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)

(E)-beta-Fluoromethylene-m-tyrosine (MDL 72394) is not per se an inhibitor of monoamine oxidase (MAO) but is a substrate of aromatic L-amino acid decarboxylase (AADC) which liberates the potent MAO inhibitor (E)-beta-fluoromethylene-m-tyramine (MDL 72392). When co-administered to animals with the peripherally selective AADC inhibitor, carbidopa, MDL 72394 inhibited MAO selectively in the brain. Chronic (14 days plus 3 days withdrawal) administration of 0.5 mg/kg per day p.o. MDL 72394, 0.1 mg/kg per day p.o. MDL 72394 combined with 10 mg/kg per day p.o. carbidopa or 50 mg/kg per day p.o. pargyline produced equivalent inhibition of rat brain MAO and decreased the binding of [3H]clonidine and [3H]RX 781094 to the alpha 2-adrenoceptor and of [3H]dihydroalprenolol to the beta-adrenoceptor without changing binding of [3H]prazosin to the alpha 1-adrenoceptor. The locomotor depressant effect of clonidine was attenuated without attenuation of the hypotensive effect in rats treated chronically with the MAO inhibitors. Neither the sensitivity of the alpha 2-autoreceptor nor of the alpha 2-heteroreceptor was decreased in brain slices. However, the sensitivity of adenylate cyclase to activation by both noradrenaline and isoprenaline was significantly reduced. The number of 5-HT2 and 5-HT1A binding sites was decreased: the 5-HT1B binding sites remained unchanged. The effect of chronic MAO inhibitor treatment on 5-HT1A receptors was associated with a decrease in the behavioural response to 8-hydroxy-2-(di-n-propylamino)tetralin and the decrease in 5-HT2 binding was related to a small reduction in the sensitivity of the inositol phosphate system to stimulation by 5-HT. The lack of effect of chronic MAO treatment on the 5-HT autoreceptor measured in cortical slices corresponded to a lack of effect on the 5-HT1B binding site except that chronic administration of pargyline produced a small but significant decrease in 5-HT autoreceptor sensitivity. Overall, the data show that chronic administration of MDL 72394 has a profile of effects on central monoamine receptor binding and function similar to that seen following chronic administration of a number of clinically effective antidepressants.
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PMID:Monoamine receptor sensitivity changes following chronic administration of MDL 72394, a site-directed inhibitor of monoamine oxidase. 378 Aug 61

The serotonin syndrome has increasingly been recognised in patients who have received combined serotonergic drugs. This syndrome is characterised by a constellation of symptoms (confusion, fever, shivering, diaphoresis, ataxia, hyperelflexia, myoclonus or diarrhoea) in the setting of the recent addition of a serotonergic agent. The most common drug combinations causing the serotonin syndrome are monoamine oxidase inhibitors (MAOIs) and serotonin selective reuptake inhibitors (SSRIs), MAOIs and tricyclic antidepressants, MAOIs and tryptophan, and MAOIs and pethidine (meperidine). This syndrome is caused by excess serotonin (5-hydroxytryptamine; 5-HT) availability in the CNS at the 5-HT1A-receptor. There may also be some interaction with dopamine and 5-HT2-receptors. This syndrome probably has a low incidence, even among patients taking these drug combinations, and there is likely to be some other as yet unidentified inciting factor causing some patients to develop a full serotonin syndrome. Because fatalities and severe complications have accompanied the serotonin syndrome, the previously described drug combinations should be used cautiously or not at all. The serotonin syndrome is usually mild and, if managed with drug withdrawal and supportive therapy, generally improves within hours. Patients who develop hyperthermia should be treated aggressively with external cooling and paralysis. Methysergide and cyproheptadine appear to be useful adjuncts in treating the serotonin syndrome.
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PMID:The serotonin syndrome. Implicated drugs, pathophysiology and management. 757 68

Nefazodone is a new antidepressant drug with a pharmacologic profile distinct from that of the tricyclic, monoamine oxidase inhibitor, and serotonin selective reuptake inhibitor antidepressants. Nefazodone was initially discovered for its ability to block 5-HT2A receptors and its reduced potency as an alpha 1-adrenergic blocker. It was later shown to inhibit both serotonin and norepinephrine uptake in vitro, attributes which most likely impart its clinical efficacy and which differentiate nefazodone from its chemical predecessor trazodone. The combination of these two mechanisms may ultimately result in a facilitation of 5-HT1A-mediated neurotransmission, which may be beneficial for treating symptoms of depression as evidenced by recent clinical findings. In addition, the preclinical profile of nefazodone demonstrates that it has decreased anticholinergic and antihistaminic activity relative to traditional agents. Clinical findings to date are consistent with these observations.
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PMID:Pharmacology and neurochemistry of nefazodone, a novel antidepressant drug. 1081 10

Previous results from our laboratory indicate that small doses of the alpha-2 adrenergic agonist clonidine increase serotonin (5-HT) neurotransmission by attenuating the release of endogenous norepinephrine (NE), as a result of the activation of alpha-2 adrenergic autoreceptors on NE neurons, and that high doses decrease 5-HT neurotransmission by activating directly alpha-2 adrenergic heteroreceptors on 5-HT terminals. In addition, we have shown that long-term treatments with a monoamine oxidase inhibitor or a selective NE, but not a 5-HT, reuptake inhibitor abolish the effect of a high dose of clonidine, but not that of a small dose of clonidine. The aim of the present study was to determine whether the alpha-2 adrenergic antagonists idazoxan (10 mg/kg/day x 21 days s.c.) and mianserin (5 mg/kg/day x 21 days s.c.), or electroconvulsive shocks (6 or 7 over a 2-week period) would also affect the alpha-2 adrenoceptors modulating 5-HT neurotransmission in the rat hippocampus. The responsiveness of these hetereceptors was tested in parallel with those of the terminal 5-HT1B autoreceptors and of the postsynaptic 5-HT1A and alpha-2 adrenergic receptors. None of the above treatments altered the responsiveness of the 5-HT1B autoreceptors, as assessed by comparing the differential effectiveness of 1 and 5 Hz electrical stimulations of the 5-HT pathway. Idazoxan and mianserin did not affect the responsiveness of the postsynaptic 5-HT1A and alpha-2 adrenergic receptors as indicated by the unchanged suppressant effects of microiontophoretically applied 5-HT and NE.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of long-term alpha-2 adrenergic antagonists and electroconvulsive treatments on the alpha-2 adrenoceptors modulating serotonin neurotransmission. 791 78

Electrophysiological studies suggest that 5-HT autoreceptor desensitization may be responsible for the delayed clinical efficacy of some antidepressant drugs, such as selective 5-HT reuptake inhibitors (SSRI) and certain MAO inhibitors (MAOI). In the present study we have used in vivo microdialysis to test this hypothesis. Rats were treated for 2 weeks with the antidepressant SSRI citalopram (5 mg/kg, s.c., b.i.d.). After 24 hr withdrawal, dialysis probes were implanted in the dorsal hippocampus (DH) and the frontal cortex (FCx). The rats then received as acute challenge, a 5-HT1A autoreceptor-active dose of the reference 5-HT1A agonist 8-OH-DPAT (0.025 mg/kg s.c.). The 8-OH-DPAT-induced changes in dialysate 5-HT from the DH and the FCx were monitored and taken as an index of autoreceptor sensitivity. Chronic citalopram and control animals responded similarly to 8-OH-DPAT with a drop of 5-HT of about 50-65%; no significant difference between the chronic citalopram and control groups were obtained, either in the DH or in the FCx. These data suggest that cell body 5-HT1A autoreceptors do not desensitize in response to repeated administration with antidepressant SSRI drugs such as citalopram.
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PMID:Lack of 5-HT1A autoreceptor desensitization following chronic citalopram treatment, as determined by in vivo microdialysis. 798 70

The present study provides evidence that, in mice subjected to the forced swimming test, the anti-immobility effect of the tricyclic antidepressants, desipramine and imipramine (16-32 mg/kg) was antagonized by the acute co-administration of a benzodiazepine, diazepam (0.25-2 mg/kg) and lorazepam (0.125 mg/kg). This effect cannot be accounted for by variations in plasma and/or brain levels of each compound since brain and plasma concentrations of desipramine and plasma levels of diazepam and desmethyldiazepam, measured immediately after the swimming test, were not significantly modified by the co-administration. Diazepam (2 mg/kg) also counteracted the reduction of time spent immobile induced by the MAO inhibitors, toloxatone (256 mg/kg) and selegiline (4 mg/kg) and the 5-HT1A receptor agonist, 8-OH-DPAT (1 mg/kg), but not by the psychostimulant, caffeine (32 mg/kg). The sedative neuroleptic, thioridazine (4 mg/kg) was also found to reverse the anti-immobility effect of desipramine whereas the non-benzodiazepine anxiolytics, alpidem (8 mg/kg) and buspirone (0.5 mg/kg) did not. These results indicate that the observed interactions were unlikely to be accounted for by a reduction of the stressful aspect of the situation whereas the participation of some motor or sedative component could not be totally ruled out.
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PMID:Benzodiazepines reverse the anti-immobility effect of antidepressants in the forced swimming test in mice. 810 Jun 21

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

Chronic administration of antidepressant drugs enhances synaptic serotonergic transmission. Nefazodone, a member of a new class of antidepressants, has a pharmacologic profile that is distinct from the first-generation agents (e.g., tricyclics and monoamine oxidase inhibitors) as well as the more selectively acting second-generation agents (e.g., serotonin or norepinephrine uptake inhibitors, and serotonin type 1A partial agonists). Nefazodone acts both as a 5-HT2 receptor antagonist and as a serotonin (5-HT) reuptake inhibitor. Nefazodone's potent 5-HT2 antagonism in combination with 5-HT reuptake inhibition appears to enhance 5-HT1A-mediated neurotransmission. Nefazodone has very selective serotonergic effects, with negligible affinity for cholinergic and histamine receptors and low affinity for alpha 1-adrenergic receptors. It is also free of cardiotoxicity and is well tolerated even at high doses. The two primary effects on serotonergic neurotransmission, 5-HT2 antagonism and 5-HT reuptake inhibition, are thought to contribute importantly to nefazodone's therapeutic efficacy and clinical utility. It is postulated that 5-HT2 antagonism dampens the activating side effects experienced by some patients when treated with existing 5-HT reuptake inhibitors. Nefazodone's effectiveness as an antidepressant drug has been shown in a series of well-controlled, placebo-comparison studies of somewhat differing designs involving patients with major depression. In placebo-controlled studies comparing nefazodone and the tricyclic antidepressant imipramine, the drugs produced comparable and significant therapeutic benefit. Nefazodone is associated with fewer adverse events than imipramine. Nefazodone lacks the troublesome anticholinergic side effects of tricyclic antidepressants, as well as serotonergic/noradrenergic-mediated effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Novel serotonergic mechanisms and clinical experience with nefazodone. 813 Nov 54

We have studied the effect of serotonin on synaptic transmission in rat hippocampal subiculum slices. Electrical stimulation of the alveus induced a field potential in the subiculum. The non-NMDA glutamate receptor antagonist, NBQX (3 x 10(-6) mol/l) suppressed the response by 78%, indicating that the signal involves glutamatergic neurons. Application of serotonin suppressed (EC50 = 3.6 x 10(-6) mol/l) the amplitude of the evoked potentials in a reversible, concentration-dependent manner. The responses to 5-HT were not altered after pretreatment with the 5-HT uptake blocker, fluvoxamine (10(-5) mol/l) or a combination of the MAO inhibitor pargyline (10(-5) mol/l) and ascorbic acid (10(-4) mol/l). The responses to 5-HT were also unaffected by pretreatment with the 5-HT1A selective antagonist NAN-190 (10(-6) mol/l), the 5-HT2A antagonist ketanserin (10(-6) mol/l) or the 5-HT3/5-HT4 antagonist ICS 205-930 (10(-6) mol/l). The 5-HT1B selective agonist CP 93,129 mimicked the effects of serotonin, but was more potent (EC50 4.1 x 10(-7) mol/l). The 5-HT1B receptor antagonist, (+/-)21-009 (3 x 10(-7) mol/l), antagonized the response to 5-HT and CP 93,129 with a pKB value of 7.1 and 7.2, respectively. These results suggest that the effect of 5-HT in the rat subiculum is mediated by 5-HT1B receptors.
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PMID:Serotonergic modulation of neurotransmission in the rat subicular cortex in vitro: a role for 5-HT1B receptors. 813 98

A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HT1C receptors in the brain. Conventional tricyclic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine) as well as mianserin and trazodone were found to display high to low nanomolar affinity for 5-HT1C receptors. Antidepressants of other chemical classes and with other mechanisms of action (affecting amine uptake systems: fluoxetine, citalopram, sertraline, fluvoxamine, nomifensine, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had negligible affinities (micromolar range) for 5-HT1C receptors, except fluoxetine. When tested in an in vivo rat model thought to reveal functional agonistic or antagonistic properties at 5-HT1C receptors, all antidepressants displaying high affinity for this receptor type (except clomipramine and trimipramine) were antagonists at 5-HT1C receptors. Antidepressants with a lower affinity for 5-HT1C receptors (except nomifensine) were inactive in this functional in vivo model. Taken together, these results suggest that antagonism at brain 5-HT1C receptors is a component of the antiserotonergic properties of a number of established antidepressants. In addition, the study confirmed that 5-HT1A receptors functionally interact with 5-HT1C receptors, which suggests that some degree of activity at 5-HT1A receptors may also be an important property for antidepressant activity.
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PMID:Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs. 845 78


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