above mechanisms.
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PMID:The pathophysiology of migraine: year 2005. 1635 90

This review outlines the history of our knowledge of the neuropharmacology of 5-hydroxytryptamine (5-HT; serotonin), focusing primarily on the work of U.K. scientists. The existence of a vasoconstrictive substance in the blood has been known for over 135 years. The substance was named serotonin and finally identified as 5-HT in 1949. The presence of 5-HT in the brain was reported by Gaddum in 1954 and it was Gaddum who also demonstrated that the action of 5-HT (in the gut) was antagonised by the potent hallucinogen lysergic acid diethylamide. This provoked the notion that 5-HT played a pivotal role in the control of mood and subsequent investigations have generally confirmed this hypothesis. Over the last 50 years a good understanding has been gained of the mechanisms involved in control of the storage, synthesis and degradation of 5-HT in the brain. Knowledge has also been gained on control of the functional activity of this monoamine, often by the use of behavioural models. A considerable literature also now exists on the mechanisms by which many of the drugs used to treat psychiatric illness alter the functional activity of 5-HT, particularly the drugs used to treat depression. Over the last 20 years the number of identified 5-HT receptor subtypes has increased from 2 to 14, or possibly more. A major challenge now is to utilise this knowledge to develop receptor-specific drugs and use the information gained to better treat central nervous system disorders.
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PMID:Neuropharmacology of 5-hydroxytryptamine. 1640 98

This study utilised the selective 5-ht(5A) receptor antagonist, SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), to investigate 5-ht5A receptor function in guinea pig brain. SB-699551-A competitively antagonised 5-HT-stimulated [35S]GTPgammaS binding to membranes from human embryonic kidney (HEK293) cells transiently expressing the guinea pig 5-ht5A receptor (pA2 8.1+/-0.1) and displayed 100-fold selectivity versus the serotonin transporter and those 5-HT receptor subtypes (5-HT(1A/B/D), 5-HT2A/C and 5-HT7) reported to modulate central 5-HT neurotransmission in the guinea pig. In guinea pig dorsal raphe slices, SB-699551-A (1 microM) did not alter neuronal firing per se but attenuated the 5-CT-induced depression in serotonergic neuronal firing in a subpopulation of cells insensitive to the 5-HT1A receptor-selective antagonist WAY-100635 (100 nM). In contrast, SB-699551-A (100 or 300 nM) failed to affect both electrically-evoked 5-HT release and 5-CT-induced inhibition of evoked release measured using fast cyclic voltammetry in vitro. SB-699551-A (0.3, 1 and 3 mg/kg s.c.) did not modulate extracellular levels of 5-HT in the guinea pig frontal cortex in vivo. However, when administered in combination with WAY-100635 (0.3 mg/kg s.c.), SB-699551-A (0.3, 1 or 3 mg/kg s.c.) produced a significant increase in extracellular 5-HT levels. These studies provide evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain.
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PMID:SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), a novel 5-ht5A receptor-selective antagonist, enhances 5-HT neuronal function: Evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain. 1684 20

A number of molecular genetic studies have investigated if serotonin (5-HT) receptor subtypes are involved in the pathogenesis of depression, suicidal behavior, aggression, and impulsive behavior. Existence of many receptor subtypes for a single transmitter permits a great diversity of signaling raising the possibility that they may serve as genetic markers for suicidal behavior. Most previous studies of suicide have analyzed polymorphisms of the receptors 5-HT1A, 5-HT1B, 5-HT2A, fewer have examined 5-HT1F. We report a study of possible association between the polymorphisms in the 5-HT receptor genes (1A, 1B, 1F, and 2A) and suicidal behavior on a sample of 226 suicide victims and 225 healthy control subjects. No significant differences in genotype frequency distributions between the suicide victims and healthy control subjects were observed for four polymorphisms; three were not polymorphic. A single polymorphism, C-1420T in gene 5-HT2A, showed a slight association with suicide (chi2= 4.94, df = 2, P = 0.067), but the correlation was not statistically significant. None of the tested genetic variants of serotonin receptors appears to be associated with suicidal behavior in the Slovenian population which has a relatively high suicide rate.
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PMID:Association study of seven polymorphisms in four serotonin receptor genes on suicide victims. 1685 20

The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all 3 major dopaminergic pathways. There are at least fourteen 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.
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PMID:Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. 1704 11

Hibernation is a unique physiological state characterized by profound reversible sleep-like state, depression in body temperature and metabolism. The serotonin 5-hydroxytryptamine(1A) (5-HT(1A)) receptor gene sequence in typical seasonal hibernator, ground squirrel (Spermophilus undulatus), was specified. It was found that the fragment encoding the fifth transmembrane domain showed 93.6% of homology with the analogous fragment of the mouse and rat genes and displayed 88.5% homology with the human 5-HT(1A) receptor gene. Using primers designed on the basis of obtained sequence, the expression of 5-HT(1A) receptor gene in the brain regions in active, entering into hibernation, hibernating and coming out of hibernation ground squirrels was investigated. Significant structure-specific changes were revealed in the 5-HT(1A) messenger RNA (mRNA) level in entry into hibernation and in arousal. An increase in the 5-HT(1A) gene expression was found in the hippocampus during the prehibernation period and in ground squirrels coming out of hibernation, thus confirming the idea of the hippocampus trigger role in the hibernation. Significant decrease in 5-HT(1A) receptor mRNA level in the midbrain was found in animals coming out of hibernation. There was no considerable changes in 5-HT(1A) receptor mRNA level in different stages of sleep-wake cycle in the frontal cortex. Despite drastically decreased body temperature in hibernating animals (about 37 degrees C in active and 4-5 degrees C in hibernation), 5-HT(1A) receptor mRNA level in all examined brain regions remained relatively high, suggesting the essential role of this 5-HT receptor subtype in the regulation of hibernation and associated hypothermia.
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PMID:The brain 5-HT1A receptor gene expression in hibernation. 1771 50

The neurotransmitter 5-hydroxytryptamine (5-HT, serotonin) mediates important brain functions and contributes to the pathophysiology and successful drug treatment of many common psychiatric disorders, especially depression. It is established that a key mechanism involved in the control of 5-HT neurones is feedback inhibition by presynaptic 5-HT autoreceptors, which are located on 5-HT cell bodies and nerve terminals. However, recent experiments have discovered an unexpected complexity of 5-HT neurone control, specifically in the form of postsynaptic 5-HT feedback mechanisms. These mechanisms have the physiological effects of 5-HT autoreceptors but use additional 5-HT receptor subtypes and operate through neural inputs to 5-HT neurones. A postsynaptic feedback system that excites 5-HT neurones has also been reported. This article discusses current knowledge of the pharmacology and physiology of these new found 5-HT feedback mechanisms and considers their possible contribution to depression pathophysiology and utility as a resource of novel antidepressant drug strategies.
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PMID:Important messages in the 'post': recent discoveries in 5-HT neurone feedback control. 1799 55


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