The paradoxical effects of SKF83959, a novel dopamine D1-like receptor agonist, in the rat acoustic startle reflex paradigm

Zhang, Zhang-Jin; Jiang, Xiaolong; Zhang, Steven E.; Hough, Christopher J.; He, Lei; Chen, Jianguo; Zhen, Xuechu

doi:10.1016/j.neulet.2005.03.001

Cited by 21 publications

(16 citation statements)

References 35 publications

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“…This compound has also been reported to have seemingly paradoxical effects on the D 1 R, exhibiting both antagonist and agonist properties, depending on the system (Panchalingam and Undie, 2001;Cools et al, 2002;Zhang et al, 2005). In our current studies, we treated D 1 R and D 2 R cotransfected cells with SKF83959 and, surprisingly, were unable to elicit a calcium response (Fig.…”

Section: Resultsmentioning

confidence: 60%

D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

et al. 2013

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The D 1 dopamine receptor (D 1 R) has been proposed to form a hetero-oligomer with the D 2 dopamine receptor (D 2 R), which in turn results in a complex that couples to phospholipase Cmediated intracellular calcium release. We have sought to elucidate the pharmacology and mechanism of action of this putative signaling pathway. Dopamine dose-response curves assaying intracellular calcium mobilization in cells heterologously expressing the D 1 and D 2 subtypes, either alone or in combination, and using subtype selective ligands revealed that concurrent stimulation is required for coupling. Surprisingly, characterization of a putative D 1 -D 2 heteromer-selective ligand, 6-chloro-2,3,4,5-tetrahydro-3-methyl-1-(3-methylphenyl)-1H-3-benzazepine-7,8-diol (SKF83959), found no stimulation of calcium release, but it did find a broad range of cross-reactivity with other G protein-coupled receptors. In contrast, SKF83959 appeared to be an antagonist of calcium mobilization. Overexpression of G qa with the D 1 and D 2 dopamine receptors enhanced the dopamine-stimulated calcium response. However, this was also observed in cells expressing G qa with only the D 1 R. Inactivation of G i or G s with pertussis or cholera toxin, respectively, largely, but not entirely, reduced the calcium response in D 1 R and D 2 R cotransfected cells. Moreover, sequestration of G bg subunits through overexpression of G protein receptor kinase 2 mutants either completely or largely eliminated dopamine-stimulated calcium mobilization. Our data suggest that the mechanism of D 1 R/D 2 R-mediated calcium signaling involves more than receptor-mediated G q protein activation, may largely involve downstream signaling pathways, and may not be completely heteromer-specific. In addition, SKF83959 may not exhibit selective activation of D 1 -D 2 heteromers, and its significant cross-reactivity to other receptors warrants careful interpretation of its use in vivo.

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Section: Resultsmentioning

confidence: 60%

D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

et al. 2013

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“…To date, limited studies have focused on the characterization of latency. Zhang et al [37] reported that a dopamine D1-like receptor agonist reduced latency but increased the startle amplitude in rats, both in a dose-dependent manner. We observed a positive, rather than negative, behavioral correlation between latency and ASR.…”

Section: Discussionmentioning

confidence: 99%

Fabp7 Maps to a Quantitative Trait Locus for a Schizophrenia Endophenotype

et al. 2007

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Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis on 1,010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected six major loci for PPI, six for the acoustic startle response, and four for latency to response peak, some of which were sex-dependent. A promising candidate on the Chromosome 10-QTL was Fabp7 (fatty acid binding protein 7, brain), a gene with functional links to the N-methyl-D-aspartic acid (NMDA) receptor and expression in astrocytes. Fabp7-deficient mice showed decreased PPI and a shortened startle response latency, typical of the QTL's proposed effects. A quantitative complementation test supported Fabp7 as a potential PPI-QTL gene, particularly in male mice. Disruption of Fabp7 attenuated neurogenesis in vivo. Human FABP7 showed altered expression in schizophrenic brains and genetic association with schizophrenia, which were both evident in males when samples were divided by sex. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental, and glial theories of schizophrenia pathology and the PPI endophenotype, with larger or overt effects in males. We also discuss the results from the perspective of fetal programming.

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“…This has led to the hypothesis that the behavioral actions of SKF-83959 may be mediated by its unique actions at PLC/calcium signaling at D 1 -D 2 heterodimers (Rashid et al , 2007a; Hasbi et al , 2009; Downes and Waddington, 1993; Deveney and Waddington, 1995; Fujita et al , 2010; Perreault et al , 2010; Arnt et al , 1992). This widespread belief that SKF-83959 is the first highly biased D 1 ligand has led many to consider it an important probe for studying the mechanisms related to D 1 signaling (Zhang et al , 2009; Yu et al , 2008; Zhang et al , 2007; Zhang et al , 2005; Perreault et al , 2011). …”

Section: Introductionmentioning

confidence: 99%

SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C

et al. 2014

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SKF-83959 [6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine] is reported to be a functionally selective dopamine D1 receptor ligand with high bias for D1-mediated phospholipase C (PLC) versus D1-coupled adenylate cyclase signaling. This signaling bias is proposed to explain behavioral activity in both rat and primate Parkinson’s disease models, and a D1-D2 heterodimer has been proposed as the underlying mechanism. We have conducted an in-depth pharmacological characterization of this compound in dopamine D1 and D2 receptors in both rat brain and heterologous systems expressing human D1 or D2 receptors. Contrary to common assumptions, SKF-83959 is similar to the classical, well-characterized partial agonist SKF38393 in all systems. It is a partial agonist (not an antagonist) at adenylate cyclase in vitro and ex vivo, and is a partial agonist in D1-mediated β-arrestin recruitment. Contrary to earlier reports, it does not have D1-mediated effects on PLC signaling in heterologous systems. Because drug metabolites can also contribute, its 3-N-demethylated analog also was synthesized and tested. As expected from the known structure-activity relationships of the benzazepines, this compound also had high affinity for the D1 receptor and somewhat higher intrinsic activity than the parent ligand, and also might contribute to in vivo effects of SKF-83959. Together, these data demonstrate that SKF-83959 is not a highly-biased functionally selective D1 ligand, and that its reported behavioral data can be explained solely by its partial D1 agonism in canonical signaling pathway(s). Mechanisms that have been proposed based on the purported signaling novelty of SKF-83959 at PLC should be reconsidered.

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The paradoxical effects of SKF83959, a novel dopamine D1-like receptor agonist, in the rat acoustic startle reflex paradigm

Cited by 21 publications

References 35 publications

D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

Fabp7 Maps to a Quantitative Trait Locus for a Schizophrenia Endophenotype

SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C

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The paradoxical effects of SKF83959, a novel dopamine D1-like receptor agonist, in the rat acoustic startle reflex paradigm

Cited by 21 publications

References 35 publications

D1-D2Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

D1-D2Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

Fabp7 Maps to a Quantitative Trait Locus for a Schizophrenia Endophenotype

SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C

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D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms