Abstract

The long-term goals of our studies are to identify the molecular mechanisms of desensitization of serotonin 2A (5-HT2A) receptor signaling. Adaptive changes in post-synaptic 5-HT2A receptor signaling underlie the mechanism of action of several drug treatments for psychiatric disorders including anxiety, schizophrenia, depression, and bipolar disorder. Paradoxically, chronic treatment with both 5-HT2A receptor agonist such as DOI and antagonists including olanzapine desensitize 5-HT2a receptor signaling. Atypical antipsychotics are 5-HT2A receptor antagonists. Although these drugs are widely used, significant numbers of individuals are refractory to drug therapy and their effectiveness is delayed about 2 weeks after treatment is initiated. To help to resolve these problems, we plan to investigate the mechanisms by which 5-HT2A receptor signaling is desensitized. We will examine the mechanisms of desensitization of 5-HT2A receptor signaling induced with 5-HT2A receptor agonists (Aim 1), 5-HT2a receptor antagonists (Aim 2) and regulators of G protein signaling (RGS) proteins (Aim 3) in cells in culture and in vivo. Our hypothesis is that Jak/Stat signaling is critical for antagonist-induced desensitization, while the receptor-G protein functioning is reduced in agonist-induced desensitization of 5-HT2.A receptor signaling. We will test the hypothesis that RGS proteins also cause adaptive changes leading to 5-HT2A receptor desensitization via mechanisms in addition to acting as GTPase-activating proteins (GAPs). Neuroendocrine responses to 5-HT2A receptor-stimulation will be used as an index of desensitization of 5-HT2A receptor signaling in vivo. A major advantage of the neuroendocrine challenge tests is that the results obtained in experimental animals can be rapidly applied to humans since these tests can be performed in humans. Ultimately the purpose of these studies is to identify new targets for therapeutic intervention for psychiatric disorders currently treated with drugs that alter 5-HT2A receptor signaling. By understanding the mechanisms involved in neuroadaptation, new approaches can be developed to reduce the delay in therapeutic response and treat individuals refractory to current therapies

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH068612-02
Application #
6760864
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (03))
Program Officer
Desmond, Nancy L
Project Start
2003-07-01
Project End
2007-04-30
Budget Start
2004-07-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$236,800
Indirect Cost

  Institution

Name
Loyola University Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153

  Publications

Mi, Zhen; Si, Tuda; Kapadia, Khushboo et al. (2017) Receptor-stimulated transamidation induces activation of Rac1 and Cdc42 and the regulation of dendritic spines. Neuropharmacology 117:93-105
Dai, Ying; Dudek, Nichole L; Li, Qian et al. (2011) Phospholipase C, Ca2+, and calmodulin signaling are required for 5-HT2A receptor-mediated transamidation of Rac1 by transglutaminase. Psychopharmacology (Berl) 213:403-12
Singh, R K; Jia, C; Garcia, F et al. (2010) Activation of the JAK-STAT pathway by olanzapine is necessary for desensitization of serotonin2A receptor-stimulated phospholipase C signaling in rat frontal cortex but not serotonin2A receptor-stimulated hormone release. J Psychopharmacol 24:1079-88
Singh, Rakesh K; Dai, Ying; Staudinger, Jeff L et al. (2009) Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signalling by olanzapine, clozapine and MDL 100907. Int J Neuropsychopharmacol 12:651-65
Shi, Ju; Landry, Michelle; Carrasco, Gonzalo A et al. (2008) Sustained treatment with a 5-HT(2A) receptor agonist causes functional desensitization and reductions in agonist-labeled 5-HT(2A) receptors despite increases in receptor protein levels in rats. Neuropharmacology 55:687-92
Dai, Y; Dudek, N L; Patel, T B et al. (2008) Transglutaminase-catalyzed transamidation: a novel mechanism for Rac1 activation by 5-hydroxytryptamine2A receptor stimulation. J Pharmacol Exp Ther 326:153-62
Singh, Rakesh K; Shi, Ju; Zemaitaitis, Bozena W et al. (2007) Olanzapine increases RGS7 protein expression via stimulation of the Janus tyrosine kinase-signal transducer and activator of transcription signaling cascade. J Pharmacol Exp Ther 322:133-40
Muma, N A; Singh, R K; Vercillo, M S et al. (2007) Chronic olanzapine activates the Stat3 signal transduction pathway and alters expression of components of the 5-HT2A receptor signaling system in rat frontal cortex. Neuropharmacology 53:552-62
Shi, Ju; Damjanoska, Katerina J; Singh, Rakesh K et al. (2007) Agonist induced-phosphorylation of Galpha11 protein reduces coupling to 5-HT2A receptors. J Pharmacol Exp Ther 323:248-56
Shi, Ju; Zemaitaitis, Bozena; Muma, Nancy A (2007) Phosphorylation of Galpha11 protein contributes to agonist-induced desensitization of 5-HT2A receptor signaling. Mol Pharmacol 71:303-13

Showing the most recent 10 out of 12 publications