Effects of repeated cyclosporin 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 repeated administration of cyclosporin A (CsA) on rat dyskinesia induced by repeated 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 treated with both CsA and IDPN, the concentration of dopamine was significantly increased in the striatum and nucleus accumbens compared with the group treated with IDPN alone. Furthermore, in the electrophoretic mobility shift assay, the injection of CsA + IDPN increased binding activities 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 rats treated with IDPN alone. The levels of D₁-receptor mRNA in the striatum were significantly decreased in the IDPN-treated rats but were at the control level in the rats given CsA + IDPN. These findings suggest that the behavioral aggravation of the IDPN-induced dyskinesia caused by CsA administration may be due to the acceleration of the pre- and post-synaptic dopaminegic systems via activation of transcription factors which bind upstream to tyrosine hydroxylase and D₁-receptor genes, and that the immunophilin binding agents such as CsA are involved in this aggravated dyskinesia.