LOSS OF HALOPERIDOL-INDUCED GENE-EXPRESSION AND CATALEPSY IN PROTEIN-KINASE A-DEFICIENT MICE

The antipsychotic drug, haloperidol, elicits the expression of neurote nsin and c-fos mRNA in the dorsal lateral region of the striatum and p roduces an acute cataleptic response in rodents that correlates with t he motor side effects of haloperidol in humans, Mice harboring a targe ted disruption of the RII beta subunit of protein kinase A have a prof ound deficit in cAMP-stimulated kinase activity in the striatum, When treated with haloperidol, RII beta 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 neurot ensin peptide is directly injected into the lateral ventricle, demonst rating that the kinase deficiency does not interfere with the action o f neurotensin but rather its synthesis and release, These results esta blish a direct role for protein kinase A as a mediator of haloperidol induced gene induction and cataleptic behavior.