Caffeine Regulates Neuronal Expression of the Dopamine 2 Receptor Gene
Open Access
- 26 November 2003
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 64 (6), 1463-1473
- https://doi.org/10.1124/mol.64.6.1463
Abstract
The psychoactive drug caffeine influences neuronal physiology; however, it is unknown whether it can dynamically alter the expression of genes that influence neurotransmission. Here, we report that caffeine stimulates transcription of the dopamine 2 receptor (D2R) gene in PC-12 cells and primary striatal cultures and increases D2R protein expression in the striatum. Physiological doses of caffeine and the specific adenosine 2A receptor antagonist 8-(3-chlorostyryl) caffeine both increased the activity of a D2R/luciferase reporter construct within 24 h, and simultaneous treatment with 2-[p-(2-carboxyethyl)phenethylamino]-5′-N-ethylcarboxamidoadenosine (CGS 21680), a specific adenosine 2A receptor agonist, eliminated this effect. Tests of additional constructs revealed that specific regions of the D2R promoter (-117/-75) and 5′-untranslated region (+22/+317) were required for activation of D2R gene expression by caffeine. In primary striatal cultures, caffeine increased spontaneous firing of neurons between 12 and 80 min after treatment, whereas it increased D2R mRNA expression after only 4 h. These results indicate that regulation of D2R gene expression by caffeine occurs after the initial physiological response has subsided. In vivo, female mice treated with a dose of caffeine (50 mg/kg) showed 1.94- and 2.07-fold increases in D2R mRNA and protein expression, respectively. In contrast, male mice exhibited a 31% decrease in D2R mRNA expression and showed no changes in D2R protein expression. Collectively, these results demonstrate for the first time that caffeine alters D2R expression in neurons. They also suggest that caffeine consumption can lead to sexually dimorphic patterns of gene expression in the brain.Keywords
This publication has 33 references indexed in Scilit:
- Sexually dimorphic effects of morphine and MK-801: sex steroid-dependent and -independent mechanismsJournal of Applied Physiology, 2002
- Adenosine A2A agonist CGS 21680 decreases the affinity of dopamine D2 receptors for dopamine in human striatumNeuroReport, 2001
- Neuroprotection by Caffeine and A2AAdenosine Receptor Inactivation in a Model of Parkinson's DiseaseJournal of Neuroscience, 2001
- Prospective study of caffeine consumption and risk of Parkinson's disease in men and womenAnnals of Neurology, 2001
- Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neuronsNature Neuroscience, 2000
- Sexual dimorphism in the response to N-methyl-d-aspartate receptor antagonists and morphine on behavior and c-Fos induction in the rat brainNeuroscience, 1999
- Signaling via A2A adenosine receptor in four PC12 cell clones.Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie, 1999
- Adenosine–dopamine receptor–receptor interactions as an integrative mechanism in the basal gangliaTrends in Neurosciences, 1997
- Multiple promoter elements differentially regulate the expression of the mouse tenascin geneProceedings of the National Academy of Sciences of the United States of America, 1997
- Dopamine denervation leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatumBrain Research, 1992