Fyn Is Required for Haloperidol-induced Catalepsy in Mice

Abstract

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 haloperidolinduced 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 Fyndeficient 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 Fyndeficient 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.Typical antipsychotic agents, such as haloperidol and chlorpromazine, have extrapyramidal side effects (EPS) 2 that resemble Parkinson disease. Drug-induced catalepsy, the impairment of movement initiation, in rodents is an animal model of EPS and is mainly caused by blockade of the dopamine D 2 receptor (D 2 -R) (1, 2).Haloperidol-induced responses are also dependent on N-methyl-Daspartate receptor (NMDA-R) activity, because prior administration of the NMDA-R antagonist MK-801 attenuates haloperidol-induced catalepsy (3, 4). D 2 -R and NMDA-R are co-expressed in close proximity along the dendrites of medium spiny neurons in the striatum, and they are functionally coupled in terms of controlling extrapyramidal functions (5).The NMDA-Rs are hetero-oligomeric ligand-gated ion channels composed of a single NR1 subunit and one type of NR2 (A-D) subunit (6). The most abundant receptor subunits in the striatum are NR1, NR2A, and NR2B (7, 8). These three subunits are involved in extrapyramidal functions (5), and we have found that an NR2B-selective antagonist attenuates haloperidol-induced catalepsy (9).Phosphorylation of tyrosine residues on the NMDA-R has been reported to modulate its channel characteristics (10, 11). Depriving the striatum of dopaminergic input increases the tyrosine phosphorylation of the striatal NMDA-R and the motor response (12, 13), but infusing the striatum with a tyrosine kinase inhibitor, genistein, attenuates both the tyrosine phosphorylation and the motor response induced by dopaminergic deprivation (13).Fyn is a member of the Src family kinases (SFKs) and is associated with the NMDA-R at postsynaptic d...

Antagonism of Dopamine D2 Receptors Alters Phosphorylation of Fyn in the Rat Medial Prefrontal Cortex

“…Another D2R antagonist haloperidol was injected at a dose of 1 mg/kg calculated as the salt. This dose was chosen because haloperidol at this dose (1 h prior to brain tissue collection) increased tyrosine phosphorylation of several proteins in the mouse striatum (Hattori et al, 2006). …”

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