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P Celada

Publications and source records attributed to P Celada.

At least 19 recordsLinked to original sources
PubMed2001

Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism.

We examined the in vivo effects of the hallucinogen 4-iodo-2,5-dimethoxyamphetamine (DOI). DOI suppressed the firing rate of 7 of 12 dorsal raphe (DR) serotonergic (5-HT) neurons and partially inhibited the rest (ED(50) = 20 microg/kg, i.v.), an effect reversed by M100907 (5-HT(2A) antagonist) and picrotoxinin (GABA(A) antagonist). DOI (1 mg/kg, s.c.) reduced the 5-HT release in medial prefrontal cortex (mPFC) to 33 +/- 8% of baseline, an effect also antagonized by M100907. However, the local application of DOI in the mPFC increased 5-HT release (164 +/- 6% at 100 microm), an effect antagonized by tetrodotoxin, M100907, and BAY x 3702 (5-HT(1A) agonist) but not by SB 242084 (5-HT(2C) antagonist). The 5-HT increase was also reversed by NBQX (AMPA-KA antagonist) and 1S,3S-ACPD (mGluR 2/3 agonist) but not by MK-801 (NMDA antagonist). AMPA mimicked the 5-HT elevation produced by DOI. Likewise, the electrical-chemical stimulation of thalamocortical afferents and the local inhibition of glutamate uptake increased the 5-HT release through AMPA receptors. DOI application in mPFC increased the firing rate of a subgroup of 5-HT neurons (5 of 10), indicating an enhanced output of pyramidal neurons. Dual-label fluorescence confocal microscopic studies demonstrated colocalization of 5-HT(1A) and 5-HT(2A) receptors on individual cortical pyramidal neurons. Thus, DOI reduces the activity of ascending 5-HT neurons through a DR-based action and enhances serotonergic and glutamatergic transmission in mPFC through 5-HT(2A) and AMPA receptors. Because pyramidal neurons coexpress 5-HT(1A) and 5-HT(2A) receptors, DOI disrupts the balance between excitatory and inhibitory inputs and leads to an increased activity that may mediate its hallucinogenic action.

Amphetamines↗
PubMed2001

Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: Involvement of serotonin-1A, GABA(A), and glutamate receptors.

Anatomical evidence indicates that medial prefrontal cortex (mPFC) neurons project to the dorsal raphe nucleus (DR). In this study, we functionally characterized this descending pathway in rat brain. Projection neurons in the mPFC were identified by antidromic stimulation from the DR. Electrical stimulation of the mPFC mainly inhibited the activity of DR 5-HT neurons (55 of 66). Peristimulus time histograms showed a silence of 150 +/- 9 msec poststimulus (latency, 36 +/- 1 msec). The administration of WAY-100635 and picrotoxinin partly reversed this inhibition, indicating the involvement of 5-HT(1A) and GABA(A) receptors. In rats depleted of 5-HT with p-chlorophenylalanine, the electrical stimulation of mPFC mainly activated 5-HT neurons (31 of 40). The excitations (latency, 17 +/- 1 msec) were antagonized by MK-801 and NBQX. Likewise, MK-801 prevented the rise in DR 5-HT release induced by electrical stimulation of mPFC. The application of 8-OH-DPAT in mPFC significantly inhibited the firing rate of DR 5-HT neurons and, in dual-probe microdialysis experiments, reduced the 5-HT output in mPFC and DR. Furthermore, the application of WAY-100635 in mPFC significantly antagonized the reduction of 5-HT release produced by systemic 8-OH-DPAT administration in both areas. These results indicate the existence of a complex regulation of DR 5-HT neurons by mPFC afferents. The stimulus-induced excitation of some 5-HT neurons by descending excitatory fibers releases 5-HT, which inhibits the same or other DR neurons by acting on 5-HT(1A) autoreceptors. Afferents from the mPFC also inhibit 5-HT neurons through the activation of GABAergic interneurons. Ascending serotonergic pathways may control the activity of this descending pathway by acting on postsynaptic 5-HT(1A) receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

How does pindolol improve antidepressant action?

Since 1994, the beta-adrenoceptor and 5-HT(1A/1B) receptor ligand pindolol has been used to accelerate or enhance the clinical effects of antidepressant drugs, such as the selective 5-HT reuptake inhibitors (SSRIs), that act primarily on 5-HT-containing neurones. Pindolol was initially thought to act by preventing the inhibition of 5-HT release, elicited by SSRIs and other 5-HT-acting drugs, as a result of its ability to antagonize the action of 5-HT at midbrain raphe 5-HT(1A) autoreceptors that control the activity of ascending 5-HT-mediated pathways. However, the partial agonist properties of pindolol at 5-HT(1A) receptors and beta-adrenoceptors suggest that other explanations for its action are also possible. In this article, recent controversial data on the mechanism of action of pindolol, which are crucial for the development of more rapid and efficient antidepressant therapies, will be discussed.

Adrenergic beta-Antagonists↗
PubMed2001

The role of 5-HT1B receptors in the regulation of serotonin cell firing and release in the rat brain.

The release of 5-HT in terminal areas of the rodent brain is regulated by 5-HT1B receptors. Here we examined the role of 5-HT1B receptors in the control of 5-HT output and firing in the dorsal raphe nucleus (DR), median raphe nucleus (MnR) and forebrain of the rat in vivo. The local perfusion (30-300 microM) of the selective 5-HT1B receptor agonist CP-93,129 to freely moving rats decreased 5-HT release in the DR and more markedly in the MnR. Likewise, 300 microM CP-93,129 reduced 5-HT output in substantia nigra pars reticulata, ventral pallidum, lateral habenula and the suprachiasmatic nucleus. The effect of CP-93,129 was prevented by SB-224289, but not by WAY-100635, selective 5-HT1B and 5-HT1A receptor antagonists, respectively. SB-224289 did not alter dialysate 5-HT in any raphe nuclei. The intravenous administration of the brain-penetrant selective 5-HT1B receptor agonist CP-94,253 (0.5-2.0 mg/kg) to anesthetized rats decreased dialysate 5-HT in dorsal hippocampus and globus pallidus, increased it in MnR and left it unaltered in the DR and medial prefrontal cortex. SB-224289, at a dose known to block 5-HT1B autoreceptor-mediated effects (5 mg/kg), did not prevent the effect of CP-94,253 on MnR 5-HT. The intravenous administration of CP-94,253 (0.05-1.6 mg/kg) to anesthetized rats increased the firing rate of MnR, but not DR-5-HT neurons. The local perfusion of CP-94,253 in the MnR showed a biphasic effect, with 5-HT reductions at 0.3-3 microM and increase at 300 microM. These results suggest that 5-HT cell firing and release in midbrain raphe nuclei (particularly in the MnR) are under control of 5-HT1B receptors. The activation of 5-HT1B autoreceptors (possibly located on 5-HT nerve endings and/or varicosities within DR and MnR) reduces 5-HT release. The effects of higher concentrations of 5-HT1B receptor agonists seem more compatible with the activation of 5-HT1B heteroreceptors on inhibitory neurons.

Animals↗
PubMed2000

In vivo actions of the selective 5-HT1A receptor agonist BAY x 3702 on serotonergic cell firing and release.

We investigated the effects of the novel 5-HT1A receptor agonist BAY x 3702 on the serotonergic function in rat brain using single unit recordings in the dorsal raphe nucleus (DR) of anesthetized rats and in vivo microdialysis in freely moving rats. The administration of BAY x 3702 (0.25-4 microg/kg i.v.) suppressed the firing activity of 5-HT neurones. This effect was antagonized by a low dose of the selective 5-HT1A receptor antagonist WAY 100635 (5 microg/kg i.v.). In microdialysis experiments, BAY x 3702 (10-100 microg/ kg s.c.) reduced dose-dependently the 5-HT output in the dorsal and median raphe (MnR) nucleus, dorsal hippocampus (DHPC) and medial prefrontal cortex (mPFC) in a regionally selective manner. Maximal effects were observed in the MnR and mPFC, with reductions to approximately 15% of baseline at a dose of 0.1 mg/kg s.c. The decrease in 5-HT output produced in the DR and DHPC was more moderate, to 45% of baseline at 0.1 mg/kg s.c. BAY x 3702. WAY 100635 (0.3 mg/kg s.c.) completely antagonized the effect of BAY x 3702 (30 microg/kg s.c.). The application of BAY x 3702 in the DR (1-100 microM) reduced the local 5-HT output to 25% of baseline. In rats implanted with two dialysis probes (in DR and mPFC) the application of BAY x 3702 (30 microM) in the DR reduced the 5-HT output in the DR and that in mPFC. These effects were significantly antagonized by the co-perfusion of WAY 100635 (100 microM) in the DR. Overall, these results indicate that the systemic administration of BAY x 3702 reduces the 5-HT release with high potency through the activation of midbrain 5-HT1A receptors.

Analysis of Variance↗
PubMed1999

Striatal, pallidal, and pars reticulata evoked inhibition of nigrostriatal dopaminergic neurons is mediated by GABA(A) receptors in vivo.

Dopaminergic neurons express both GABA(A) and GABA(B) receptors and GABAergic inputs play a significant role in the afferent modulation of these neurons. Electrical stimulation of GABAergic pathways originating in neostriatum, globus pallidus or substantia nigra pars reticulata produces inhibition of dopaminergic neurons in vivo. Despite a number of prior studies, the identity of the GABAergic receptor subtype(s) mediating the inhibition evoked by electrical stimulation of neostriatum, globus pallidus, or the axon collaterals of the projection neurons from substantia nigra pars reticulata in vivo remain uncertain. Single-unit extracellular recordings were obtained from substantia nigra dopaminergic neurons in urethane anesthetized rats. The effects of local pressure application of the selective GABA(A) antagonists, bicuculline and picrotoxin, and the GABA(B) antagonists, saclofen and CGP-55845A, on the inhibition of dopaminergic neurons elicited by single-pulse electrical stimulation of striatum, globus pallidus, and the thalamic axon terminals of the substantia nigra pars reticulata projection neurons were recorded in vivo. Striatal, pallidal, and thalamic induced inhibition of dopaminergic neurons was always attenuated or completely abolished by local application of the GABA(A) antagonists. In contrast, the GABA(B) antagonists, saclofen or CGP-55845A, did not block or attenuate the stimulus-induced inhibition and at times even increased the magnitude and/or duration of the evoked inhibition. Train stimulation of globus pallidus and striatum also produced an inhibition of firing in dopaminergic neurons of longer duration. However this inhibition was largely insensitive to either GABA(A) or GABA(B) antagonists although the GABA(A) antagonists consistently blocked the early portion of the inhibitory period indicating the presence of a GABA(A) component. These data demonstrate that dopaminergic neurons of the substantia nigra pars compacta are inhibited by electrical stimulation of striatum, globus pallidus, and the projection neurons of substantia nigra pars reticulata in vivo. This inhibition appears to be mediated via the GABA(A) receptor subtype, and all three GABAergic afferents studied appear to possess inhibitory presynaptic GABA(B) autoreceptors that are active under physiological conditions in vivo.

Afferent Pathways↗
PubMed1999

GABAergic control of rat substantia nigra dopaminergic neurons: role of globus pallidus and substantia nigra pars reticulata.

Dopaminergic neurons in vivo fire spontaneously in three distinct patterns or modes. It has previously been shown that the firing pattern of substantia nigra dopaminergic neurons can be differentially modulated by local application of GABA(A) and GABA(B) receptor antagonists. The GABA(A) antagonists, bicuculline or picrotoxin, greatly increase burst firing in dopaminergic neurons whereas GABA(B) antagonists cause a modest shift away from burst firing towards pacemaker-like firing. The three principal GABAergic inputs to nigral dopaminergic neurons arise from striatum, globus pallidus and from the axon collaterals of nigral pars reticulata projection neurons, each of which appear to act in vivo primarily on GABA(A) receptors (see preceding paper). In this study we attempted to determine on which afferent pathway(s) GABA(A) antagonists were acting to cause burst firing. Substantia nigra dopaminergic neurons were studied by single unit extracellular recordings in urethane anesthetized rats during pharmacologically induced inhibition and excitation of globus pallidus. Muscimol-induced inhibition of pallidal neurons produced an increase in the regularity of firing of nigral dopaminergic neurons together with a slight decrease in firing rate. Bicuculline-induced excitation of globus pallidus neurons produced a marked increase in burst firing together with a modest increase in firing rate. These changes in firing rate were in the opposite direction to what would be expected for a monosynaptic GABAergic pallidonigral input. Examination of the response of pars reticulata GABAergic neurons to similar manipulations of globus pallidus revealed that the firing rates of these neurons were much more sensitive to changes in globus pallidus neuron firing rate than dopaminergic neurons and that they responded in the opposite direction. Pallidal inhibition produced a dramatic increase in the firing rate of pars reticulata GABAergic neurons while pallidal excitation suppressed the spontaneous activity of pars reticulata GABAergic neurons. These data suggest that globus pallidus exerts significant control over the firing rate and pattern of substantia nigra dopaminergic neurons through a disynaptic pathway involving nigral pars reticulata GABAergic neurons and that at least one important way in which local application of bicuculline induces burst firing of dopaminergic neurons is by disinhibition of this tonic inhibitory input.

Action Potentials↗
PubMed1998

Relationship between blood serotonergic variables, melancholic traits, and response to antidepressant treatments.

The relationship between peripheral serotonergic variables, melancholic traits, and clinical improvement after antidepressant treatment was examined in 83 drug-free major depressive patients. Plasma serotonin (5-HT) concentrations was lower in untreated melancholic patients (1.00 +/- 0.11 vs. 1.84 +/- 0.28 ng/mL, p < 0.008; N = 40 and 43, respectively). A tendency was observed for plasma 5-hydroxyindoleacetic acid (p < 0.06), whereas platelet 5-HT and plasma tryptophan did not differ between groups. After blood sampling and clinical ratings, treatment began with fixed doses of 5-HT uptake inhibitors (clomipramine or fluvoxamine), monoamine oxidase inhibitors, or tianeptine, a 5-HT uptake enhancer. There was no significant difference in response rates between patients with and without melancholic traits. The relationship between the clinical response at 6 weeks (>50% reduction of baseline Hamilton score) and the pretreatment values of biochemical variables was examined. Responders had a lower pretreatment platelet 5-HT (530 +/- 36 vs. 664 +/- 50 ng/10(9) platelets, p < 0.03; N = 44 and 39, respectively). Patients with a platelet 5-HT concentration above 800 ng/10(9) platelets had a lower response rate than those below this value (p < 0.003). This difference was maximal in the subgroup of patients treated with 5-HT uptake inhibitors (N = 49). In this subgroup, the response rates of patients with 5-HT concentrations below and above the cutoff point were, respectively, 70% and 17% (p < 0.001). A pretreatment platelet 5-HT value above 800 ng/10(9) platelets had a predictive value for a negative response of 92%. These results suggest the presence of biochemical differences in the peripheral serotonergic system between melancholic and nonmelancholic patients. The inverse relationship between the pretreatment platelet 5-HT content and clinical response may be useful in the investigation of the relationship between the 5-HT system and antidepressant response.

Adult↗
PubMed1996

Local infusion of brain-derived neurotrophic factor modifies the firing pattern of dorsal raphé serotonergic neurons.

Previous studies have reported a neuromodulatory effect of brain-derived neurotrophic factor (BDNF) on serotonin neurons in the central nervous system. In the present study, we examined the effects of local infusion of BDNF on the electrophysiological activity of serotonergic neurons in the rat dorsal raphé nucleus with extracellular single unit recording in vivo. Compared with vehicle-infused rats, chronic administration of BDNF (10-14 days) caused serotonergic neurons to fire in a significantly less regular pattern, without altering the mean firing rate or other measures of electrical activity. These results suggest that the ability of similar infusions of BDNF to produce behavioral effects (i.e. analgesia and an antidepressant-like effect) associated with elevated serotonin turnover may be in part the result of more irregular firing patterns of dorsal raphé neurons.

Animals↗
PubMed1994

Reduction of in vivo striatal 5-hydroxytryptamine release by 8-OH-DPAT after inactivation of Gi/G(o) proteins in dorsal raphe nucleus.

5-HT1A receptor agonists reduce firing-dependent terminal 5-HT synthesis and release by activating somatodendritic 5-HT1A receptors. We have examined the effects of 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT, 0.1 mg/kg s.c.) on in vivo striatal 5-HT release in conscious rats with somatodendritic 5-HT1A receptors inactivated by the application of pertussis toxin in the dorsal raphe nucleus. The uncoupling of 5-HT1A receptors from hyperpolarizing potassium channels was demonstrated by the inability of the intra-raphe application of citalopram to reduce striatal release (control animals had a 47% reduction, an effect prevented by previous treatment with the 5-HT1A antagonist (-)-tertatolol). Yet 8-OH-DPAT (0.1 mg/kg s.c.) decreased striatal 5-HT release by 66% (peak effect) in pertussis toxin-treated rats, a value comparable to that found in naive animals (74%). This raises the possibility that other 8-OH-DPAT-sensitive serotonergic receptors different from 5-HT1A autoreceptors may be involved in the control of terminal 5-HT release.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

The effects of brofaromine, a reversible MAO-A inhibitor, on extracellular serotonin in the raphe nuclei and frontal cortex of freely moving rats.

The effects of brofaromine, a reversible inhibitor of MAO-A, on the extracellular content of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) have been studied in two regions of the rat brain (midbrain raphe nuclei and frontal cortex). In both areas, locally infused brofaromine induced dose-dependent increases of 5-HT which were more marked in the raphe nuclei. Brofaromine increased extracellular 5-HT more markedly than clorgyline, suggesting that other factors (i.e. inhibition of 5-HT uptake) may be involved in its local effects. Systemic (3 mg/kg, s.c.) brofaromine did not modify extracellular 5-HT in any brain area examined. In contrast, the concurrent administration of brofaromine and deprenyl led to significant changes in the concentration of 5-HT and 5-HIAA in the brain extracellular space. The results are discussed in relation to the role of MAO-A in the control of 5-HT output.

Animals↗
PubMed1994

Effects of chronic treatment with dexfenfluramine on serotonin in rat blood, brain and lung tissue.

We have examined the effects of continuous treatment (0.5, 1, 2.5 and 5 mg.kg-1.day-1 for 14 days, using minipumps) with dexfenfluramine (dF) on the concentration of serotonin (5-hydroxytryptamine, 5-HT) in blood, lungs and brain frontal cortex. 5-HT concentration was decreased in whole blood and tissues by the two higher doses (2.5 and 5 mg.kg-1.day-1). The concentration of dF in plasma was above detection limit only in these two treatment groups. The concentration of 5-HT in plasma (extracellular) was not modified dose-dependently, although values higher than controls were noted in the 2.5 mg.kg-1 group. Significant correlations were observed between the concentration of 5-HT in whole blood and that of 5-HT (and 5-HT + 5-HIAA) in frontal cortex. Both correlated inversely with the plasma concentration of dF. These results show that treatment with dF for two weeks reduces the concentration of intracellular 5-HT in peripheral stores (platelets, lung endothelial cells) without a concurrent increase of the extracellular 5-HT pool in blood. Correlation data suggest that whole blood 5-HT content may have a predictive value of dF-induced reductions of 5-HT in brain tissue after long-term treatment.

Animals↗
PubMed1993

Monoamine oxidase inhibitors increase preferentially extracellular 5-hydroxytryptamine in the midbrain raphe nuclei. A brain microdialysis study in the awake rat.

We have examined the local and systemic effects of clorgyline, tranylcypromine and deprenyl on extracellular serotonin (5-HT) and 5-hydroxyindoleacetic acid in the raphe nuclei and in frontal cortex of awake, freely-moving rats using microdialysis. When administered through the dialysis probe, monoamine oxidase (monoamine: oxygen oxidoreductase (deaminating), E.C. 1.4.3.4., MAO) inhibitors increased 5-HT output in a dose-dependent manner in both brain areas. The effects were more pronounced in the raphe nuclei for the three MAO inhibitors at all doses assayed. When the monoamine oxidase inhibitors were given i.p., dialysate 5-HT increased dramatically, after tranylcypromine (15 mg/kg), in raphe nuclei and frontal cortex (area under the curve (AUC) to 4 h post-treatment: 63-fold and 11-fold, respectively) whereas the effects of clorgyline (10 mg/kg) were much less pronounced (+47% increase in the AUC for raphe nuclei, P < 0.09; +18% increase in the AUC for frontal cortex, n.s.). Deprenyl (2.5 mg/kg, i.p.) induced a moderate (+22%) increase of dialysate 5-HT from the raphe nuclei but did not cause a change in dialysate 5-HT from the frontal cortex (+4%). However, clorgyline, or deprenyl, dramatically increased dialysate 5-HT in animals which had been pre-treated with the above dose of deprenyl, or clorgyline, respectively, showing that the blockade of both forms of MAO results in much larger increases of extracellular 5-HT than does the blockade of either form alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

p-chlorophenylalanine increases tryptophan-5-hydroxylase mRNA levels in the rat dorsal raphe: a time course study using in situ hybridization.

The effects of a single dose of p-chlorophenylalanine on the mRNA encoding tryptophan-5-hydroxylase (EC 1.14.16.4) in the rat dorsal raphe nucleus were analyzed using in situ hybridization. The levels of tryptophan-5-hydroxylase mRNA were markedly increased in cell bodies located in the ventromedial part of the dorsal raphe 1-2 days after p-chlorophenylalanine (300 mg/kg, i.p.) administration. This was followed by a decrease in the amount of tryptophan-5-hydroxylase mRNA, which returned to basal values by 5 days after treatment. An almost symmetric time course was observed for the midbrain serotonin concentration. Our results on the temporal pattern of changes in tryptophan-5-hydroxylase mRNA levels in the ventromedial part of the dorsal raphe are opposite to those reported for the enzyme activity and serotonin concentration after p-chlorophenylalanine treatment. These changes may result from modifications in enzyme mRNA expression, suggesting that tryptophan-5-hydroxylase gene transcription is involved in feedback mechanisms regulating serotonin synthesis.

Animals↗
PubMed1993

Plasma 5-hydroxyindoleacetic acid as an indicator of monoamine oxidase-A inhibition in rat brain and peripheral tissues.

We have examined the changes induced by the monoamine oxidase (MAO; EC 1.4.3.4) inhibitors tranylcypromine, clorgyline, and deprenyl on MAO activity and 5-hydroxytryptamine (serotonin, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content in rat brain and blood (plasma and whole blood). The decreases of MAO-A activity observed in the liver and lungs after different doses of clorgyline or tranylcypromine correlated significantly (r > 0.80 in all cases) with the decline of plasma 5-HIAA. This was unaffected by 0.25 and 5 mg kg-1 of deprenyl, indicating that 5-HT was deaminated exclusively in the periphery by MAO-A. It is interesting that very potent and significant correlations (r > 0.75) were found between plasma 5-HIAA and MAO-A activity, 5-HIAA and 5-HT content in brain tissue. These results suggest that plasma 5-HIAA can be used confidently as a peripheral indicator of the inhibition of MAO-A in brain. This may represent a favorable alternative to the analysis of 5-HIAA in CSF in psychiatric patients undergoing antidepressant treatment with nonspecific MAO inhibitors or with the new selective MAO-A inhibitors.

Animals↗
PubMed1992

Effects of acute and chronic treatment with fluvoxamine on extracellular and platelet serotonin in the blood of major depressive patients. Relationship to clinical improvement.

The effects of the treatment with fluvoxamine (FVX) on platelet and plasma serotonin (5-HT) have been examined in eleven drug-free major depressive patients. Acute FVX was without effect, whereas the repeated oral treatment (100-150 mg daily, 12 weeks) reduced platelet 5-HT (-89%, P less than 0.001) and plasma 5-HT (-60%, P less than 0.02). Patients who responded to the treatment at 6 weeks (Hamilton score less than or equal to 10) had significantly lower (-39%, P less than 0.02) pretreatment values of platelet 5-HT than the rest. This suggests that 'low 5-HT' patients may have a more rapid improvement after fluvoxamine. Platelet 5-HT and HDRS correlated significantly along the treatment (r = 0.679, P less than 0.01). These data demonstrate a marked action of fluvoxamine as 5-HT uptake inhibitor at therapeutic doses and confirm that this mechanism is relevant for its efficacy as antidepressant drug.

Adult↗
PubMed1992

Monoamine oxidase inhibitors phenelzine and brofaromine increase plasma serotonin and decrease 5-hydroxyindoleacetic acid in patients with major depression: relationship to clinical improvement.

We have examined the effects of two monoamine oxidase (MAO) inhibitors with different mechanisms of action--phenelzine and brofaromine--on peripheral serotonergic (5-hydroxytryptamine [5-HT]) measures, sensitive to the inhibition of MAO-A (intra- and extracellular 5-HT and related metabolites in blood). Both drugs increased the concentration of 5-HT in platelet-free plasma (254%, p less than 0.001) in patients with depressive illness (DSM-III-R) after 6 weeks of daily treatment. Platelet 5-HT was also increased significantly in both drug treatment groups but more marked in the patient group treated with phenelzine. The acid/amine ratio at 6 weeks was 30% of pretreatment values (p less than 0.000) and individual variability correlated significantly with the Hamilton Rating Scale for Depression. Plasma 5-HT increased more markedly in responders than in nonresponders and a significant inverse relationship surfaced between plasma 5-HT and the Hamilton Rating Scale for Depression. The results support other reports of comparable antidepressant efficacy for brofaromine and phenelzine, both inhibitors of MAO-A in humans. The consistent relationship we found between the biochemical and clinical changes again suggests and supports a key role of 5-HT in the antidepressant effect of these MAO inhibitors.

Adult↗