Opposing Patterns of Signaling Activation in Dopamine D1 and D2 Receptor-Expressing Striatal Neurons in Response to Cocaine and Haloperidol
Journal of Neuroscience. 2008-05-28; 28(22): 5671-5685
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1. J Neurosci. 2008 May 28;28(22):5671-85. doi: 10.1523/JNEUROSCI.1039-08.2008.
Opposing patterns of signaling activation in dopamine D1 and D2
receptor-expressing striatal neurons in response to cocaine and haloperidol.
Bertran-Gonzalez J(1), Bosch C, Maroteaux M, Matamales M, Hervé D, Valjent E,
(1)Inserm UMR-S 839, Paris, France.
Psychostimulants and other drugs of abuse activate extracellular signal-regulated
kinase (ERK) in the striatum, through combined stimulation of dopamine D(1)
receptors (D1Rs) and glutamate NMDA receptors. Antipsychotic drugs activate
similar signaling proteins in the striatum by blocking dopamine D(2) receptors
(D2Rs). However, the neurons in which these pathways are activated by
psychotropic drugs are not precisely identified. We used transgenic mice, in
which enhanced green fluorescent protein (EGFP) expression was driven by D1R
promoter (drd1a-EGFP) or D2R promoter (drd2-EGFP). We confirmed the expression of
drd1a-EGFP in striatonigral and drd2-EGFP in striatopallidal neurons. Drd2-EGFP
was also expressed in cholinergic interneurons, whereas no expression of either
promoter was detected in GABAergic interneurons. Acute cocaine treatment
increased phosphorylation of ERK and its direct or indirect nuclear targets,
mitogen- and stress-activated kinase-1 (MSK1) and histone H3, exclusively in
D1R-expressing output neurons in the dorsal striatum and nucleus accumbens.
Cocaine-induced expression of c-Fos and Zif268 predominated in D1R-expressing
neurons but was also observed in D2R-expressing neurons. One week after repeated
cocaine administration, cocaine-induced signaling responses were decreased, with
the exception of enhanced ERK phosphorylation in dorsal striatum. The responses
remained confined to D1R neurons. In contrast, acute haloperidol injection
activated phosphorylation of ERK, MSK1, and H3 only in D2R neurons and induced
c-fos and zif268 predominantly in these neurons. Our results demonstrate that
cocaine and haloperidol specifically activate signaling pathways in two
completely segregated populations of striatal output neurons, providing direct
evidence for the selective mechanisms by which these drugs exert their long-term
PMID: 18509028 [Indexed for MEDLINE]