Role of dopamine and glutamate receptors in intracellular mechanisms for cocaine action
Item
-
Title
-
Role of dopamine and glutamate receptors in intracellular mechanisms for cocaine action
-
Identifier
-
d_2009_2013:e97266f91cf3:10034
-
identifier
-
10030
-
Creator
-
Sun, Wei-Lun,
-
Contributor
-
Shirzad Jenab
-
Date
-
2009
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Psychobiology | Neurosciences | cocaine | dopamine | glutamate | p-ERK
-
Abstract
-
Accumulating evidence suggests that cocaine exerts its behavioral and biochemical effects through dopamine and glutamate transmission. However, the underlying mechanisms are not well understood. The purpose of this proposal is to assess the role of dopamine D1 and NMDA receptors and related signal transduction pathways in response to acute cocaine. We hypothesize that cocaine-induced intracellular cascades are mediated by dopamine D1 and NMDA receptors. In addition, the receptor physical interaction between them is altered by cocaine. To study the intracellular mechanisms induced by cocaine, we measured extracellular signal-regulated kinase (ERK) and dopamine- and cAMP-regulated phosphoprotein (DARPP-32) pathways. Overall, a single cocaine administration increased ERK-mediated signaling proteins, phosphoryation of cAMP response element-binding protein kinase regulator, pp90 ribosomal S6 kinase, and c-Fos protein levels in the caudate-putamen (CPu). Acute cocaine administration also induced phosphorylation of the striatal-enriched protein tyrosine phosphatase and decreased the phosphorylation of DARPP-32 protein at the Thr-75 site.;To study the role of dopamine D1 and NMDA receptors on cocaine-induced early gene (IEG), c-Fos, FosB and p-MKP-1 protein levels were measured. Acute cocaine administration time dependently increased IEG protein expression and phosphorylation in the CPu and nucleus accumbens (NAc). In the CPu, the cocaine-induced c-Fos and FosB proteins expression is totally abolished by pre-administration of dopamine D1 receptor antagonist, SCH23390. In the NAc, SCH23390 also inhibited cocaine-induced c-Fos protein expression. The pre-treatment of NMDA receptor antagonist, MK-801, partially reduced cocaine-activated c-Fos protein expression in the CPu. Furthermore, the escalation of p-MKP-1 after acute cocaine administration is dependent on both the activation of dopamine D1 and NMDA receptors in both brain regions examined.;At the receptor level, we found that acute cocaine reduced NMDA-NR1 and dopamine D1 receptor protein-protein interactions in the CPu. Interestingly, the administration of NMDA and MK-801 also decreased the physical interaction between these receptors. These results indicated that pharmacological receptors manipulation resulted in the dissociation of receptors interactions.;Taken together, we suggest that acute cocaine may regulate the intracellular transduction and underlying IEG through dopamine D1 and NMDA receptors as well as through their physical interactions.
-
Type
-
dissertation
-
Source
-
2009_2013.csv
-
degree
-
Ph.D.
-
Program
-
Psychology
