EFFECTS OF REPEATED CYCLOSPORINE-A ADMINISTRATION ON IMINODIPROPIONITRILE-INDUCED DYSKINESIA AND TRE- CRE-BINDING ACTIVITIES IN RAT-BRAIN/

To clarify the involvement of immunophilin ligands in the pathogenesis and pathophysiology of dyskinesia, we examined the effects of repeate d administration of cyclosporin A (CsA) on rat dyskinesia induced by r epeated injection of iminodipropionitrile (IDPN 100 mg/kg, i.p., for 7 days). The addition of CsA treatment (5 mg/kg, s.c., 1 h before each IDPN injection) exacerbated IDPN-induced dyskinesia. In the group trea ted with both CsA and IDPN, the concentration of dopamine was signific antly increased in the striatum and nucleus accumbens compared with th e group treated with IDPN alone. Furthermore, in the electrophoretic m obility shift assay, the injection of CsA + IDPN increased binding act ivities of transcription factors to the TPA (12-O-tetradecanoylphorbol -13-acetate)-responsive element (TRE) and to the cAMP response element (CRE) in the striatum and nucleus accumbens, compared with those in r ats treated with IDPN alone. The levels of D-1-receptor mRNA in the st riatum were significantly decreased in the IDPN-treated rats but were at the control level in the rats given CsA + IDPN. These findings sugg est that the behavioral aggravation of the IDPN-induced dyskinesia cau sed by CsA administration may be due to the acceleration of the pre- a nd post-synaptic dopaminegic systems via activation of transcription f actors which bind upstream to tyrosine hydroxylase and D-1-receptor ge nes, and that the immunophilin binding agents such as CsA are involved in this aggravated dyskinesia. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.