Loss of haloperidol induced gene expression and catalepsy in protein kinase A-deficient mice.
The antipsychotic drug, haloperidol, elicits the expression of neurotensin and c-fos mRNA in the dorsal lateral region of the striatum and produces an acute cataleptic response in rodents that correlates with the motor side effects of haloperidol in humans. Mice harboring a targeted disruption of the RIIbeta subunit of protein kinase A have a profound deficit in cAMP-stimulated kinase activity in the striatum. When treated with haloperidol, RIIbeta mutant mice fail to induce either c-fos or neurotensin mRNA and the acute cataleptic response is blocked. However, both wild-type and mutant mice become cataleptic when neurotensin peptide is directly injected into the lateral ventricle, demonstrating that the kinase deficiency does not interfere with the action of neurotensin but rather its synthesis and release. These results establish a direct role for protein kinase A as a mediator of haloperidol induced gene induction and cataleptic behavior.
Adams
M R
MR
Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
Brandon
E P
EP
Chartoff
E H
EH
Idzerda
R L
RL
Dorsa
D M
DM
McKnight
G S
GS
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy; D003342:Corpus Striatum / Q000187:drug effects*; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000172:deficiency* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology*; D051379:Mice; D008817:Mice, Mutant Strains; D009496:Neurotensin / Q000096:biosynthesis / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000302:isolation & purification; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015398:Signal Transduction; D013469:Sulpiride / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D014150:Antipsychotic Agents; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; C517838:Prkar2b protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D009496:Neurotensin; D013469:Sulpiride; D017868:Cyclic AMP-Dependent Protein Kinases; D006220:Haloperidol