Involvement of N-methyl-D-aspartate receptors and intracellular signaling pathways in D2 dopamine receptor antagonistmediated gene expression.

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Title Involvement of N-methyl-D-aspartate receptors and intracellular signaling pathways in D2 dopamine receptor antagonistmediated gene expression.
Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author Adams, Amy C.
Date 2000-08
Description Cortical afferents excite striatal efferent neurons through activation of N-methyl-D-aspartate (NMDA) and non-NMDA receptors, which can be modulated by D2 dopamine receptors. The negative coupling of D2 dopamine receptors to adenylyl cyclase has led to the presumption that protein kinase A (PKA) plays a necessary role in D2/NMDA receptor interactions and in immediate early gene expression induced by D2 receptor blockade. It has been suggested from previous studies that activation of PKA by D2 receptor blockade may lead to NMDA receptor phosphorylation in the dendrites or phosphorylation of transcription factors in the nucleus. Thus, the levels and cellular localization of activated PKA may determine if D2 antagonist-mediated gene expression is dependent on NMDA receptor activation. However, this has never been directly demonstrated in vivo . This dissertation tested the overall hypothesis that immediate early gene expression induced by the D2 dopamine receptor antagonist eticlopride is dependent on PKA activation and that the levels of activated PKA will determine whether striatal immediate early gene induction in response to D2 receptor blockade is dependent on NMDA receptor activation in vivo . Specific aim 1 examined the effects of NMDA receptor antagonists on striatal gene expression after administration of low or high doses of eticlopride. The results showed that NMDA antagonists blocked induction by a low dose of eticlopride in all regions of the striatum, whereas induction by a higher dose of eticlopride was only blocked in the medial and central striatum. Fewer D2 dopamine receptors and thus less PKA activation in these regions might have explained why the expression was more sensitive to NMDA receptor blockade. Therefore, specific aim 2 examined the effects of PKA inhibition or activation on eticlopride-induced gene expression. The results suggest that PKA is not solely responsible for this gene expression. Specific aim 3 was designed to determine the effects of other signaling pathways on eticlopride-mediated gene expression. Inhibition of the mitogen-activated (MAP) and calcium/calmodulin-dependent (CaM) protein kinase pathways had no effect on eticlopride-induced expression. These findings suggest for the first time that PKA is not necessary for D2 antagonist-mediated gene induction and that multiple signaling pathways may be involved.
Type Text
Publisher University of Utah
Subject Kinase; Basal ganglia
Subject MESH Receptors, Dopamine; Receptors, Dopamine D2
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Involvement of N-methyl-D-aspartate receptors and intracellular signaling pathways in D2 dopamine receptor antagonistmediated gene expression." Spencer S. Eccles Health Sciences Library. Print version of "Involvement of N-methyl-D-aspartate receptors and intracellular signaling pathways in D2 dopamine receptor antagonistmediated gene expression." available at J. Willard Marriott Library Special Collection. QH9.7 2000 .A33.
Rights Management © Amy C. Adams.
Format application/pdf
Format Medium application/pdf
Identifier us-etd2,9782
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
ARK ark:/87278/s6d79s2g
Setname ir_etd
ID 193829
Reference URL https://collections.lib.utah.edu/ark:/87278/s6d79s2g
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