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)

The present electrophysiological experiments were undertaken to investigate the effect of desipramine and d-amphetamine on noradrenergic neurotransmission in the rat central nervous system. The effectiveness of electrical stimulation of the locus coeruleus and of microiontophoretic application of norepinephrine (NE) in suppressing the firing activity of CA3 pyramidal neurons was studied in the dorsal hippocampus. Desipramine (0.5 and 5 mg/kg i.v.) and d-amphetamine (0.25 and 5 mg/kg i.v.) decreased the effectiveness of locus coeruleus stimulation and prolonged the effect of microiontophoretically applied NE on the same pyramidal neurons. Subsequent i.v. administration of idazoxan, an alpha 2-adrenoceptor antagonist, reversed the effects of desipramine and d-amphetamine on the effectiveness of locus coeruleus stimulation and decreased that of microiontophoretically applied NE. In addition, idazoxan prevented the effect of subsequent administration of desipramine (5 mg/kg i.v.) on the effectiveness of locus coeruleus stimulation. High doses of d-amphetamine (5 and 10 mg/kg i.v.) decreased the firing activity of hippocampus pyramidal neurons by 70 and 98%, respectively, whereas low doses of desipramine (0.5 mg/kg i.v.) or of d-amphetamine (0.25 mg/kg i.v.) were without effect. After lesioning of NE projections with 6-hydroxydopamine, the effect of the 5 mg/kg dose of d-amphetamine on the firing activity of hippocampus pyramidal neurons was markedly reduced, whereas the cumulative 10 mg/kg dose of d-amphetamine completely suppressed, as in control rats, the firing activity of these neurons. This effect of d-amphetamine in 6-hydroxydopamine-pretreated rats was reversed by the administration of the 5-HT1A receptor antagonist BMY 7378. These data provide evidence that acute administration of desipramine and d-amphetamine decreases the effectiveness of locus coeruleus stimulation by increasing the activation of terminal alpha 2-adrenoceptor autoreceptors. In addition, acute administration of high doses of d-amphetamine decreases the firing rate of hippocampus pyramidal neurons by increasing NE and serotonin release.
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PMID:Effect of desipramine and amphetamine on noradrenergic neurotransmission: electrophysiological studies in the rat brain. 133 78

The influence of chronic administration of desipramine (16 mg/kg per day for 8 days) or citalopram (1 mg/kg per day for 8 days) on the serotonergic and noradrenergic stimulations of phosphoinositide hydrolysis and cyclic AMP formation was investigated in rat cerebral cortical slices. This was done by means of a prelabelling method allowing the simultaneous measurement of the accumulations of (3H) inositol phosphates ((3H)IP) and of (14C) cyclic AMP. Our results show that neither of the two drugs altered the inhibition of adenylate cyclase activity induced by serotonin1 (5-HT1) receptor agonists nor did they alter 5-HT1A and 5-HT1B receptor densities. Similarly they did not modify the stimulation of the inositol phosphate metabolism induced by 5-HT or norepinephrine (NE). Desipramine treatment decreased both beta-adrenoceptor-elicited cyclic AMP accumulation (-37%) and beta-adrenoceptor density (-29%), whereas citalopram was without effect. These results reinforce the idea that the ability of antidepressants to decrease the activity of the beta-adrenoceptor-adenylate cyclase complex is not common to all antidepressants, and provide no evidence for the involvement of 5-HT1A and/or 5-HT1B in the mechanism of action of these drugs.
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PMID:Cyclic AMP and inositol phosphate accumulations in rat brain cortical slices following chronic citalopram or desipramine administration. 795 21

The mechanisms of the antinociceptive effect of desipramine (DMI) are only partly known. It is generally accepted that excitatory amino acids act as neurotransmitters in primary nociceptive fibres and recent in vitro studies have shown an interaction between tricyclic antidepressants and the N-methyl-D-aspartic acid (NMDA) receptor complex. In this study, the modulatory effect of DMI on the biting and scratching behaviour induced by intrathecal (i.th.) administration of NMDA (0.25 nmol) was investigated. Desipramine was administered acutely, either intrathecally (0.7-35 micrograms) or intraperitoneally (i.p., 10 mg/kg), or chronically in the drinking water (0.15 g/l) for 3 weeks. The NMDA-induced behaviour was significantly reduced both after acute and chronic administration of DMI. Several studies have shown a functional upregulation of the 5-HT1A receptor after chronic treatment with DMI. The activation of this receptor using the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), leads to a reduction in NMDA-induced behaviour. Using the 5-HT1A antagonist NAN-190 (10 micrograms, i.th.), the effect of chronic administration of DMI on the NMDA-induced behaviour was reversed. However, NAN-190 also increased NMDA-induced behaviour in the control group, suggesting that a tonic inhibition of this behaviour, mediated by the 5-HT1A receptor, may exist. These findings indicate that DMI may reduce glutaminergic transmission at the spinal NMDA receptor. As this receptor is central in spinal nociceptive transmission, this could be one mechanism for the antinociceptive effect of DMI.
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PMID:Reduction of NMDA-induced behaviour after acute and chronic administration of desipramine in mice. 833 22

Improved clinical antidepressant efficacy may result if the acute inhibition of 5-HT cell firing induced by antidepressants is prevented. Here we examined whether inhibition of 5-HT cell firing by non-selective 5-HT uptake inhibiting antidepressant drugs is reversed by a selective 5-HT1A receptor antagonist. In addition, we examined whether concomitant blockade of NA uptake offsets the inhibition of 5-HT cell firing resulting from 5-HT uptake blockade. Antidepressants which block 5-HT uptake (paroxetine, clomipramine, amitriptyline, venlafaxine), all caused dose-dependent and complete inhibition of 5-HT cell firing. Desipramine, a selective NA uptake blocker, caused a slight reduction in firing. The selective 5-HT1A receptor antagonist, WAY 100635, reversed the inhibition of 5-HT cell firing induced by clomipramine, amitriptyline, venlafaxine, and paroxetine, but not that induced by the alpha 1 adrenoceptor antagonist, prazosin. Desipramine, at a dose which increased extracellular NA in the DRN, reversed the effect of prazosin but did not alter the ability of paroxetine to inhibit 5-HT cell firing. Our data indicate that antidepressant drugs with 5-HT uptake blocking properties inhibit 5-HT cell firing via activation of 5-HT1A autoreceptors, and do so irrespective of their effects on NA uptake. These data are discussed in relation to the application of 5-HT1A receptor antagonists to enhance the clinical efficacy of antidepressant drugs.
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PMID:Inhibition of 5-HT cell firing in the DRN by non-selective 5-HT reuptake inhibitors: studies on the role of 5-HT1A autoreceptors and noradrenergic mechanisms. 915 61

The effects of antidepressant drugs on the synthesis of noradrenaline and serotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were investigated simultaneously: the alpha2C-autoreceptor modulating dopa/noradrenaline synthesis, and the alpha2A-heteroreceptor and 5-HT1A-autoreceptor modulating 5-HTP/5-HT synthesis. Acute treatment (2 h, i.p.) with desipramine (1-10 mg/kg), protriptyline (0.3-10 mg/kg) and nisoxetine (3-10 mg/kg), selective NA reuptake blockers, dose-dependently decreased dopa synthesis in cortex (15%-40%) and hippocampus (20%-53%). Fluoxetine (1-10 mg/kg) and zimelidine (1-10 mg/kg), selective 5-HT reuptake blockers, did not alter dopa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP synthesis in cortex (14%-43%) and hippocampus (27%-54%). Desipramine and protryptyline did not alter 5-HTP synthesis in cortex but in hippocampus it was decreased (36%). Repeated desipramine (10 mg/kg for 1-21 days) or fluoxetine (3 mg/kg for 3-21 days) treatment resulted in a time-dependent loss in their ability to decrease dopa or 5-HTP synthesis. Desipramine (1-21 days) did not alter 5-HTP synthesis in cortex, but in hippocampus it was decreased (21%-37%, days 1-14) followed by recovery to control values (day 21). Fluoxetine (3-21 days) did not alter brain dopa synthesis. To further assess the desensitization of alpha2C-autoreceptors, alpha2A-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTP/5-HT after chronic desipramine and fluoxetine, the effects of clonidine (agonist at alpha2-auto/heteroreceptors) and 8-OH-DPAT (agonist at 5-HT1A-autoreceptors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decreased dopa and 5-HTP synthesis in cortex (58% and 54%) and hippocampus (54% and 42%). In desipramine-treated rats (10 mg/kg, 21 days), but not in fluoxetine-treated ones (3 mg/kg, 14 days), the effect of clonidine was attenuated in cortex (12% and 18%) and only for dopa synthesis in hippocampus (31%). In saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis in cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not in desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (9%). These findings indicate that acute treatment with cyclic antidepressant drugs results in activation of inhibitory alpha2C-autoreceptors, alpha2A-heteroreceptors and/or 5-HT1A-autoreceptors regulating the synthesis of dopa/NA and/or 5-HTP/5-HT in brain, whereas chronic treatment with these drugs is followed by desensitization of these presynaptic receptors.
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PMID:Activation and desensitization by cyclic antidepressant drugs of alpha2-autoreceptors, alpha2-heteroreceptors and 5-HT1A-autoreceptors regulating monamine synthesis in the rat brain in vivo. 1049 82