The International Journal of Neuropsychopharmacology

Research Article

The effect of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex

Min Kyung Kima1a2, Se Hyun Kima2a3, Hyun Sook Yua1a2, Hong Geun Parka1a2, Ung Gu Kanga3, Yong Min Ahna3 and Yong Sik Kima1a3 c1

a1 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

a2 Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea

a3 Department of Psychiatry and Behavioral Science and Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

Abstract

Clozapine is an antipsychotic drug that has a greater efficacy than other medications in some contexts, especially for the treatment of treatment-resistant schizophrenia. However, clozapine induces more metabolic side-effects involving abnormality in lipid metabolism compared to other antipsychotics. AMP-activated protein kinase (AMPK) plays a central role in controlling lipid metabolism through modulating the downstream acetyl CoA carboxylase (ACC) and carnitine palmitoyl transferase 1 (CPT1) pathway. In this study, we investigated the effect of a single intraperitoneal injection of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex, which has been implicated as a target site for this antipsychotic drug. At 2 h after injection, the clinically relevant dose of clozapine had activated AMPK, with increased phosphorylation of AMPKα at Thr172, and had inactivated ACC, with increased phosphorylation of ACC at Ser79. In addition, clozapine activated the brain-specific isoform of CPT1, CPT1c, whose activity is inhibited by unphosphorylated ACC, in the rat frontal cortex. Immunohistochemistry and immunofluorescence analysis showed that clozapine induced an increase in number of p-AMPKα (Thr172)- and p-ACC (Ser79)-positive cells among the neurons of the rat frontal cortex. Taken together, these results show that clozapine activated the AMPK-ACC-CPT1 pathway in the neurons of the rat frontal cortex. These findings indicate that the antipsychotic agent clozapine affects the lipid regulatory system of neurons in the brain.

(Received March 19 2011)

(Reviewed April 25 2011)

(Revised May 25 2011)

(Accepted May 25 2011)

(Online publication June 28 2011)

Correspondence:

c1 Address for correspondence: Y. S. Kim, M. D., Ph.D., Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea. Tel.: 82-2-2072-2204 Fax: 82-2-744-7241 Email: kys@snu.ac.kr