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)

To explore 5-HT1A receptor responsivity in panic disorder (PD), hypothermic, neuroendocrine and behavioral responses to the selective partial 5-HT1A receptor agonist ipsapirone (IPS) were investigated in patients with primary PD and healthy controls. Fourteen patients and matched controls received a single oral dose of 0.3 mg/kg IPS or placebo under double-blind, random-assignment conditions. IPS induced hypothermia and corticotropin (ACTH)/cortisol release but had only minimal effects on behavior. Compared with controls, the patients with PD exhibited significantly attenuated thermoregulatory and neuroendocrine responses to IPS. Although the healthy subjects reported increased drowsiness and the PD patients rated themselves more nervous and less calm following administration of IPS, no consistent changes in ratings of anxiety or panic symptoms were recorded. The impaired hypothermic and ACTH/cortisol responses following 5-HT1A receptor activation reflects subsensitivity of both the pre- and post-synaptic 5-HT1A receptor-effector system, thus supporting the hypothesis that a 5-HT1A receptor-related serotonergic dysfunction may be linked to the pathophysiology of PD. Future studies of 5-HT1A receptor-effector complex function in conjunction with assessment of the responsivity of other subtypes (e.g. 5-HT2, 5-HT3) should promote the evaluation of 5-HT system integrity in anxiety disorders and its involvement in anxiolytic drug effects.
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PMID:5-HT1A receptor-effector system responsivity in panic disorder. 134 19

1. Azapirones, selective partial agonists at the 5-HT1A receptor subtype, induce hypothermia and corticotropin (ACTH)/cortisol release as specific functional correlates of central 5-HT1A receptor activation. 2. Compared to controls, hypothermic and ACTH/cortisol responses to the azapirone ipsapirone are attenuated in patients with unipolar depression and panic disorder but not in patients with obsessive-compulsive disorder. The impaired thermic and neuroendocrine responses are associated with increased basal cortisol secretion in depressed patients but not in patients with panic disorder. 3. Chronic treatment with the selective 5-HT reuptake inhibitor fluoxetine decreases 5-HT1A receptor-mediated responses in patients with obsessive-compulsive disorder, while long-term treatment with the tricyclic antidepressant amitriptyline further decreases hypothermia following ipsapirone but has no effect on ACTH/cortisol release. 4. Alteration of the 5-HT1A receptor and/or its signal transduction pathways may play a role in the pathophysiology and treatment of anxiety disorders and depression.
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PMID:5-HT1A receptor responsivity in anxiety disorders and depression. 176 90

Buspirone, an azapirone derivative and a 5-HT1A partial agonist, is the first nonbenzodiazepine anxiolytic introduced into medicine for the treatment of generalized anxiety disorder. A series of well-controlled clinical trials demonstrated that its anxiolytic properties were similar to those of various benzodiazepines and significantly better than placebo. More recently, antidepressant effects were also observed. Patients with clinical indications for which buspirone seems to be particularly appropriate are those with generalized anxiety disorder, those with chronic anxiety, the anxious elderly, and, perhaps, many patients of all ages who suffer from mixed symptoms of anxiety and depression. Studies conducted with patients suffering from panic disorder have so far been inconclusive, and thus buspirone is, for the present at least, not recommended for routine treatment of panic disorder. Buspirone seems to be most helpful in anxious patients who do not demand immediate gratification or the immediate relief they associate with the benzodiazepine response. Slower and more gradual onset of anxiety relief is balanced by the increased safety and lack of dependency-producing aspects of buspirone. Finally, whether or not buspirone may possess "curative" properties, in addition to "anxiety-suppressant" properties, that allow the patient to improve coping skills with time requires further exploration.
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PMID:Buspirone in clinical practice. 221 69

The mouse defense test battery (MDTB) has been designed to investigate defensive reactions in Swiss-Webster mice to situations associated with a natural predator, the rat, such as flight, avoidance, defensive threat, defensive attack, and risk assessment activities. The present study evaluated the ability of 8-OH-DPAT (0.05-10 mg/kg, SC, 5) and gepirone (2.5-10 mg/kg, IP, 30), a full- and a partial agonist at 5-HT1A sites, as well as pirenperone (0.25-1 mg/kg, IP, 30), a preferential 5-HT2A receptor antagonist, to exert an anxiolytic-like action in the MDTB. The most consistent effect of both 5-HT1A receptor agonists across tests was a marked reduction in predator assessment activity and defensive attack behavior. In contrast, neither of the two ligands was able to reduce flight responses to the approaching predator, and both failed to reduce in a specific manner contextual defense behaviors after the predator was removed. The 5-HT2A receptor antagonist pirenperone did not provide significant indication of an anxiolytic effect on predator assessment activity and postpredator potentiation of contextual defense responses, and had negligible influence on antipredator defensive behavior. The most interesting exception to this profile was a dose-related reduction in flight-related measures. In view of previous results indicating that the panic-promoting drug yohimbine increases flight/escape reactions and that the panicolytic compound alprazolam reduces these responses, we tentatively suggest that the preferential 5-HT2A receptor antagonist pirenperone may have some efficacy in improving panic attacks. In addition, the lack of effect of the 5-HT1A receptor agonists on these flight responses is consistent with clinical findings indicating that these agents are of limited use in the treatment of panic disorder. These findings suggest that the MDTB provides behavioural measures capable of differentiating between various classes of antianxiety drugs.
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PMID:5-HT1A agonists modulate mouse antipredator defensive behavior differently from the 5-HT2A antagonist pirenperone. 766 34

Rats may produce ultrasonic vocalizations (USV) in threatening situations. USV of adult male rats in association with aversive stimulation was evaluated as a screening method for anxiolytic drugs. The triazolobenzodiazepine alprazolam, the 5-HT uptake inhibitors fluvoxamine and clomipramine, the mixed 5-HT/NA uptake inhibitor imipramine, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378, the alpha 2-adrenoceptor agonist clonidine and the alpha 2-adrenoceptor antagonist yohimbine reduced conditioned USV. The classical benzodiazepines (BZD) diazepam and chlordiazepoxide were ineffective or had a very low potency to decrease USV. The partial BZD receptor agonists bretazenil, alpidem and zolpidem, the BZD receptor antagonist flumazenil, the NA uptake inhibitors desipramine and maprotiline, and the 5-HT3 receptor antagonist ondansetron had no effect on conditioned USV. The dopamine-D2 receptor antagonist haloperidol reduced USV at a very high dose. In separate experiments the effects of these drugs on locomotor activity were assessed. There was, however, no direct relationship between effects on motor behaviour and USV. In conclusion, the sensitivity of conditioned USV to 5-HT uptake inhibitors and alprazolam versus the insensitivity to classical benzodiazepines and NA uptake inhibitors provides a very interesting profile, which closely resembles the psychopharmacology of panic disorder. Also the face validity of conditioned USV towards situational panic attacks is high. We therefore propose conditioned USV in adult male rats as a novel behavioural paradigm to screen for anti-panic drugs.
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PMID:Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic drugs. 772

The role of serotonin in psychiatry has been the focus of speculation for several decades. The literature since 1966 is reviewed (and referenced) and five organizing questions are identified: (1) What are the major hypotheses regarding the involvement of the serotonin system in panic disorder? (2) Is there a serotonin system defect associated with panic disorder? (3) Is a serotonin system defect the cause of panic disorder? (4) Are the 5-HT1A agonists and the 5-HT2 antagonists effective in this condition? (5) Are serotonin selective uptake inhibitors (SSUIs) effective in panic disorder via the serotonin system or some other mechanism? Though the role of the serotonin system in panic disorder and social phobia is uncertain there is increasing agreement that SSUIs effectively treat panic disorder but further double-blind placebo-controlled studies are needed.
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PMID:Serotonin in panic disorder and social phobia. 791 Nov 42

Classic antidepressant drugs, amine uptake inhibitors of the imipramine type and the monoamine oxidase inhibitors, alter the functioning of serotonin (5-hydroxytryptamine, 5-HT) neurons in the brain. This discovery, made more than two decades ago, has had a profound impact on the study of depressive illness as well as on the development of new models of antidepressant treatment. Apart from their obvious clinical value, antidepressant drugs have come to be used as research tools to study the pathophysiology of depressive illness. A main goal in the development of antidepressant drugs has been to design drugs with more selective effects on the nerve cells that are thought to be important in depressive illness, thereby avoiding unnecessary side effects and possibly enhancing therapeutic effects. Drugs that selectively affect 5-HT neurons have proved to be uptake inhibitors--including fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram--and are now available. All of them appear to have an antidepressant effect equivalent to standard reference compounds, with a different spectrum of side effects. One of the most interesting aspects of the serotonergic drugs is their broad spectrum of action, in particular, their effects in patients with obsessive-compulsive disorder, panic disorder, and possibly some disorders of impulse control. There is still relatively little knowledge of which aspects of 5-HT function are important for the antidepressant, antiobsessive, and antipanic effects. The availability of drugs that selectively affect the different 5-HT receptors, such as the partial 5-HT1A agonist gepirone, will presumably be helpful for modern studies of the "anatomy of melancholy."
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PMID:Serotonin selective antidepressant drugs: past, present, future. 813 Nov 53

The amygdala (AM) and the periaqueductal gray (PAG) represent the rostral and the caudal pole, respectively, of a longitudinally organized neural system, that is responsible for the integration of behavioral and physiological manifestations of defensive reactions against innate and learned threats. Microinjection of benzodiazepine (BZD) anxiolytics, GABAA receptor agonists or 5-HT receptor antagonists into the AM has anxiolytic effects in conflict tests and other models of conditioned fear, while similar administration of 5-HT or of a 5-HT1A receptor agonist has anxiogenic effects. On the other hand, in the test of electrical stimulation of the PAG, microinjection of 5-HT, 5-HT mimetics, or of drugs that enhance the action of endogenous 5-HT into the same brain area has an antiaversive effect, like BZD and GABAA agonists. Furthermore, microinjection of midazolam, of the NMDA receptor antagonist AP-7, or of the 5-HT1A/1B receptor blocker propranolol increased the exploration of the open arms of the elevated plus-maze, having therefore an anxiolytic effect. These results point to an inhibitory role of the GABA-BZD system in both the AM and the PAG. In contrast, 5-HT seemingly enhances conditioned fear in the AM, while inhibiting unconditioned fear in the PAG. Thus, 5-HT2/1C antagonists reportedly release punished behavior when injected into the AM, whereas they antagonized the antiaversive effect of 5-HT, zimelidine and 5-HT1A/1B receptor blockers in the PAG. Since reported clinical studies revealed that one of such compounds, ritanserin, relieves generalized anxiety but tends to aggravate panic disorder, a relationship may be established between the AM and anxiety and the PAG and panic.
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PMID:Role of the amygdala and periaqueductal gray in anxiety and panic. 813 40

Serotonin (5-HT) reuptake inhibitors (SSRIs) such as fluvoxamine are interesting compounds. Initially launched as antidepressants, they have been found to be active in various psychiatric disorders besides depression, including obsessive-compulsive disorder, panic disorder, and eating disturbances. Preliminary data suggest their efficacy in alcohol and drug abuse, aggression, and posttraumatic stress disorder as well. Along with those clinical findings, new preclinical data have emerged. For example, fluvoxamine has demonstrated activity in various models of anxiety in rodents. Its anxiolytic activity can be clearly discriminated from that of the benzodiazepines. In the DRL 72-sec paradigm, fluvoxamine exhibits a good antidepressant profile, similar to those of imipramine and flesinoxan. Studies have shown that fluvoxamine does not down-regulate beta-adrenoceptors; apparently, that property is not a conditio sine qua non for antidepressant activity. Results of studies of the mechanism of action of fluvoxamine in which drug discrimination tests were performed with rats and pigeons suggest that the fluvoxamine stimulus is not (or is only to a very limited degree) dependent on activation of 5-HT1A receptors or 5-HT1B/1D receptors, or both. Experimentation is ongoing in those animal models.
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PMID:Preclinical evidence on the psychotropic profile of fluvoxamine. 837 18

A common action of many antidepressants is the inhibition of the reuptake of the biogenic amines norepinephrine, serotonin (5-HT) and/or dopamine into nerve terminals. Another postulated mechanism of action for many antidepressants is the downregulation of beta-adrenergic receptors postsynaptically after chronic administration. Many antidepressants have been reported to produce changes in the regulation of 5-HT1 and 5-HT2 receptors chronically. None of these mechanisms is completely satisfactory as a common antidepressant mechanism of action. Is it possible to unify these hypotheses of antidepressant action? A number of receptor changes have been recognized in depression. Usually, these implicated receptors are linked to a G protein. Thus, it could be hypothesized that depression may be the result of a disorder of the large family of receptor-linked G proteins. Depression, a disorder in which there seems to be an important genetic component, could be expressed in either the receptor or in the G proteins, leading to a defective linkage between the receptor and the G protein, resulting in abnormal transduction mechanisms. The concept of antidepressants is changing rapidly as these agents appear with new therapeutic indications other than depression, such as panic disorder, obsessive compulsive disorder, etc. It can be expected that the presently available antidepressants might eventually be considered anxiolytics or that benzodiazepines and 5-HT1A agonists could come to be viewed as disinhibiting substances.
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PMID:The future of antidepressants. 867 34


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