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)

Different groups of rats were trained to discriminate either 0.3 mg/kg of flesinoxan (N = 13) or 0.1 mg/kg of 8-OH-DPAT (N = 7) from saline in a two-lever operant drug discrimination task using a fixed ratio 10 schedule of reinforcement. Once trained, animals in both groups displayed a dose-related decrease in discriminative performance upon administration of lower doses of the drug used in training. In generalization tests, flesinoxan generalized to 8-OH-DPAT in 8-OH-DPAT-trained animals and 8-OH-DPAT substituted for flesinoxan in flesinoxan-trained animals. Buspirone substituted partially for both the flesinoxan and the 8-OH-DPAT cue. The results of the present study indicate similarity between the discriminative stimulus effects of flesinoxan and the stimulus produced by the 5-HT1A agonist 8-OH-DPAT. These results, coupled with the finding that flesinoxan has a significant affinity and selectivity for 5-HT1A binding sites, suggest that the stimulus effects of flesinoxan are mediated by a 5-HT1A mechanism.
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PMID:Discriminative stimulus properties of flesinoxan. 214 Jun 7

The azapirone class of anxiolytic drugs is being evaluated for clinical use in the treatment of depression. Buspirone, a serotonin (5-hydroxytryptamine, 5-HT) partial agonist active at the 5-HT1A receptor subtype, was evaluated in the treatment of depression in a series of five placebo-controlled, parallel group studies involving 382 patients with DSM-III major depression and significant associated anxiety symptoms (both Hamilton depression [HAM-D] and Hamilton anxiety [HAM-A] scales greater than or equal to 18). Buspirone therapy was initiated at 15 mg/day with individual dose titration to a maximum of 90 mg/day and resulted in marked improvement in both depressive and anxiety symptoms. Analyses of the composite data base from the five studies show significant (p less than 0.05) improvement in mean HAM-D, HAM-A, and Clinical Global Impression-Global Improvement scale ratings for buspirone-treated compared with placebo-treated patients. Of particular interest was significant improvement in cardinal depression symptoms, e.g., depressed mood, guilt, work and interest, anergia, and diurnal variation of mood. Subset analyses revealed that patients with melancholic-type major depression and patients with more severe symptoms (judged by higher initial HAM-D or HAM-A total scores) responded better to buspirone than did patients who were less ill. The buspirone dose most frequently associated with clinically significant improvement was 40 mg/day. Gepirone, an analogue of buspirone with highly selective binding affinity for the 5-HT1A receptor subtype, also shows promise of antidepressant efficacy in preliminary controlled clinical trials. These data suggest that azapirones, which as partial agonists modulate 5-HT1A receptor function, have clinically important antidepressant properties.
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PMID:Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression. 219 3

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 side effects and unwanted or unnecessary ancillary pharmacological properties of benzodiazepine anxiolytic drugs resulted in a continuing search for new agents with improved profiles of activity. Buspirone was the first novel drug to emerge from this search in almost thirty years. Investigations into its mechanism of action revealed a key role for serotonin in the pharmacotherapy of anxiety. A variety of serotonergic agents are now in preclinical and clinical development as anxiolytics, including 5-HT1A partial agonists, 5-HT2 antagonists, and 5-HT3 antagonists. In addition to the new drugs which will be developed as a consequence of these investigations, their clinical efficacy will prompt the development of new animal models of psychopathology, leading us ever closer to a full understanding of the neurobiological substrates of anxiety. In addition, deployment of these new agents in the armamentaria of the clinician and the basic scientist will lead to new insights into the treatment of other disorders and the biochemical mechanisms by which the effects of these drugs are obtained.
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PMID:Serotonin agents in anxiety. 225 34

Buspirone was studied to determine whether the detailed profile of male sexual behavior observed following treatment with the prototypical 5-HT1A ligand, 8-OH-DPAT, can be generalized to other 5-HT1A agonist drugs. Systemic and intrathecal (IT) routes of administration were compared. Like DPAT, significant reduction in intromission frequency followed IT infusion of buspirone (80-160 micrograms) as did intraperitoneal (IP) injection (1-4 mg/kg). IT doses of 80-160 micrograms and all IP doses significantly reduced ejaculation latency. Intercopulatory interval significantly decreased following IP buspirone but not after IT infusion although there were trends in that direction. All IP doses and 80 micrograms IT significantly shortened the postejaculatory interval. Buspirone inhibited erection and/or ejaculation in the ex copula reflex test. A decrease in percentage of rats displaying erections and ejaculation occurred following either route of administration. Ejaculation was significantly inhibited at the low IT dose of 40 micrograms. We conclude that buspirone affects sexual behavior very much like DPAT or other 5-HT1A drugs, to the extent known. Sexual effects of buspirone were generally similar regardless of route of administration, but the effective doses were clearly lower with IT treatment.
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PMID:Effects of intrathecal and systemic administration of buspirone on genital reflexes and mating behavior in male rats. 234 70

Dyskinetic movements and dystonic postures may be induced by neuroleptics in monkeys that have undergone previous neuroleptic treatment, and these motor abnormalities constitute a primate model of drug-induced extrapyramidal symptomatology. In view of previous suggestions that brain serotonergic systems may tonically inhibit dopamine neurons, the effects of several new and selective 5-HT2 receptor antagonists and 5-HT1A receptor agonists were investigated in this model. Setoperone, a dopamine D2 receptor antagonist with extremely potent 5-HT2 antagonism, caused dyskinetic movements. Although ritanserin is a potent 5-HT2 antagonist with very weak dopamine antagonist properties, this drug did not antagonize dyskinesias but induced them when administered at a high dose (30 mg/kg). Buspirone induced dyskinesias and blocked apomorphine-induced climbing, supporting prior reports that it has dopamine antagonist effects. Gepirone, a 5-HT1A agonist with less marked dopamine antagonist properties, induced dyskinesias in only one of six monkeys at 30 mg/kg and did not block haloperidol-induced dyskinesias. 8-OH-DPAT partly attenuated haloperidol-induced dyskinesias, an effect possibly attributable to its weak dopamine agonist properties. Tonic inhibition of brain extrapyramidal dopamine systems by serotonin systems does not appear to characterize neuroleptic-related dyskinesias in squirrel monkeys.
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PMID:Effects of 5-HT1A agonists and 5-HT2 antagonists on haloperidol-induced dyskinesias in squirrel monkeys: no evidence for reciprocal 5-HT-dopamine interaction. 252 57

The effects of acute and long-term treatment with buspirone on synaptic transmission in the hippocampus were compared in alert rats with chronic indwelling electrodes and cannula. Buspirone produced a transient dose-dependent reduction in the amplitude of the excitatory postsynaptic potential (EPSP) when acutely injected either systemically (0.3-3.0 mg/kg i.p.) or directly into the hippocampus (0.1-1.0 microgram i.h.). Whereas acute application of 0.5 mg/kg i.p. produced a 20% reduction which reversed within 2 h, during long-term treatment with this relatively low dose there was a gradual reduction of the baseline EPSP amplitude which reached a maximum (40%) between days 7-14 and which did not reverse completely until 72 h after the last injection. Intrahippocampal injection of either buspirone or 5-hydroxytryptamine did not have any additional effect during the period of baseline reduction. The 5-HT1A receptor antagonist spiroxatrine (1 mg/kg i.p.) produced a transient reversal of the effect of chronic buspirone. It is concluded that the chronic inhibitory effect of buspirone is probably an extension of its acute action on 5-HT1A receptors in the hippocampus.
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PMID:Serotonergic involvement in the inhibitory effects of repeated buspirone treatment on synaptic transmission in the hippocampus. 255 Feb 58

Anxiety has historically been treated by agents with a sedative component to their action. In the last decade or so it has been determined that gamma-aminobutyric acid (GABA) receptors may mediate the anxiolytic actions of the benzodiazepines, propanediol carbamates, barbiturates, and ethanol. However, inasmuch as these drugs have additional pharmacological properties (sedation, muscle relaxation, seizure control), the search for an anxioselective drug was continued. Buspirone appears to be such a drug. Clinical studies have clearly demonstrated the efficacy of buspirone in the treatment of generalized anxiety disorder without the ancillary pharmacology of earlier anxiolytics. Buspirone does not act on the GABA receptor. Rather, its most salient interaction with neurotransmitter receptors occurs at the 5-HT1A serotonin receptor. This action is supported by studies focused on receptor binding, anatomical localization, biochemistry, neurophysiology, and animal behavior. The recognition that action at 5-HT1A receptors may be a viable approach to the pharmacotherapy of anxiety is evidenced by the number of other agents of this class under development by a number of pharmaceutical companies.
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PMID:Buspirone, a new approach to the treatment of anxiety. 283 52

Extracellular single-unit recordings were made from serotonergic dorsal raphe neurons in chloral hydrate anesthetized male Sprague-Dawley rats. Buspirone, a clinically effective non-benzodiazepine anxiolytic drug, caused inhibition of firing of these neurons when given by intravenous (ED50 = 0.011 mg/kg, i.v.), intraperitoneal (ED50 = 0.088 mg/kg, i.p.), and intragastric (effective dose = 1.0-20.0 mg/kg, i.g.) injection. Buspirone also inhibited these cells when it was administered to the outside of recorded neurons by microiontophoresis (effective currents = 2-15 nA). Iontophoretically applied buspirone did not potentiate nor block the effects of iontophoretically applied GABA. Systemic administration of two putative buspirone metabolites (1,2-pyrimidinyl piperazine and 5-hydroxy buspirone) in relatively high doses had a weak effect and no effect, respectively, on dorsal raphe neuronal firing. It is concluded that buspirone potently and directly inhibits the firing of serotonergic dorsal raphe neurons in the rat. Since buspirone inhibits the firing of serotonergic dorsal raphe neurons and binds to 5-HT1A receptors, the present study supports the notion that central serotonergic systems may be involved in the therapeutic effects of anxiolytic drugs.
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PMID:Inhibition of serotonergic dorsal raphe neurons by systemic and iontophoretic administration of buspirone, a non-benzodiazepine anxiolytic drug. 287 3

Buspirone, gepirone and ipsaperone administered intraperitoneally (40 mg/kg) to naive rats were found to be proconvulsive for strychnine-induced seizures. The dose of strychnine required to induce seizures in 50% of test animals (CD50) was 2.18 mg/kg in naive rats, while CD50s for rats treated with the azaspirodecanediones ipsaperone, gepirone and buspirone were 1.65, 0.97 and 0.70 mg/kg respectively. Azaspirodecanediones have high affinity for the 5-HT1A serotonin receptor, however, the specific 5-HT1A agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT) had no effect on strychnine seizure in naive rats (CD50 = 2.0 mg/kg). The strychnine specific proconvulsive effects of inferior olive lesions and buspirone were additive, resulting in a CD50 of 0.1 mg/kg. This observation indicates that the buspirone-induced decrease in strychnine seizure threshold does not require intact inferior olive-climbing fiber pathways. Cerebellar sites for possible azaspirodecanedione action are discussed.
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PMID:Strychnine seizure potentiation by azaspirodecanedione anxiolytics in rats. 290 77


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