TY - JOUR
T1 - D1 dopamine receptor activation of NFAT-mediated striatal gene expression
AU - Groth, Rachel D.
AU - Weick, Jason P.
AU - Bradley, Katherine C.
AU - Luoma, Jessie I.
AU - Aravamudan, Bharathi
AU - Klug, Jason R.
AU - Thomas, Mark J.
AU - Mermelstein, Paul G.
PY - 2008/1
Y1 - 2008/1
N2 - 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.
AB - 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.
KW - Glutamate receptor subunit 2
KW - Inositol-1, 4, 5-trisphosphate receptor type 1
KW - Mouse
KW - Nuclear factor of activated T-cells 4
KW - Rat
KW - Striatum
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UR - http://www.scopus.com/inward/citedby.url?scp=37749009688&partnerID=8YFLogxK
U2 - 10.1111/j.1460-9568.2007.05980.x
DO - 10.1111/j.1460-9568.2007.05980.x
M3 - Article
C2 - 18184313
AN - SCOPUS:37749009688
SN - 0953-816X
VL - 27
SP - 31
EP - 42
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
IS - 1
ER -