Stimulation by antipsychotic agents of mitogen-activated protein kinase (MAPK) coupled to cloned, human (h)serotonin (5-HT)1A receptors

Cussac, Didier; Duqueyroix, Delphine; Newman‐Tancredi, Adrian; Millan, Mark J.

doi:10.1007/s00213-002-1043-0

Cited by 40 publications

(14 citation statements)

References 66 publications

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“…Clozapine and quetiapine are partial 5-HT 1A agonists in vitro (Newman-Tancredi et al 2001;Cussac et al 2002). Such actions do not appear to be involved in the drugs' cue properties in vivo.…”

Section: Tests With Dopaminergic Ligandsmentioning

confidence: 91%

Characterization of the effects of receptor-selective ligands in rats discriminating the novel antipsychotic quetiapine

2004

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Together with data from a previous study (Smith and Goudie 2002) in which we observed full generalization to quetiapine with olanzapine, risperidone and clozapine, but not with typical antipsychotics (such as haloperidol) or the novel antipsychotic amisulpride, these data suggest that: i) the discriminative stimulus properties of quetiapine, like those of clozapine, probably reflect a "compound" stimulus which involves several classes of receptor; ii) the quetiapine cue is of value in analysing, and screening for, quetiapine- and clozapine-like agents in vivo; iii) blockade of muscarinic receptors is sufficient, although not necessary, to achieve full generalization to quetiapine; and iv) alpha(1-)adrenoceptors may be implicated in the quetiapine discriminative stimulus.

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Section: Tests With Dopaminergic Ligandsmentioning

confidence: 91%

Characterization of the effects of receptor-selective ligands in rats discriminating the novel antipsychotic quetiapine

2004

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“…This pathway regulates cortical neurogenesis and synaptic proliferation and plasticity (Thomas and Huganir 2004), processes implicated in schizophrenia (Harrison and Weinberger 2005). Furthermore, the ERK cascade is differentially modulated by antipsychotic drugs in vitro (Cussac et al 2002;Lu and Dwyer 2005) and in vivo in a cell-specific manner (Fumagalli et al 2006). Specifically, in vivo clozapine reduced and haloperidol increased ERK activation in mouse dorsal striatum (Pozzi et al 2003), whereas in rat prefrontal cortex the converse was observed (Ahmed et al 2008).…”

Section: Introductionmentioning

confidence: 89%

Clozapine-Induced ERK1 and ERK2 Signaling in Prefrontal Cortex Is Mediated by the EGF Receptor

Pereira¹,

Fink²,

Sundram³

2009

J Mol Neurosci

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The atypical antipsychotic drug clozapine is effective in treatment-refractory schizophrenia. The intracellular signaling pathways that mediate clozapine action remain unknown. A potential candidate is the mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK-ERK) cascade that links G-protein-coupled receptor and ErbB growth factor signaling systems, thereby regulating synaptic plasticity and connectivity, processes impaired in schizophrenia. Here, we examined how clozapine differentially modulated phosphorylation of the MAPK isoforms, ERK1/ERK2 in primary murine prefrontal cortical neurons compared to the typical antipsychotic drug haloperidol. While clozapine and haloperidol acutely decreased cortical pERK1 activation, only clozapine but not haloperidol stimulated pERK1 and pERK2 with continued drug exposure. This delayed ERK increase however, did not occur via the canonical dopamine D(2)-Gi/o-PKA or serotonin 5HT(2A)-Gq-phospholipase-C-linked signaling pathways. Rather, epidermal growth factor (EGF) receptor signaling mediated clozapine-induced ERK activation, given dose-dependent reduction of pERK1 and pERK2 stimulation with the EGF receptor inhibitor, AG1478. Immunocytochemical studies indicated that clozapine treatment increased EGF receptor (Tyr1068) phosphorylation. In vivo mouse treatment studies supported the in vitro findings with initial blockade, subsequent activation, and normalization of the cortical ERK response over 24 h. Furthermore, in vivo clozapine-induced ERK activation was significantly reduced by AG1478. This is the first report that clozapine action on prefrontal cortical neurons involves the EGF signaling system. Since EGF receptor signaling has not been previously linked to antipsychotic drug action, our findings may implicate the EGF system as a molecular substrate in treatment-resistant schizophrenia.

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“…Fourth, the atypical antipsychotic, clozapine, which displays improved capacity to treat negative symptoms with minimal liability for EPS, exhibits agonist properties at 5-HT 1A receptors in various in vitro models of receptor transduction (Assié et al 1997;Bruins Slot et al 2006;Cussac et al 2002;Elliott and Reynolds 1999;Newman-Tancredi et al 2005). The ability of clozapine to occupy 5-HT 1A receptors in nonhuman primates at clinically-relevant doses has been demonstrated by PET scans with [ 3 H]WAY100635 (Chou et al 2003).…”

Section: Introductionmentioning

confidence: 94%

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Newman‐Tancredi

Kleven²

2011

Psychopharmacology

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147

108

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Recent compounds exhibiting combined 5-HT(1A)/D(2) properties may be effective in treating a broader range of symptoms of schizophrenia and be better tolerated than existing antipsychotics. Nevertheless, further investigations are necessary to evaluate recent compounds, notably in view of their differing levels of 5-HT(1A) affinity and efficacy, which can markedly influence activity and side-effect profiles.

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Stimulation by antipsychotic agents of mitogen-activated protein kinase (MAPK) coupled to cloned, human (h)serotonin (5-HT)1A receptors

Cited by 40 publications

References 66 publications

Characterization of the effects of receptor-selective ligands in rats discriminating the novel antipsychotic quetiapine

Characterization of the effects of receptor-selective ligands in rats discriminating the novel antipsychotic quetiapine

Clozapine-Induced ERK1 and ERK2 Signaling in Prefrontal Cortex Is Mediated by the EGF Receptor

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

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