Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells

Heusler, Peter; Newman‐Tancredi, Adrian; Loock, Timothé; Cussac, Didier

doi:10.1016/j.ejphar.2007.11.046

Cited by 25 publications

(31 citation statements)

References 48 publications

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“…1). This absence of agonist-induced endocytosis has been reported for the 5-HT 1A R in several studies on different cell lines (Pucadyil et al, 2004;Renner et al, 2012), whereas an effect was reported in other studies (Della Rocca et al, 1999;Heusler et al, 2008). Such differences suggest that agonist-induced 5-HT 1A R internalization depends strongly on the recombinant vectors used for 5-HT 1A R expression, the cell type, and very probably other experimental conditions.…”

Section: Agonist-induced Internalization Of the 5-ht 1a Rmentioning

confidence: 51%

Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT_1ASerotonin Receptor

et al. 2013

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Section: Agonist-induced Internalization Of the 5-ht 1a Rmentioning

confidence: 51%

Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT_1ASerotonin Receptor

et al. 2013

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“…hippocampus 7±3%, [31]; e.g. hippocampus 11±11%, [27] [54,55] and also to better characterise the activation and internalisation of 5-HT 1A autoreceptors by agonists [25,56], SSRIs [24,26,27,57] and atypical antipsychotics [58]. Fig.…”

Section: Discussionmentioning

confidence: 99%

MicroPET imaging of 5-HT1A receptors in rat brain: a test–retest [18F]MPPF study

Aznavour

Benkelfat

Gravel

et al. 2008

Eur J Nucl Med Mol Imaging

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Purpose Earlier studies have shown that positron emission tomography (PET) imaging with the radioligand [ 18 F]MPPF allows for measuring the binding potential of serotonin 5-hydroxytryptamine 1A (5-HT 1A ) receptors in different regions of animal and human brain, including that of 5-HT 1A autoreceptors in the raphe nuclei. In the present study, we sought to determine if such data could be obtained in rat, with a microPET (R4, Concorde Microsystems). Methods Scans from isoflurane-anaesthetised rats (n=18, including six test-retest) were co-registered with magnetic resonance imaging data, and binding potential, blood to plasma ratio and radiotracer efflux were estimated according to a simplified reference tissue model. ResultsValues of binding potential for hippocampus (1.2), entorhinal cortex (1.1), septum (1.1), medial prefrontal cortex (1.0), amygdala (0.8), raphe nuclei (0.6), paraventricular hypothalamic nucleus (0.5) and raphe obscurus (0.5) were comparable to those previously measured with PET in cats, non-human primates or humans. Test-retest variability was in the order of 10% in the larger brain regions (hippocampus, medial prefrontal and entorhinal cortex) and less than 20% in small nuclei such as the septum and the paraventricular hypothalamic, basolateral amygdaloid and raphe nuclei. Conclusions MicroPET brain imaging of 5-HT 1A receptors with [18 F]MPPF thus represents a promising avenue for investigating 5-HT 1A receptor function in rat.

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“…It is heuristically less interesting because it has higher affinity for the D 3 and D 4 receptors, and weak partial agonist activity at D 2 receptors [149]. Other compounds of potential interest include UH232 [23, 150], S32504 [151], SDZ 208-912 [152, 153], PD 143188 (CI-1007) [154], SLV-308 (SME-308) [155, 156], F15063 [157, 158], SSR181507 [159], (-)-OSU6162 (PNU-96391A; Figure 5) [160, 161], ACR16 [162, 163], and many others. What is of particular importance is that there has been the view that dopamine stabilization (i.e., the unique clinical effects of aripiprazole) can be explained simply “partial agonist intrinsic activity.” Thus, Tadori et al [164] compared aripiprazole, bifeprunox, SDZ 208-912, OPC-4392, and ACR16 in terms of degrees of intrinsic activity (i.e., inhibition of forskolinstimulated cAMP accumulation) in clonal CHO cell lines expressing high and low densities of human dopamine D 2L and D 2S receptors.…”

Section: Impact Of Functional Selectivity and Research Issues For mentioning

confidence: 99%

“…As one recent example, Heusler et al [158] studied the effects of antipsychotic drugs or drug candidates to cause internalization of the human D 2S receptor using hemaglutinin (HA)-tags in HEK293 cells in which there was also increased co-expression of G protein-coupled receptor kinase 2 (GRK2) and β-arrestin2. Dopamine, quinpirole and bromocriptine behaved as full agonists, whereas S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [preclamol (-)-3PPP] and sarizotan were partial agonists.…”

Section: Impact Of Functional Selectivity and Research Issues For mentioning

confidence: 99%

Third Generation Antipsychotic Drugs: Partial Agonism or Receptor Functional Selectivity?

Mailman¹,

Murthy²

2010

CPD

264

194

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Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action of some drugs, and has relevance to drug discovery. One of the clinical areas where this mechanism has particular importance is in the treatment of schizophrenia. Antipsychotic drugs have been grouped according to both pattern of clinical action and mechanism of action. The original antipsychotic drugs such as chlorpromazine and haloperidol have been called typical or first generation. They cause both antipsychotic actions and many side effects (extrapyramidal and endocrine) that are ascribed to their high affinity dopamine D 2 receptor antagonism. Drugs such as clozapine, olanzapine, risperidone and others were then developed that avoided the neurological side effects (atypical or second generation antipsychotics). These compounds are divided mechanistically into those that are high affinity D 2 and 5-HT 2A antagonists, and those that also bind with modest affinity to D 2 , 5-HT 2A , and many other neuroreceptors. There is one approved third generation drug, aripiprazole, whose actions have been ascribed alternately to either D 2 partial agonism or D 2 functional selectivity. Although partial agonism has been the more widely accepted mechanism, the available data are inconsistent with this mechanism. Conversely, the D 2 functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D 2 antagonists.Keywords functional selectivity; antipsychotic drugs; schizophrenia; receptor mechanisms; G protein-coupled receptors; dopamine receptors; serotonin receptors; drug action A. The first two generations of antipsychotic drugsThe serendipitous observations about antipsychotic actions of chlorpromazine [1] ultimately led to the finding that these antipsychotic effects were due to antidopaminergic actions [2]. Numerous antipsychotics were subsequently developed that, like chlorpromazine, work primarily as dopamine D 2 receptor antagonists. Drugs of this type (first called typical and now named first generation antipsychotics) include a variety of different chemical classes. These NIH Public Access Author ManuscriptCurr Pharm Des. Author manuscript; available in PMC 2011 January 1. Published in final edited form as:Curr Pharm Des. 2010 ; 16(5): 488-501. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript typical drugs can be classified as high, intermediate, or low potency based on their average daily dose range, with their clinical potency often highly correlated with their affinity for the dopamine D 2 receptor [3]. Thus, actions at dopamine systems have been a critical mechanism in all currently approved antipsychotic drugs and many of the compounds in the discovery and development pipeline. Dopamine systems and their rece...

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Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells

Cited by 25 publications

References 48 publications

Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT_1ASerotonin Receptor

Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT_1ASerotonin Receptor

MicroPET imaging of 5-HT1A receptors in rat brain: a test–retest [18F]MPPF study

Third Generation Antipsychotic Drugs: Partial Agonism or Receptor Functional Selectivity?

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Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells

Cited by 25 publications

References 48 publications

Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT1ASerotonin Receptor

Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT1ASerotonin Receptor

MicroPET imaging of 5-HT1A receptors in rat brain: a test–retest [18F]MPPF study

Third Generation Antipsychotic Drugs: Partial Agonism or Receptor Functional Selectivity?

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Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT_1ASerotonin Receptor

Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT_1ASerotonin Receptor