The serotonin (5-HT) and norepinephrine neurons have reciprocal interactions at the level of their cell bodies and nerve terminals. As an illustration of such connections, selective serotonin reuptake inhibitors (SSRIs) gradually enhance serotonin transmission not only in the forebrain but also in the locus ceruleus, thereby decreasing norepinephrine neuronal firing. In contrast, blocking 5-HT2A receptors in the presence of serotonin reuptake inhibition using the experimental compound YM992 enhances both serotonin and norepinephrine release. The latter pharmacologic effect may be a main contributor to the robust antidepressant effect of adding atypical antipsychotics in SSRI-resistant patients. In obsessive-compulsive disorder, risperidone has consistently been reported to be an effective augmentation strategy in SSRI-resistant patients. This effect may result in part from its antagonistic actions on dopaminergic receptors and alpha2-adrenoceptors on serotonin terminals.

01 Dec 2002·Biopharmaceutics & Drug DispositionQ4 · MEDICINE

Investigation of the high partition of YM992, a novel antidepressant, in rat brain ‐ in vitro and in vivo evidence for the high binding in brain and the high permeability at the BBB

Q4 · MEDICINE

Article

Author: Saburo Higuchi ; Hidetaka Kamimura ; Yuji Mano

AbstractBrain extracellular fluid (ECF) concentration of YM992, a novel antidepressant, was determined using brain microdialysis to investigate the high partition of this drug to the brain after systemic administration to rats. Plasma, cerebrospinal fluid (CSF), ECF and brain concentrations were determined at the steady‐state after intravenous infusion to rats. The concentration ratio of brain to plasma at the total concentration base was 71.3, while those of ECF to plasma and CSF to plasma at the free concentration base were comparable. The distribution volume in brain was 375 ml/g brain and in vitro binding of YM992 to rat brain was 98.1–98.5%, suggesting a high binding in the brain. The carotid artery injection study showed that the brain uptake index of YM992 was 141%, furthermore, the uptake clearance into brain after i.v. dosing to rats was 0.6 ml/min/g brain, indicating a high permeability at the blood–brain barrier (BBB). These findings suggest that the high partition of YM992 to rat brain is attributed to its high level of binding in the brain as well as its high permeability at the BBB. Copyright © 2002 John Wiley & Sons, Ltd.

01 Sep 2002·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Effects of Serotonin (5-Hydroxytryptamine, 5-HT) Reuptake Inhibition Plus 5-HT_2A Receptor Antagonism on the Firing Activity of Norepinephrine Neurons

Q3 · MEDICINE

Article

Author: Szabo, Steven T. ; Blier, Pierre

YM992 [(S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride] is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and a potent 5-HT(2A) antagonist. The aim of the present study was to assess, using in vivo extracellular unitary recordings, the effect of acute and sustained administration of YM992 (40 mg kg(-1) day(-1) s.c., using osmotic minipumps) on the spontaneous firing activity of locus coeruleus (LC) norepinephrine (NE) neurons. Acute intravenous injection of YM992 (4 mg kg(-1)) significantly decreased NE neuron firing activity by 29% and blocked the inhibitory effect of a subsequent injection of the 5-HT(2) agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride]. A 2-day treatment with YM992 decreased the firing rate of NE neurons by 66%, whereas a partial recovery was observed after a 7-day treatment and a complete one after a 21-day treatment. Following the injection of the alpha(2)-adrenoceptor antagonist idazoxan (1 mg kg(-1) i.v.), NE neuron firing was equalized in controls and 2-day YM992-treated rats. This put into evidence an increased degree of activation of alpha(2)-adrenergic autoreceptors in the treated rats. The suppressant effect of the alpha(2)-adrenoceptor agonist clonidine was significantly decreased in long-term YM992-treated rats. The recovery of LC firing activity after long-term YM992 administration could thus be explained by a decreased sensitivity of alpha(2)-adrenergic autoreceptors. Sustained SSRI administration leads to a gradual reduction of the firing activity of NE neurons during long-term administration, whereas YM992 produced opposite effects. The exact basis for the increased synaptic availability of NE by YM992 remains to be elucidated. This NE activity, resulting from 5-HT reuptake inhibition plus 5-HT(2A) receptor antagonism, might confer additional benefits in affective and anxiety disorders.

100 Deals associated with Lubazodone hydrochloride

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D04788	Lubazodone hydrochloride	-	DB09196

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Phase 2	US	Yamanouchi Pharmaceutical Co. Ltd. /Over-the-Counter Phar Bus	-
Depressive Disorder, Major	Phase 2	-	Astellas Pharma, Inc.	-
Depressive Disorder, Major	Phase 2	-	-	-

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