PHASE-DEPENDENT PHASE-SHIFT OF METHAMPHETAMINE-INDUCED CIRCADIAN-RHYTHM BY HALOPERIDOL IN SCN-LESIONED RATS

Haloperidol, a non-selective dopamine receptor antagonist, was injected intraperitoneally in to suprachiasmatic nucleus (SCN)-lesioned rats at various phases of the locomotor activity rhythm induced by methamphetamine (MAP) treatment. A single injection of haloperidol shifted the phase of MAP-induced locomotor rhythm phase dependently, while saline injection had no effect on the phase. A phase-response curve of MAP-induced rhythm for haloperidol had a small phase-advancing area at CT 13 to 15, a large phase-delaying area at CT 3 to 7 and a dead zone at CT 17 to 1. Although the day-to-day variation of MAP-induced locomotor rhythm was about 2.5-times as great as that of light entrainable circadian rhythm, the phase shifts of both directions were statistically significant. Phase delay shifts at CT 5 depended on the dose of haloperidol. In addition to the phase-shifting effect, haloperidol suppressed the MAP-induced locomotor activity for about 10 h regardless of the phase of the injection. Pentobarbital also suppressed the locomotor activity for a similar duration. However, significant phase shift was not detected with pentobarbital injected at CT 5 or CT 13, at the phase where haloperidol induced the maximal phase delay or advance, respectively. Present findings suggest that the dopaminergic mechanism is involved in the entrainment and/or oscillatory mechanism of the MAP-induced rhythm.