TY - JOUR
T1 - cDNA array reveals increased expression of glucose-dependent insulinotropic polypeptide following chronic clozapine treatment
T2 - Role in atypical antipsychotic drug-induced adverse metabolic effects
AU - Sondhi, S.
AU - Castellano, J. M.
AU - Chong, V. Z.
AU - Rogoza, R. M.
AU - Skoblenick, K. J.
AU - Dyck, B. A.
AU - Gabriele, J.
AU - Thomas, N.
AU - Ki, K.
AU - Pristupa, Z. B.
AU - Singh, A. N.
AU - MacCrimmon, D.
AU - Voruganti, P.
AU - Foster, J.
AU - Mishra, R. K.
N1 - Funding Information:
This work was supported by the Ontario Mental Health Foundation and National Institute of Health Grant NS20035 and the Canadian Institute of Health Research Grant MT2637.
PY - 2006/3
Y1 - 2006/3
N2 - Clozapine is an atypical antipsychotic drug with unique pharmacological and therapeutic properties. Unlike the typical antipsychotic drug, haloperidol, clozapine does not cause extrapyramidal side effects; however, weight gain, dyslipidemia, and type II diabetes are commonly associated with the use of this drug in subjects with schizophrenia. The aim of this study was to profile gene expression in the rat striatum following clozapine treatment. Chronic treatment with clozapine revealed upregulation of several genes including the glucose-dependent insulinotropic polypeptide (GIP) gene by over 200% in the rat striatum. The cDNA array results for the GIP gene were confirmed by real-time RT-PCR as well as by radioimmunoassay. Expression of the GIP gene in the central nervous system is consistent with the results of retinal GIP gene expression as reported by other investigators. Taken together, these findings implicate the possible role of GIP as a neuromodulator in the central nervous system. GIP is an insulinotropic agent with stimulatory effects on insulin synthesis and release from the pancreas. However, changes in brain GIP levels are most likely unrelated to the metabolic adverse effects (dyslipidemia, type II diabetes, weight gain) associated with clozapine treatment. Therefore, we also measured GIP gene expression in the K-cell-rich regions, duodenum and jejunum (small intestine), and plasma GIP levels using radioimmunoassay following chronic treatment with clozapine. GIP mRNA levels in the small intestine and the plasma GIP at the protein level were significantly elevated in clozapine-treated subjects. Furthermore, as observed in humans, chronic clozapine treatment also caused weight gain, and increased levels of insulin, triglycerides and leptin in the plasma. These results suggest that adverse metabolic effects associated with clozapine treatment may be related to its ability to increase intestinal gene expression for GIP.
AB - Clozapine is an atypical antipsychotic drug with unique pharmacological and therapeutic properties. Unlike the typical antipsychotic drug, haloperidol, clozapine does not cause extrapyramidal side effects; however, weight gain, dyslipidemia, and type II diabetes are commonly associated with the use of this drug in subjects with schizophrenia. The aim of this study was to profile gene expression in the rat striatum following clozapine treatment. Chronic treatment with clozapine revealed upregulation of several genes including the glucose-dependent insulinotropic polypeptide (GIP) gene by over 200% in the rat striatum. The cDNA array results for the GIP gene were confirmed by real-time RT-PCR as well as by radioimmunoassay. Expression of the GIP gene in the central nervous system is consistent with the results of retinal GIP gene expression as reported by other investigators. Taken together, these findings implicate the possible role of GIP as a neuromodulator in the central nervous system. GIP is an insulinotropic agent with stimulatory effects on insulin synthesis and release from the pancreas. However, changes in brain GIP levels are most likely unrelated to the metabolic adverse effects (dyslipidemia, type II diabetes, weight gain) associated with clozapine treatment. Therefore, we also measured GIP gene expression in the K-cell-rich regions, duodenum and jejunum (small intestine), and plasma GIP levels using radioimmunoassay following chronic treatment with clozapine. GIP mRNA levels in the small intestine and the plasma GIP at the protein level were significantly elevated in clozapine-treated subjects. Furthermore, as observed in humans, chronic clozapine treatment also caused weight gain, and increased levels of insulin, triglycerides and leptin in the plasma. These results suggest that adverse metabolic effects associated with clozapine treatment may be related to its ability to increase intestinal gene expression for GIP.
KW - Antipsychotic agents
KW - Gastric inhibitory polypeptide
KW - Metabolic side effects
KW - Schizophrenia
KW - Type II diabetes mellitus
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U2 - 10.1038/sj.tpj.6500346
DO - 10.1038/sj.tpj.6500346
M3 - Article
C2 - 16402076
AN - SCOPUS:33645078674
SN - 1470-269X
VL - 6
SP - 131
EP - 140
JO - Pharmacogenomics Journal
JF - Pharmacogenomics Journal
IS - 2
ER -