D1 dopamine receptor activation of NFAT-mediated striatal gene expression

• Published in: The European journal of neuroscience Vol. 27; no. 1; pp. 31 - 42
• Main Authors: Groth, Rachel D., Weick, Jason P., Bradley, Katherine C., Luoma, Jessie I., Aravamudan, Bharathi, Klug, Jason R., Thomas, Mark J., Mermelstein, Paul G.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2008
• Subjects: 5-trisphosphate receptor type 1; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology; Animals; Animals, Newborn; Brain-Derived Neurotrophic Factor - metabolism; Cells, Cultured; Chromatin Immunoprecipitation - methods; Cocaine - pharmacology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine Uptake Inhibitors - pharmacology; Electrophoretic Mobility Shift Assay - methods; Excitatory Amino Acid Agonists - pharmacology; Gene Expression - drug effects; Gene Expression - physiology; glutamate receptor subunit 2; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Inositol 1,4,5-Trisphosphate Receptors - metabolism; inositol-1; inositol‐1, 4, 5‐trisphosphate receptor type 1; Male; Membrane Potentials - drug effects; Membrane Potentials - physiology; Mice; Mice, Inbred C57BL; mouse; NFATC Transcription Factors - metabolism; nuclear factor of activated T-cells 4; rat; Rats; Receptors, AMPA - metabolism; Receptors, Dopamine D1 - physiology; striatum; Transfection - methods
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2007.05980.x

Exposure to drugs of abuse activates gene expression and protein synthesis that result in long‐lasting adaptations in striatal signaling. Therefore, identification of the transcription factors that couple drug exposure to gene expression is of particular importance. Members of the nuclear factor of activated T‐cells (NFATc) family of transcription factors have recently been implicated in shaping neuronal function throughout the rodent nervous system. Here we demonstrate that regulation of NFAT‐mediated gene expression may also be a factor in drug‐induced changes to striatal functioning. In cultured rat striatal neurons, stimulation of D1 dopamine receptors induces NFAT‐dependent transcription through activation of L‐type calcium channels. Additionally, the genes encoding inositol‐1,4,5‐trisphosphate receptor type 1 and glutamate receptor subunit 2 are regulated by striatal NFATc4 activity. Consistent with these in‐vitro data, repeated exposure to cocaine triggers striatal NFATc4 nuclear translocation and the up‐regulation of inositol‐1,4,5‐trisphosphate receptor type 1 and glutamate receptor subunit 2 gene expression in vivo, suggesting that cocaine‐induced increases in gene expression may be partially mediated through activation of NFAT‐dependent transcription. Collectively, these findings reveal a novel molecular pathway that may contribute to the enduring modifications in striatal functioning that occur following the administration of drugs of abuse.