Decoding Dopamine Signaling
Department of Psychiatry, The University of Texas Southwestern Medical Center at Dallas 75390, USA.Cell (Impact Factor: 32.24). 08/2005; 122(2):153-5. DOI: 10.1016/j.cell.2005.07.011
Dopamine is a key neurotransmitter that is important for many physiological functions including motor control, mood, and the reward pathway. In this issue of Cell, the laboratories of Marc Caron and Li-Huei Tsai identify two very different molecules--beta-arrestin 2 and Par-4, respectively--that unexpectedly are involved in dopamine signaling via the D2 receptor. These two new signaling pathways mediate the actions of dopamine on behavior and facilitate crosstalk between different signaling pathways that are activated by binding of dopamine to the D2 receptor.
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- "The phospholipid signal transduction system is also initiated when dopamine binds to the D1R-like/D2R hetero-oligomers , leading to activation of PLC and increased calcium levels (Rashid et al. 2007; So et al. 2009). Other D2-like receptor-coupled signaling pathways have been reported, including the regulation of G b/c activity (Hernandez-Lopez et al. 2000), the complex b-arrestin 2/protein phosphatase 2A-Akt pathway which stimulates the glycogen synthase kinase 3 (GSK-3) (Neve et al. 2004) and the activation of PAR4 (Bibb 2005). In addition, in the presence of the D3R preferring agonist 7-OH-DPAT, D3R shows unique properties involving activation of phospholipase D (PLD) through a complex formed with the monomeric G-protein Rho (Everett and Senogles 2010). "
ABSTRACT: The ankyrin repeat and kinase domain containing 1 (ANKK1) TaqIA polymorphism has been extensively studied as a marker of the gene for dopamine receptor D2 (DRD2) in addictions and other dopamine-associated traits. In vitro mRNA and protein studies have shown a potential connection between ANKK1 and the dopaminergic system functioning. Here, we have investigated whether Ankk1 expression in the brain is regulated by treatment with dopaminergic agonists. We used quantitative RT-PCR of total brain and Western blots of specific brain areas to study Ankk1 in murine brain after dopaminergic treatments. We found that Ankk1 mRNA was upregulated after activation of D1R-like dopamine receptors with SKF38393 (2.660 ± 1.035-fold; t: 4.066, df: 11, P = 0.002) and apomorphine (2.043 ± 0.595-fold; t: 3.782, df: 8, P = 0.005). The D2R-like agonist quinelorane has no effect upon Ankk1 mRNA (1.004 ± 0.580-fold; t: 0.015, df: 10, P = 0.9885). In contrast, mice treatment with the D2R-like agonists 7-OH-DPAT and aripiprazole caused a significant Ankk1 mRNA downregulation (0.606 ± 0.057-fold; t: 2.786, df: 10, P = 0.02 and 0.588 ± 0.130-fold; t: 2.394, df: 11, P = 0.036, respectively). With respect the Ankk1 proteins profile, no effects were found after SKF38393 (t: 0.54, df: 2, P = 0.643) and Quinelorane (t: 0.286, df: 8, P = 0.782) treatments. In contrast, the D2R-like agonist 7-OH-DPAT (±) caused a significant increment of Ankk1 in the striatum (t: 2.718, df: 7; P = 0.03) when compared to the prefrontal cortex. The activation of D1R-like and D2-R-like leads to opposite transcriptional regulation of Ankk1 by specific pathways.
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- "The PI3K-dependent cascade, in turn, phosphorylates and activates some specific downstream kinases, such as protein kinase B (PKB or Akt) and protein kinase C (PKC). Among the downstream effectors implicated in psychiatric disorders (Lovestone et al., 2007) and, remarkably, in D 2 -like receptors signaling machinery (Bibb, 2005), the Akt-dependent inactivation of glycogen synthase kinase-3 (GSK-3) pathway should be also considered. The functional decrease of IR signaling and consequent upregulation of GSK-3 content and activity, recently described in the cortex of schizophrenic patients (Zhao et al., 2006), is in support of the evidence describing the occurrence of downregulation of Akt signaling in schizophrenia. "
ABSTRACT: Beside the therapeutic improvement over first-generation antipsychotics, the fact that prescription of atypical agents is also associated to the emergence of severe metabolic derangement in patients is not a mystery anymore. Body weight gain, dyslipidemia, adiposity, impaired glucose homeostasis, insulin and leptin resistance and new-onset type II diabetes are all part of a syndromic cluster of vast medical concern. Thus, clinical reports and rodent models of atypical antipsychotic-associated metabolic impairment have growth in parallel as separate territories. This review focuses on the attempt to take a snapshot of the present developing moment and to describe to what extent clinical data are reflected by the findings derived from animal studies. This aim is pursued through different steps that, starting from the criteria necessary to characterize the "atypicality" of atypical drugs, then explore the consistency among clinical and animal-based data. The endpoint of this survey consists in the analysis of the potential mechanisms underlying the metabolic derangement induced by this class of drugs. It is, indeed, our opinion that some atypical antipsychotics should be viewed as potent obesogenic factors that can be exploited as valuable tools to shed light into the elusive dilemma of obesity. For this reason, recently identified obesogenic and diabetogenic mechanisms are the background on which the present work is built and some novel forthcoming lines of investigation suggested.
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- "Dopamine plays important roles in many physiological functions, including motor control, mood and the reward pathway42, and as a neurotransmitter, it binds to the five types of dopamine receptor, D1, D2, D3, D4 and D5, and their variants. The D1 and D5 receptors are members of the D1-like family (D1L), whereas the D2, D3 and D4 receptors are members of the D2-like family (D2L). "
ABSTRACT: Animal models for Parkinson's disease (PD) are essential for understanding its pathogenesis and for development and testing of new therapies. Discoveries of endogenous neurogenesis in the adult mammalian brain give new insight into the cell-based approach for treatment of neurodegenerative disorders, such as PD. Although a great deal of interest has been focused on endogenous neurogenesis in neurotoxin-induced animal models for PD, it still remains controversial whether neural stem cells migrate into the injured area and contribute to repopulation of depleted dopaminergic neurons in neurotoxin-injured adult brains. The purpose of this review is to examine the data available regarding neurogenesis in neurotoxin-induced animal models of PD. It is hoped that data from the animal investigations available in the literature will promote understanding of the neurotoxin-induced animal models for PD.