A single injection of the psychostimulant, amphetamine, upregulates immediate early gene (IEG) and opioid peptide gene expression in the rat striatum. These genomic responses may be important in neuronal plasticity related to long-term changes in behavior. In exploring intracellular signaling pathways trans-mitting surface receptor stimulation to nuclear gene expression, we recently found that metabotropic glutamate receptors (mGluR) which are coupled to multiple second messenger systems through G proteins and are highly expressed in the striatum, regulate acute amphetamine-stimulated IEG as well as opioid gene expression in the striatum. Based on this encouraging finding, we propose in this project to further characterize the regulation of amphetamine-stimulated striatal gene expression by mGluRs and mGluR-linked intracellular signaling pathways. The hypothesis is that striatal mGluR activity contributes to the ability of acute amphetamine to stimulate IEG and opioid gene expression in the rat striatum and that increases in phosphoinositide hydrolysis, the best known and most thoroughly investigated cellular response to mGluR activation, serve as the signaling pathway bridging surface mGluR stimulation to nuclear gene expression. This hypothesis will be tested in two aims which are to (1) examine the effects of enhancement and reduction of striatal mGluR activity by injections of mGluR selective agonists and antagonists, respectively, on acute amphetamine-stimulated striatal IEG and opioid gene expression in a well characterized rat in vivo model, and (2) evaluate the contribution of the mGluR phosphoinositide-linked signaling pathways, i.e., intracellular Ca2+ mobilization and protein kinase C, to mGluR-sensitive gene expression in primary striatal cultured neurons from neonatal rats with both pharmacological (activators/inhibitors) and molecular (antisense technique) approaches. We will rely on in situ hybridization to analyze striatal mRNA expression in vivo and in vitro. This project should provide new insight into the signal transduction coupling stimulus-transcription in response to amphetamine, and improve understanding of the molecular plasticity underlying psychostimulant-induced long-term changes in behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29DA010355-04
Application #
6024052
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Colvis, Christine
Project Start
1997-09-16
Project End
2002-04-30
Budget Start
1999-01-22
Budget End
1999-04-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Missouri Kansas City
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
Kansas City
State
MO
Country
United States
Zip Code
64110
Mao, Li-Min; Faris, Hunter J; Wang, John Q (2018) Muscarinic Acetylcholine Receptors Inhibit Fyn Activity in the Rat Striatum In Vivo. J Mol Neurosci 64:523-532
He, Nan; Mao, Li-Min; Sturich, Adrian W et al. (2018) Inhibition of basal and amphetamine-stimulated extracellular signal-regulated kinase (ERK) phosphorylation in the rat forebrain by muscarinic acetylcholine M4 receptors. Brain Res 1688:103-112
Mao, Li-Min; Wang, Henry H; Wang, John Q (2017) Antagonism of Muscarinic Acetylcholine Receptors Alters Synaptic ERK Phosphorylation in the Rat Forebrain. Neurochem Res 42:1202-1210
Yang, Ju Hwan; Mao, Li-Min; Choe, Eun Sang et al. (2017) Synaptic ERK2 Phosphorylates and Regulates Metabotropic Glutamate Receptor 1 In Vitro and in Neurons. Mol Neurobiol 54:7156-7170
Xue, Bing; Fitzgerald, Cole A; Jin, Dao-Zhong et al. (2016) Amphetamine elevates phosphorylation of eukaryotic initiation factor 2? (eIF2?) in the rat forebrain via activating dopamine D1 and D2 receptors. Brain Res 1646:459-466
Mao, Li-Min; Wang, John Q (2016) Synaptically Localized Mitogen-Activated Protein Kinases: Local Substrates and Regulation. Mol Neurobiol 53:6309-6315
Mao, Li-Min; Wang, Qiang (2016) Phosphorylation of group I metabotropic glutamate receptors in drug addiction and translational research. J Transl Neurosci (Beijing) 1:17-23
Jin, Dao-Zhong; Xue, Bing; Mao, Li-Min et al. (2015) Metabotropic glutamate receptor 5 upregulates surface NMDA receptor expression in striatal neurons via CaMKII. Brain Res 1624:414-423
Mao, Li-Min; Jin, Dao-Zhong; Xue, Bing et al. (2014) Phosphorylation and regulation of glutamate receptors by CaMKII. Sheng Li Xue Bao 66:365-72
Wang, John Q; Guo, Ming-Lei; Jin, Dao-Zhong et al. (2014) Roles of subunit phosphorylation in regulating glutamate receptor function. Eur J Pharmacol 728:183-7

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