Fyn is required for haloperidol-induced catalepsy in mice.
Fyn-mediated tyrosine phosphorylation of N-methyl-D-aspartate (NMDA) receptor subunits has been implicated in various brain functions, including ethanol tolerance, learning, and seizure susceptibility. In this study, we explored the role of Fyn in haloperidol-induced catalepsy, an animal model of the extrapyramidal side effects of antipsychotics. Haloperidol induced catalepsy and muscle rigidity in the control mice, but these responses were significantly reduced in Fyn-deficient mice. Expression of the striatal dopamine D(2) receptor, the main site of haloperidol action, did not differ between the two genotypes. Fyn activation and enhanced tyrosine phosphorylation of the NMDA receptor NR2B subunit, as measured by Western blotting, were induced after haloperidol injection of the control mice, but both responses were significantly reduced in Fyn-deficient mice. Dopamine D(2) receptor blockade was shown to increase both NR2B phosphorylation and the NMDA-induced calcium responses in control cultured striatal neurons but not in Fyn-deficient neurons. Based on these findings, we proposed a new molecular mechanism underlying haloperidol-induced catalepsy, in which the dopamine D(2) receptor antagonist induces striatal Fyn activation and the subsequent tyrosine phosphorylation of NR2B alters striatal neuronal activity, thereby inducing the behavioral changes that are manifested as a cataleptic response.
Hattori
Kotaro
K
Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan. hattori@ncnp.go.jp
Uchino
Shigeo
S
Isosaka
Tomoko
T
Maekawa
Mamiko
M
Iyo
Masaomi
M
Sato
Toshio
T
Kohsaka
Shinichi
S
Yagi
Takeshi
T
Yuasa
Shigeki
S
D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced* / Q000473:pathology; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D005838:Genotype; D006220:Haloperidol / Q000494:pharmacology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000737:chemistry; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry
D018726:Anti-Dyskinesia Agents; D014150:Antipsychotic Agents; D007211:Indoles; D010880:Piperidines; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine; C104750:3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole; D011505:Protein-Tyrosine Kinases; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D006220:Haloperidol; D002118:Calcium; D004298:Dopamine