title: The effect of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex.
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 Thr(172), and had inactivated ACC, with increased phosphorylation of ACC at Ser(79). 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 (Thr(172))- and p-ACC (Ser(79))-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.
authors: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Min Kyung
authors: MK
authors: Kim
authors: Se Hyun
authors: SH
authors: Kim
authors: Hyun Sook
authors: HS
authors: Yu
authors: Hong Geun
authors: HG
authors: Park
authors: Ung Gu
authors: UG
authors: Kang
authors: Yong Min
authors: YM
authors: Ahn
authors: Yong Sik
authors: YS
authors: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D003024:Clozapine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D002334:Carnitine O-Palmitoyltransferase; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D003024:Clozapine