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J. Biol. Chem., Vol. 280, Issue 8, 6309-6315, February 25, 2005

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Effect of Haloperidol on mPer1 Gene Expression in Mouse Suprachiasmatic Nuclei^*

Jarupa Viyoch, Naoya Matsunaga, Miyako Yoshida, Hideto To, Shun Higuchi, and Shigehiro Ohdo

From the Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

The effect of a typical neuroleptic haloperidol (Hal) on mPer1 gene expression was investigated in mouse suprachiasmatic nuclei (SCN). Hal induced mPer1 mRNA levels both in vivo and in cultured SCN cells. For mechanisms underlying Hal-induced mPer1 expression, N-methyl-D-aspartate (NMDA) glutamate receptor subtype, the phosphorylation form of the transcription factor, and the Ser-133 phosphorylation form of cAMP-responsive element-binding protein (CREB) played an important role, because the induction of mPer1 mRNA significantly decreased after pretreatment with a non-competitive NMDA receptor antagonist, such as MK-801 or CREB antisense. These results suggest that Hal may increase CREB phosphorylation and mPer1 expression according to the activation of the NMDA receptor through the dopaminergic pathways. Although the injection of Hal during the light period increased the amplitude of mPer1 mRNA rhythmicity in a nondrug state, the injection of the drug during the dark period disturbed the rhythmic pattern of mPer1 mRNA. These results suggest that the rhythmicity of clock genes in SCN may be disturbed depending on the dosing time of Hal. On the other hand, because the induction of mPer1 mRNA by Hal seems to be at least partly caused by the NMDA receptor, showing a phase shift or resetting effect of the circadian clock, Hal may also cause such phase shift effects.

Received for publication, October 14, 2004 , and in revised form, November 30, 2004.

^* This study was supported by Grants-in-aid for Scientific Research on Priority Areas "Cancer" 14030062, 15025254, and 16023245 (to S. O.) and Grant-in-aid for Scientific Research (B) 16390042 (to S. O.) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-92-642-6658; Fax: 81-92-642-6660; E-mail: ohdo{at}phar.kyushu-u.ac.jp.

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