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Comprehensive Profiling of Dopamine Regulation in Substantia Nigra and Ventral Tegmental Area
Published on: August 10, 2012
MK-801 prevents dopamine D1 but not serotonin 2A stimulation of striatal preprotachykinin mRNA expression
1Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Abstract:
We examined dopamine (DA) and serotonin (5-HT) receptor-mediated influences on striatal preprotachykinin (PPT, tachykinin precursor) mRNA regulation in organotypic slice cultures. A 3 h exposure to SKF-38393 (10 microM, DA D1 agonist) or DOI (10 microM, 5-HT2 agonist) increased PPT mRNA levels to 196.4% and 154.0%, respectively. Responses to SKF-38393 were prevented by SCH-23390 (10 microM, D1 antagonist) whereas DOI-stimulated increases were prevented by ketanserin (10 microM, 5-HT2A antagonist). Since striatal tachykinin neurons also possess NMDA receptors that regulate gene expression, stimulation of PPT message levels was examined in the presence of MK-801, a non-competitive NMDA antagonist. Alone, MK-801 (10 nM) did not significantly alter basal PPT message levels. However, MK-801 prevented SKF-38393-stimulated increases in PPT mRNA expression while DOI-induced expression was not affected. These results provide evidence that D1 regulation of striatal tachykinin expression is dependent on NMDA-type glutamate neurotransmission while 5-HT2A regulation appears independent.
Insights
Dopamine D1 and serotonin 5-HT2A receptors regulate striatal preprotachykinin (PPT) mRNA. D1 receptor regulation requires NMDA receptor activity, while 5-HT2A receptor regulation is independent.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Striatal preprotachykinin (PPT) mRNA expression is modulated by neurotransmitter receptors.
- Dopamine (DA) and serotonin (5-HT) pathways play critical roles in regulating neuronal activity and gene expression in the striatum.
Purpose of the Study:
- To investigate the specific roles of dopamine D1 and serotonin 5-HT2 receptors in regulating striatal PPT mRNA levels.
- To determine the involvement of NMDA receptors in dopamine D1-mediated regulation of PPT mRNA.
Main Methods:
- Organotypic striatal slice cultures were used to examine receptor-mediated effects.
- Treatment with specific agonists (SKF-38393 for D1, DOI for 5-HT2) and antagonists (SCH-23390 for D1, ketanserin for 5-HT2A) was employed.
- The impact of NMDA receptor antagonist MK-801 on PPT mRNA levels was assessed.
Main Results:
- Dopamine D1 agonist (SKF-38393) and serotonin 5-HT2 agonist (DOI) significantly increased striatal PPT mRNA levels.
- D1-mediated increases were blocked by a D1 antagonist (SCH-23390), and 5-HT2-mediated increases were blocked by a 5-HT2A antagonist (ketanserin).
- NMDA receptor antagonist MK-801 blocked the D1 agonist-induced increase in PPT mRNA but did not affect the 5-HT2 agonist-induced increase.
Conclusions:
- Dopamine D1 receptor regulation of striatal tachykinin (PPT) expression is dependent on NMDA receptor activity.
- Serotonin 5-HT2A receptor regulation of striatal tachykinin expression appears to be independent of NMDA receptor activity.
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