Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been recently suggested that the central serotonin (5-HT) nervous system may be involved in the modulation of anxiety. Especially, the possible importance of 5-HT1A receptors in anxiety was raised by evidence that the anxiolytic properties of 5-HT1A-receptor agonists have now been confirmed in clinical studies. On the other hand, in preclinical studies using various animal models of anxiety, these novel agents tend to have weak and/or variable effects in some paradigms used to detect the anxiolytic activities of benzodiazepines. These differential patterns of drug effects within various models promote the concept of "multiplicity of anxiety". Recently, a new experimental model called the T-maze was developed in attempts to analyze a different type of anxiety; i.e., conditioned fear and unconditioned fear response. The results of a series of behavioral studies using the T-maze test suggest that distinct 5-HT pathways may modulate the different classes of anxiety. In our recent studies using the hole-board test, apparent differential behavioral effects between benzodiazepine anxiolytics and 5-HT1A agonists on emotionality of stressed mice were also observed. These results suggest that benzodiazepine or 5-HT1A receptors may play a different role in modulating emotionality. These studies may provide new information to investigate the pathophysiological characteristics of various types of anxiety disorders and to develop novel therapeutic agents.
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PMID:[Multiplicity of anxiety and serotonin nervous system]. 1087 13

An overview of the behavioral, electrophysiological and neurochemical data found in the literature concerning the involvement of serotonin (5-HT) receptors in the regulation of anxiety was presented on the basis of animal models. At present, 5-HT receptors are classified into 7 families including at least 14 subtypes. Among these 5-HT receptors, it is conceivable that 5-HT1A-receptor-mediated effects are the most important part of the mechanism of anxiety. The demonstrated efficacy of 5-HT1A-receptor partial agonists in anxiety disorders has emphasized the importance of these receptors. Enhanced anxiety was observed in mutant mice lacking 5-HT1A receptors. In 5-HT1B receptors knockout mice, on the other hand, aggressive behavior was increased. Some of the selective antagonists acting on 5-HT2 and 5-HT3 receptors have shown the anxiolytic effects in various animal models. Inactivation of mRNA encoding 5-HT6 receptors using antisense oligonucleotide produced decreases in cortical 5-HT release enhanced by anxiety. These observations lead to the suggestion that different mechanisms, mediated by various 5-HT receptors, are involved in the pathogenesis of anxiety.
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PMID:[Possible involvement of serotonin receptors in anxiety disorders]. 1087 14

The purpose of this study was to examine the anxiolytic effects of serotonin (5-HT) reuptake inhibitors and to clarify their action mechanisms and roles in the brain serotonergic system in the psychopathology of anxiety. It has been proposed that conditioned fear stress (CFS)-induced freezing behavior in rats could be used as a model of anxiety. In the experiment using this model, acute treatment with the 5-HT reuptake inhibitors reduced CFS-induced freezing behavior, while acute treatment with the noradrenaline or dopamine reuptake inhibitors failed to alter CFS-induced freezing. CFS elevated extracellular 5-HT levels in the medial prefrontal cortex, and this elevations of 5-HT level was followed by a resolution of the freezing. A dose of 10 mg/kg of a selective 5-HT reuptake inhibitor (SSRI), citalopram, administered 60 min before exposure to CFS increased extracellular 5-HT concentrations immediately and potently, and reduced freezing. The 5-HT1A receptor antagonists, particularly at low doses, enhanced the antifreezing effect of citalopram. While the antifreezing effect of citalopram (10 mg/kg) disappeared by prolongation of the period between conditioning and exposure to CFS, acute challenge of citalopram (10 mg/kg) reduced freezing in the rats into which citalopram (10 mg/kg) had been injected twice daily for 7 days. From these findings, it is indicated that 1) 5-HT reuptake inhibitors decrease anxiety, 2) 5-HT release is increased at the nerve terminal under anxiety conditions, 3) the elevation of 5-HT levels in the terminal has an anxiolytic action which is closely related to the pharmacological effects of SSRI-class of anxiolytics, and 4) 5-HT1A receptor antagonist enhances the antifreezing effect of SSRI by blocking the autoreceptor-mediated negative feedback mechanisms of 5-HT neurons. By prolonging the period between conditioning and exposure to CFS, the author recognized the feasibility to establish an animal model which reflects the psychopathology of anxiety disorder more precisely. Presynaptic 5-HT1A receptor desensitization may account for the mechanism of action of repeated treatment with SSRI.
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PMID:[Anxiolytic effects of serotonin reuptake inhibitors and their mechanism of action]. 1119 34

Sustained administration of the selective serotonin (5-HT) reuptake inhibitors (SSRIs) citalopram for 2, 14, and 21 d, and paroxetine for 2 and 21 d (20 and 10 mg/kg.d, respectively, s.c. using osmotic minipumps) produced a gradual decrease in spontaneous firing activity of locus coeruleus (LC) noradrenergic neurons. In contrast, sustained desipramine administration for 2 and 21 d (10 mg/kg.d) robustly reduced LC firing activity, though only to the same extent, following these two treatment periods. The enhancement of the firing rate of LC neurons produced by the 5-HT1A agonist 8-OH-DPAT (10-50 &mgr;g/kg, i.v.) in desipramine- and citalopram-treated rats was abolished, indicating a desensitization of 5-HT1A receptors. However, the attenuation of the firing rate of LC neurons induced by the 5-HT2 agonist DOI (5-50 &mgr;g/kg, i.v.) was decreased approx. 2-fold in citalopram-treated rats but not significantly altered in desipramine-treated rats. Since 5-HT neurons exert a tonic inhibitory effect on LC neurons, it appears that enhancing 5-HT neurotransmission by sustained SSRI administration leads to a reduction of the firing rate of noradrenergic neurons. In conclusion, SSRIs attenuate the activity of noradrenergic neurons with a delay that is consistent with their beneficial effect in depression and some anxiety disorders, such as panic, generalized and social anxiety disorders. However, given the hyperadrenergic state often observed in anxiogenic conditions the latter phenomenon is believed to contribute more to the anxiolytic effect of SSRIs than to their antidepressant action.
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PMID:Progressive attenuation of the firing activity of locus coeruleus noradrenergic neurons by sustained administration of selective serotonin reuptake inhibitors. 1134 73

Although selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs) are widely used in the chronic treatment of several anxiety disorders, increased anxiety has been observed in some patients at the beginning of treatment with these compounds. Similar increases in anxiety-related behaviors have been observed in animal studies following a single injection with SSRIs. The mechanism underlying this effect is unclear. The aim of the present study was to investigate the effects of a variety of psychoactive compounds on the anxiogenic-like activity of fluoxetine. The drugs used included the benzodiazepine diazepam, the 5-HT1A receptor partial agonist buspirone, the 5-HT1A receptor antagonists pindolol and WAY-100635, the non-selective 5-HT2 receptor antagonists methiothepin, mianserin and ritanserin, the non-selective dopamine (DA) receptor antagonist haloperidol, the D1 antagonist SCH23390, the selective D2 antagonist raclopride, the D2/3 agonist quinelorane, the cholecystokininB (CCK(B)) receptor antagonist LY 288513, and the corticotropin-releasing factor1 (CRF1) receptor antagonist CP-154,526. Experiments were performed in the free-exploration test. This model is based on the strong neophobic reactions exhibited by BALB/c mice when confronted simultaneously with a familiar and a novel environment. When administered alone, diazepam (1 and 2 mg/kg), buspirone (1 mg/kg) and mianserin (0.3 mg/kg) produced anxiolytic-like effects as they significantly increased exploratory activity of the novel compartment. In contrast, fluoxetine (20 mg/kg) almost completely suppressed exploration of the novel area. Diazepam reversed the anxiogenic-like as well as the locomotor impairment induced by fluoxetine, while quinelorane blocked only the anxiogenic action of fluoxetine. None of the other compounds was able to counteract this effect. Taken together, these results suggest that dopaminergic mechanisms may underlie, at least in part, the behavioral effects of fluoxetine in the free-exploration test, whereas 5-HT1A 5-HT2, CCK(B) and CRF1 receptors may not be involved primarily in these effects.
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PMID:An investigation of the mechanisms responsible for acute fluoxetine-induced anxiogenic-like effects in mice. 1148 52

The most common and successful therapyfor the majority of patients suffering from anxiety is treatment with benzodiazepines (BZDs). The problem of drug-induced dependency following treatment with these drugs may be avoided by developing more selective and specific BZD compounds, such as 2,3-substituted BZDs. Alternative approaches to the treatment of anxiety include the following: (i) antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), which are active in treating most anxiety disorders, including GAD; (ii) metabotropic glutamate (mGluR2) receptor agonists, which negatively modulate glutamate neurotransmission, and CRF antagonists, which have been proposed to exhibit anxiolytic properties; (iii) 5-HT1A receptor agonists which have demonstrated anxiolytic effects in clinical studies, although preclinical studies have reported weak or variable effects; (iv) 5-HT moduline antagonists, as well as 5-HT2C receptor antagonists, which may have anxiolytic properties; and, finally, (v) other approaches which are under investigation, including CCK2 antagonists.
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PMID:Drug mechanisms in anxiety. 1181 41

An overview of the preclinical literature on the effects of the most studied clinically effective or putative non-benzodiazepine anxiolytics in existing animal models of anxiety-like behavior indicates that, with the exception of 5-HT1A agonists, these compounds display highly variable effects. Because these drugs have been shown (selective 5-HT reuptake inhibitors) or proposed (CCK(B) and CRF antagonists) to have a different spectrum of therapeutic activity in anxiety disorders than benzodiazepines, agents mainly used against generalized anxiety disorder, the screening of such compounds clearly requires the validation of new techniques that may model aspects of these conditions.
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PMID:Rodent models of anxiety-like behaviors: are they predictive for compounds acting via non-benzodiazepine mechanisms? 1189 22

In recent years generalised anxiety disorder (GAD) has become a much better defined disorder, with specific criteria distinguishing it from the other anxiety disorders; however, it still lacks the same public and scientific interests as some of the other anxiety disorders such as panic and social phobia. Nevertheless, refinement in the treatment of GAD is becoming more evident through the conduct of clinical trials. Up until the mid-1980's, treatment consisted primarily of benzodiazepines. However, as a result of growing characterisation of their abuse potential, other therapeutic options were explored. Benzodiazepines became seen as an effective short-term therapy, and buspirone and some of the newer antidepressants have become the treatment of choice for patients with GAD requiring long-term treatment. Buspirone was the first available alternative to the benzodiazepines in the US; however, the initial excitement over this agent was somewhat dampened because of its mild efficacy combined with a slow onset of action. The antidepressants were seen as beneficial for the treatment of GAD because of the high comorbidity with depression, thus allowing a better outcome for these patients. The antidepressants that offer both a good adverse effect profile and efficacy are the selective serotonin reuptake inhibitors including paroxetine, and the serotonin-norepinephrine reuptake inhibitors such as venlafaxine. Clinicians should also consider the potential benefits of psychotherapy as an adjunct to medication. There are a number of potentially new pharmacotherapies being investigated, including newer serotonin 5-HT1A receptor agonists, cholecystokinin receptor antagonists, neurokinin receptor antagonists, gabapentin and its analogues, and gamma-aminobutyric acid (GABA)A receptor modulators. However, these compounds are all in the early stages of investigation, and there are no new therapies expected to be released in the near future. Nonetheless, in the search for the ideal anxiolytic, a more positive outlook is allowed by imminent future research for new treatment options in patients with GAD.
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PMID:Generalised anxiety disorder: treatment options. 1210 25

Depression is an incapacitating disease which needs appropriate treatment. This article reviews the pharmacology of antidepressant drugs and the future perspectives of treating mood disorders such as depression. The foremost theory for explaining the biological basis of depression has been the monoamine hypothesis. Depression is due to a deficiency in one or other biogenic monoamines (serotonin, 5-HT; noradrenaline, NA; dopamine, DA). Antidepressant drugs are therefore classified according to their ability to improve monoaminergic transmission. Since this first theory, other explanations based on abnormal function of monoamine receptors or associated with impaired signalling pathways have been suggested. Notable progress has been accomplished in the treatment of major depressive disorders with new compounds recently discovered (selective serotonin reuptake inhibitors: SSRI; serotonin noradrenaline reuptake inhibitors: SNRI). Behavioural, electrophysiological and microdialysis studies have shown that serotonin (5-HT) receptors, mainly 5-HT1A, 5-HT1B and 5-HT2C sub-types, exert a key role in modulating antidepressant activity. Indirect activation of neurotransmitter receptors by antidepressants may also lead, via increases in endogenous levels of serotonin in synapses in specific brain regions, to activation of various G proteins coupled to a receptor, signal of transduction, transcription factors and neurotrophic factors such as brain-derived neurotrophic factor (BDNF). Thus, depression may be considered as a transduction mechanism anomaly. This hypothesis needs to be clarified by molecular biology. Although antidepressants have improved the therapeutic potential compared to tricyclics (TCA) in terms of reduced side effects, a number of problems still occur with these drugs. Clinical effects are not always observed until after this time has elapsed (4-6 weeks) and a substantial proportion of depressed patients show only partial or no response to antidepressants. Knowledge of the existence of links between neurotransmitter systems and the discovery of the most specific target, 5-HT receptors, should lead to improvements in antidepressant therapy. Developing drugs using innovative mechanisms such as directly acting on 5-HT receptors (5-HT1A agonists or 5-HT2 antagonists), would appear to be useful in the treatment of depression. The use of antidepressants in anxiety disorders such as obsessional compulsive disorders and even generalised anxiety, highlights the distinction between antidepressants and classic anxiolytics such as benzodiazepines, or even buspirone.
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PMID:[Mechanism of action of antidepressants and therapeutic perspectives]. 1242 59

The role of serotonin (5-hydroxytryptamine; 5-HT) in the treatment of depressive and anxiety disorders is underscored by the therapeutic action of selective 5-HT reuptake inhibitors acting to enhance the degree of activation of various 5-HT receptor subtypes. The 5-HT1A receptors are particularly relevant to the antidepressant and anxiolytic responses in human beings. They are located presynaptically in the raphe nuclei, where they act as cell body autoreceptors to inhibit the firing rate of 5-HT neurons, and are located postsynaptically in limbic and cortical regions, where they also attenuate firing activity. The azapirones are full agonists at 5-HT1A autoreceptors and are generally, but not exclusively, partial agonists at postsynaptic 5-HT1A receptors. Some of these drugs, including gepirone and other 5-HT1A agonists such as buspirone, have been reported to exert anxiolytic and antidepressive activity in double-blind, placebo-controlled, and comparative trials. Their delayed therapeutic activity is believed to result from increased activation of postsynaptic 5-HT1A receptors occurring only after 5-HT neurons regain their normal firing activity. The recovery of this parameter, which is attributable to 5-HT1A autoreceptor desensitization, also restores 5-HT release. At this point, the summed effects of a normalized level of synaptic 5-HT and the exogenous 5-HT1A agonist can be exerted on postsynaptic 5-HT1A receptors. The widespread recognition of the clinical efficacy of such agents has largely been hampered by their undesirable pharmacokinetic properties. Most 5-HT1A agonists are indeed readily absorbed but are also rapidly eliminated, thereby often producing either suboptimal therapeutic responses at low doses, or cumbersome adverse effects at higher doses. Extended-release formulations allow once-daily dosing regimens, thus avoiding sharp peak plasma concentrations. This improves compliance and permits the use of higher dosages, which may be associated with enhanced efficacy and better tolerability relative to the immediate-release formulations. In sum, 5-HT1A receptor agonism represents a valuable and efficacious therapeutic approach to major depression.
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PMID:Is there a role for 5-HT1A agonists in the treatment of depression? 1255 51


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