Behavioural Pharmacology of Dopamine D2 and D3 Receptors: Use of the Knock-out Mice Approach

Depoortère, R.; Boulay, Denis; Perrault, Ghislaine; Sanger, D. J.

doi:10.1007/978-3-662-06765-9_9

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“…However, complementary experiments have revealed that SSR181507 behaves as a partial agonist at this receptor (result not shown), thus suggesting that its antipsychotic profile can hardly be explained by an interaction with this receptor. Moreover, disappointing results regarding the behavioral phenotype of DA D 3 receptor knockout mice, and the lack of consistency in the behavioral effects of the different putative DA D 3 receptor ligands, have cast some doubt about the in vivo function of this receptor, and one step beyond, about its possible relevance in schizophrenia (Depoortere et al, 2002).…”

Section: Mesocorticolimbic Selectivity and Atypical Antipsychotic Promentioning

confidence: 99%

SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

Claustre

Peretti

Brun

et al. 2003

Neuropsychopharmacol

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monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT 1A receptors (K I ¼ 0.8, 0.2, and 0.2 nM for human D 2 , D 3 , and 5-HT 1A , respectively). In vivo, SSR181507 inhibited [ 3 H]raclopride binding to D 2 receptors in the rat (ID 50 ¼ 0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D 2 antagonist and 5-HT 1A agonist properties in the same concentration range in vitro (IC 50 ¼ 5.3 nM and EC 50 ¼ 2.3 nM, respectively, in the GTPgS model) and in the same dose range in vivo (ED 50 ¼ 1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D 2 receptor antagonism and 5-HT 1A agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.

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Section: Mesocorticolimbic Selectivity and Atypical Antipsychotic Promentioning

confidence: 99%

SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

Claustre

Peretti

Brun

et al. 2003

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

Behavioural Pharmacology of Dopamine D2 and D3 Receptors: Use of the Knock-out Mice Approach

Cited by 1 publication

References 110 publications

SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

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