The Selective 5-HT2A Receptor Antagonist M100907 Enhances Antidepressant-Like Behavioral Effects of the SSRI Fluoxetine

Marek, Gerard J.; Martı́n-Ruiz, Raúl; Abo, Allyson; Artigas, Francesc

doi:10.1038/sj.npp.1300762

Cited by 112 publications

(70 citation statements)

References 47 publications

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“…To further evaluate the contribution of 5-HT to the regulation of GSK3␤, the SSRI fluoxetine was used (23) to augment extracellular 5-HT levels. Administration of fluoxetine at a dose (5 mg/kg) that normally induces at least a 2-fold increase in extracellular 5-HT levels in the FC (23) resulted in enhanced GSK3␤ phosphorylation in FC of WT and HO R439H Tph2 knockin mice ( Fig. 3 E and F); thus, further supporting a role of 5-HT in the inhibition of GSK3␤ in this brain region.…”

Section: Activation Of Gsk3␤ In the Frontal Cortex Of R439h Tph2 Knocsupporting

confidence: 52%

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Beaulieu¹,

Zhang²,

Rodriguiz

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

341

317

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Dysregulation of brain serotonin (5-HT) neurotransmission is thought to underlie mental conditions as diverse as depression, anxiety disorders, bipolar disorder, autism, and schizophrenia. Despite treatment of these conditions with serotonergic drugs, the molecular mechanisms by which 5-HT is involved in the regulation of aberrant emotional behaviors are poorly understood. Here, we generated knockin mice expressing a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2 (Tph2). This mutant is equivalent to a rare human variant (R441H) identified in few individuals with unipolar major depression. Expression of mutant Tph2 in mice results in markedly reduced (Ϸ80%) brain 5-HT production and leads to behavioral abnormalities in tests assessing 5-HT-mediated emotional states. This reduction in brain 5-HT levels is accompanied by activation of glycogen synthase kinase 3␤ (GSK3␤), a signaling molecule modulated by many psychiatric therapeutic agents. Importantly, inactivation of GSK3␤ in Tph2 knockin mice, using pharmacological or genetic approaches, alleviates the aberrant behaviors produced by 5-HT deficiency. These findings establish a critical role of Tph2 in the maintenance of brain serotonin homeostasis and identify GSK3␤ signaling as an important pathway through which brain 5-HT deficiency induces abnormal behaviors. Targeting GSK3␤ and related signaling events may afford therapeutic advantages for the management of certain 5-HT-related psychiatric conditions. GSK-3 ͉ mood disorders ͉ serotonin ͉ Tph2 ͉ functional polymorphism S erotonin (5-HT) is involved in multiple aspects of normal brain functions ranging from the regulation of mood to the control of appetite and social interactions (1-3). Several studies have suggested a contribution of abnormal 5-HT transmission in various human psychiatric conditions and drugs acting on 5-HT neurotransmission are commonly used for the management of major depression, anxiety disorder, obsessive-compulsive disorder, autism, and schizophrenia (1-3). Although drugs that influence the 5-HT system can affect histone acetylation, modulate production of brain-derived neurotrophic factor, increase neural progenitor cell proliferation, and inhibit glycogen synthase kinase 3␤ (GSK3␤) in certain brain areas (4, 5), the mechanisms underlying the regulation of behavior by 5-HT are still obscure.There are indications that pharmacologic manipulations of 5-HT levels by different classes of drugs can affect distinct neuronal signaling mechanisms (6-9). For instance, multiple classes of 5-HT drugs, including selective 5-HT reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors, and atypical antipsychotics (5, 7, 9), inhibit brain GSK3␤ signaling. GSK3␤ is also inhibited in vivo by lithium (6, 10-12), which is often used in combination with antidepressants for the management of certain mood disorders (13). However, whether these changes in GSK3␤ are incidental or contribute to the regulation of 5-HT-related abnormal behaviors is unexplored (5...

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Section: Activation Of Gsk3␤ In the Frontal Cortex Of R439h Tph2 Knocsupporting

confidence: 52%

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Beaulieu¹,

Zhang²,

Rodriguiz

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

341

317

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“…Some authors have proposed that the excitatory action of this receptor 5-HT2a may be particularly prominent under conditions of high 5-HT release (Sharp et al, 2007), and a growing body of clinical psychopharmacological evidence is consistent with the hypothesis that blockade of 5-HT2a receptors might enhance the therapeutic effectiveness of SSRIs in depression patients (Marek et al, 2005). Thus, we speculate that high-level 5-HT release in mpFC under stress conditions could be able to activate the 5-HT2a receptor and consequently be responsible for expression of depressive-like behavior.…”

Section: Discussionmentioning

confidence: 69%

Prefrontal/Amygdalar System Determines Stress Coping Behavior Through 5-HT/GABA Connection

Andolina

Maran

Valzania

et al. 2013

Neuropsychopharmacol

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Coping is defined as the behavioral and physiological effort made to master stressful situations. The ability to cope with stress leads either to healthy or to pathogenic outcomes. The medial prefrontal cortex (mpFC) and amygdala are acknowledged as having a major role in stress-related behaviors, and mpFC has a critical role in the regulation of amygdala-mediated arousal in response to emotionally salient stimuli. Prefrontal cortical serotonin (5-hydroxytryptamine (5-HT)) is involved in corticolimbic circuitry, and GABA has a major role in amygdala functioning. Here, using mice, it was assessed whether amygdalar GABA regulation by prefrontal 5-HT is involved in processing stressful experiences and in determining coping outcomes. First (experiment 1), bilateral selective 5-HT depletion in mpFC of mice reduced GABA release induced by stress in basolateral amygdala (BLA) and passive coping in the Forced Swimming Test (FST) (experiment 2). Moreover, prefrontal-amygdala disconnection procedure that combined a selective unilateral 5-HT depletion of mpFC and infusion of an inhibitor of GABA synthesis into the contralateral BLA, thereby to disrupt prefrontal-amygdalar serial connectivity bilaterally, showed that disconnection selectively decreases immobility in the FST. These results point to prefrontal/amygdala connectivity mediated by 5-HT and GABA transmission as a critical neural mechanism in stress-induced behavior.

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“…Importantly, selective 5-HT 2A receptor antagonism has been shown to enhance D 2 -receptor-antagonist-mediated antipsychotic efficacy while reducing motor side effects and hyperprolactinemia in animal models (Gardell et al 2007; Wadenberg et al 1996). Moreover, antidepressant efficacy corresponding to occupancy of serotonin transporters (Meyer et al 2004b;Meyer 2007) can be enhanced by 5-HT 2A receptor antagonism with reduced sexual side effects (Aizenberg et al 1997; Marek et al 2005; Pullar et al 2000). A medication that combines potent 5-HT 2A receptor antagonism with optimal dopamine D 2 receptor modulation and optimal serotonin reuptake inhibition, never before achieved to our knowledge, may present an ideal balance of serotonergic and dopaminergic neurotransmission for the treatment of psychosis and mood disorders.…”

Section: Introductionmentioning

confidence: 99%

ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

et al. 2015

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RationaleCentral modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. ObjectivesThe purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT 2A receptors, dopamine D 2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. MethodsCarbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT 2A receptors, D 2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. ResultsOral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT 2A receptors and low occupancy of striatal D 2 receptors (~12 %). D 2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r 2 = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D 2 receptors and 33 % of striatal serotonin transporters. ConclusionsThe results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.

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The Selective 5-HT2A Receptor Antagonist M100907 Enhances Antidepressant-Like Behavioral Effects of the SSRI Fluoxetine

Cited by 112 publications

References 47 publications

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Prefrontal/Amygdalar System Determines Stress Coping Behavior Through 5-HT/GABA Connection

ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

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