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PNAS 104 (9): 3456-3459

Copyright © 2007 by the National Academy of Sciences.

Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase

Sangwon F. Kim*, Alex S. Huang*, Adele M. Snowman*, Cory Teuscher{dagger}, and Solomon H. Snyder*,{ddagger},§,

*The Solomon H. Snyder Department of Neuroscience, Departments of {ddagger}Pharmacology and Molecular Sciences and §Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205; and {dagger}Departments of Medicine and Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405


Figure 1
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  		Fig. 1. AAPDs activate AMPK in hypothalamic slices. (A and B) Hypothalamic slices were incubated in oxygenated artificial cerebrospinal fluid buffer with 500 nM drugs for 30 min. Phospho-AMPK (AMPK-P) and total AMPK were detected by Western blotting. (C and D) Hypothalamic slices were incubated with 500 nM clozapine or olanzapine for various times as indicated. Phospho-AMPK and total AMPK were detected by Western blotting. (E and F) Hypothalamic slices were incubated with various concentrations of clozapine or olanzapine for 30 min. (G and H) {alpha}2-APMK enzymatic activity was measured with SAMS peptides as a substrate.

 

Figure 2
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  		Fig. 2. AAPDs activate AMPK in intact animals. (A and B) Mice received clozapine (1 or 5 mg/kg) and were killed at 3 h. Hypothalami were removed and tissue lysates analyzed for phospho-AMPK or {alpha}2-AMPK activity. (C and D) Mice received clozapine (1 or 5 mg/kg) and were killed at 3 h. Various parts of brain were isolated, and {alpha}2-AMPK activity was assayed. Bars represent the mean ± SE of three independent lysates performed in triplicate. *, Student's t test (n = 5).

 

Figure 3
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  		Fig. 3. Clozapine reverses effects of leptin on phospho-AMPK in hypothalamic slices and in intact animals. (A) Hypothalamic slices were incubated with various concentrations of leptin in the absence or presence of 50 nM clozapine for 30 min. Phospho-AMPK and total AMPK were detected by Western blotting. (B and C) Mice received leptin (3 mg/kg), followed at 1 h by clozapine (5 mg/kg) and were killed at 3 h. Phospho-AMPK and total AMPK were detected by Western blotting, and {alpha}2-AMPK activity was assayed. Bars represent the mean ± SE of three independent lysates performed in triplicate. *, P < 0.001, Student's t test (n = 5).

 

Figure 4
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  		Fig. 4. Clozapine activates AMPK through histamine H1 receptors. (A) Hypothalamic slices were incubated with triprolidine (50 or 500 nM) or clozapine (200 nM) for 30 min. Phospho-AMPK and total AMPK were detected by Western blotting. (B) Hypothalamic slices were incubated with various concentrations of histamine in the absence or presence of 200 nM clozapine for 30 min. Phospho-AMPK and total AMPK were detected by Western blotting. (C) Mice were administered saline or 3 mg/kg clozapine and perfused with 4% paraformaldehyde. Immunohistochemistry was performed with an antibody specific for phospho-AMPK. (D) Quantification of immunohistochemistry. Bars represent the mean ± SE of five independent slides. *, P < 0.005; **, P < 0.001; Student's t test (n = 5).

 

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