Dopamine D2 receptors in striatal output neurons enable the psychomotor effects of cocaine.
The psychomotor effects of cocaine are mediated by dopamine (DA) through stimulation of striatal circuits. Gabaergic striatal medium spiny neurons (MSNs) are the only output of this pivotal structure in the control of movements. The majority of MSNs express either the DA D1 or D2 receptors (D1R, D2R). Studies have shown that the motor effect of cocaine depends on the DA-mediated stimulation of D1R-expressing MSNs (dMSNs), which is mirrored at the cellular level by stimulation of signaling pathways leading to phosphorylation of ERKs and induction of c-fos Nevertheless, activation of dMSNs by cocaine is necessary but not sufficient, and D2R signaling is required for the behavioral and cellular effects of cocaine. Indeed, cocaine motor effects and activation of signaling in dMSNs are blunted in mice with the constitutive knockout of D2R (D2RKO). Using mouse lines with a cell-specific knockout of D2R either in MSNs (MSN-D2RKO) or in dopaminergic neurons (DA-D2RKO), we show that D2R signaling in MSNs is required and permissive for the motor stimulant effects of cocaine and the activation of signaling in dMSNs. MSN-D2RKO mice show the same phenotype as constitutive D2RKO mice both at the behavioral and cellular levels. Importantly, activation of signaling in dMSNs by cocaine is rescued by intrastriatal injection of the GABA antagonist, bicuculline. These results are in support of intrastriatal connections of D2R+-MSNs (iMSNs) with dMSNs and indicate that D2R signaling in MSNs is critical for the function of intrastriatal circuits.
Department of Microbiology & Molecular Genetics, U904 INSERM, University of California, Irvine, CA 92697.
Geetika
G
Kharkwal
Department of Microbiology & Molecular Genetics, U904 INSERM, University of California, Irvine, CA 92697.
Daniela
D
Radl
Department of Microbiology & Molecular Genetics, U904 INSERM, University of California, Irvine, CA 92697.
Robert
R
Lewis
Department of Microbiology & Molecular Genetics, U904 INSERM, University of California, Irvine, CA 92697 borrelli@uci.edu.
Emiliana
E
Borrelli
D000818:Animals; D001522:Behavior, Animal; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects*; D018091:Receptors, AMPA / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D003042:Cocaine; D018691:Excitatory Amino Acid Antagonists; D048049:Extracellular Signal-Regulated MAP Kinases; D058787:GABA-A Receptor Antagonists; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D017448:Receptors, Dopamine D2
D2 receptor; cocaine; dopamine; medium spiny neurons; signal transduction
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