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Antipsychotic Drug-Induced Weight Gain Mediated by Histamine H1 Receptor-Linked Activation of Hypothalamic AMP-Kinase

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Antipsychotic Drug-Induced Weight Gain Mediated by Histamine H1 Receptor-Linked Activation of Hypothalamic AMP-Kinase 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†, and Solomon H. Snyder*‡§¶ *The Solomon H. Snyder Department of Neuroscience, Departments of ‡Pharmacology and Molecular Sciences and §Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205; and †Departments of Medicine and Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405 Contributed by Solomon H. Snyder, December 21, 2006 (sent for review November 28, 2006) The atypical antipsychotic drugs (AAPDs) have markedly enhanced after treatment with clozapine or olanzapine (Fig. 1 C and D). the treatment of schizophrenias but their use has been hindered by The drug actions are potent and substantial with EC50 values for the major weight gain elicited by some AAPDs. We report that both of Ϸ10 nM and with 6- and 3.5-fold maximal increases, orexigenic AAPDs potently and selectively activate hypothalamic respectively, with clozapine and olanzapine (Fig. 1 E–H). AMP-kinase, an action abolished in mice with deletion of histamine Clozapine also potently and selectively augments hypotha- H1 receptors. These findings may afford a means of developing lamic AMPK in intact animals. As little as 1 mg/kg of clozapine more effective therapeutic agents and provide insight into the markedly stimulates levels of phospho-AMPK (Fig. 2A) as well hypothalamic regulation of food intake. as AMPK catalytic activity, with 5 mg/kg producing a 3.5-fold augmentation of activity (Fig. 2B). The increase of phospho- atypical antipsychotic drugs ͉ obesity ͉ hypothalamus AMPK and AMPK catalytic activity is relatively selective for the hypothalamus, because clozapine (1 mg/kg) fails to increase he antipsychotic actions of classic neuroleptics revolution- phospho-AMPK levels in the cerebellum and liver [see support- Tized the therapy of schizophrenia, but their use has been ing information (SI) Fig. 5 A and B], and AMPK catalytic activity impeded by side effects such as extrapyramidal symptoms, is not affected in the cerebral cortex or cerebellum by clozapine tardive dyskinesia, a high incidence of nonresponders, and the (1 mg/kg) (Fig. 2C). At 5 mg/kg, clozapine elicits a 20% increase failure of negative symptoms such as apathy to respond. The in cortical AMPK activity, much less than the quadrupling of atypical antipsychotic drugs (AAPDs), pioneered by clozapine, hypothalamic AMPK activity, whereas no increase is apparent in represent an important advance in improving negative symp- the cerebellum (Fig. 2D). The effect of clozapine is maximal 3 h toms, benefiting patients who do not respond to the typical after drug administration and gradually decreases to basal levels drugs, and displaying fewer side effects (1–5). A major limitation in 24 h (SI Fig. 5F). of AAPDs is pronounced weight gain, predominantly mediated Kahn and colleagues (20) reported that the anorexigenic by increased food intake (6–10). Weight gain elicited by AAPDs peptide leptin reduces hypothalamic AMPK activity, which we is primarily related to increased food intake, although there may confirm. Clozapine reverses reductions in hypothalamic phos- also be metabolic alterations (11–13). pho-AMPK elicited by leptin (Fig. 3A) and insulin (20) (SI Fig. To directly address central systems that mediate appetite and 6). In intact mice, leptin (3 mg/kg) reduces hypothalamic phos- weight gain, we have explored hypothalamic AMPK phosphor- pho-AMPK (Fig. 3B) and catalytic activity (Fig. 3C), and ylation, which activates the enzyme (14, 15). In the periphery, clozapine reverses these actions. AMPK activation is associated with decreased lipid formation, The arcuate and paraventricular hypothalamic nuclei display because AMPK phosphorylates acetyl-CoA carboxylase (ACC) the greatest alterations of AMPK activity in response to feeding inhibiting the generation of malonyl-CoA. Malonyl-CoA is a stimuli (20). In immunohistochemical experiments phospho- substrate for fatty acid synthase so that inhibition of ACC AMPK is selectively augmented in these two nuclei with cloza- diminishes formation of fatty acids and lipid (14–16). In the pine (1 and 5 mg/kg), whereas much lesser effects are evident in hypothalamus, AMPK acts in a seemingly reciprocal fashion to the cerebral cortex (SI Fig. 7 A and B). By contrast, ziprasidone regulate food intake (15, 17–19). Kahn and collaborators (20) fails to alter phospho-AMPK in the paraventricular nucleus (SI showed that AMPK activity in the arcuate and paraventricular Fig. 8). hypothalamic nuclei is inhibited by anorexigenic agents such as We wondered whether the influence of AAPDs on hypotha- leptin and augmented by the orexigenic agouti-related protein lamic AMPK is secondary to actions of the drugs on specific (AGRP) (20). neuropeptide receptors that have been implicated in appetite We now show that orexigenic AAPDs selectively and potently regulation. Clozapine and olanzapine (10 and 100 nM) fail to stimulate hypothalamic AMPK, which has been linked to the influence ligand binding to receptors for leptin, ␣-MSH, and regulation of food intake (20), and reverse the actions of the neuropeptide Y (data not shown). anorexigenic hormone leptin. This action involves the histamine H1 receptor (H1R), because clozapine augmentation of AMPK is tm1Wat abolished in B6.129P-Hrh1 (H1RKO) mice, and orexigenic Author contributions: S.F.K. designed research; S.F.K., A.S.H., and A.M.S. performed re- potencies of neuroleptics correlate with their affinities for H1R. search; C.T. contributed new reagents/analytic tools; S.F.K., A.S.H., and S.H.S. analyzed data; and S.F.K. and S.H.S. wrote the paper. Results The authors declare no conflict of interest. In hypothalamic slices, clozapine and olanzapine markedly en- Abbreviations: AAPD, atypical antipsychotic drug; H1R, H1 receptor. hance levels of phospho-AMPK, and quetiapine, which is also See Commentary on page 3019. orexigenic, produces similar effects (Fig. 1A). However, risperi- ¶To whom correspondence should be addressed. E-mail: [email protected]. done, ziprasidone, haloperidol, and aripiprazole, which are much This article contains supporting information online at www.pnas.org/cgi/content/full/ less orexigenic (Table 1), fail to stimulate AMPK (Fig. 1B). 0611417104/DC1. Increased AMPK phosphorylation is observed as early as 5 min © 2007 by The National Academy of Sciences of the USA 3456–3459 ͉ PNAS ͉ February 27, 2007 ͉ vol. 104 ͉ no. 9 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0611417104 Downloaded by guest on October 1, 2021 CTL 1mg/kg CLO A B idol A ine AMPK-P SEE COMMENTARY CTL Clozap HaloperAripipirazol CTL ClozapineOlanzapineQuetiapineRisperidoneZiprasidone AMPK AMPK-P AMPK-P CTL 5mg/kg CLO AMPK AMPK AMPK-P Clozapine 500nM Olanzapine 500nM C D AMPK 0 5 10 20 30 (min) 0 5 10 20 30 (min) * * P<0.001 AMPK-P AMPK-P B 10 AMPK AMPK 8 6 * P<0.01 Clozapine Olanzapine E F 50nM lo 0 5 50 500 5000 (nM) 0 5 50 500 5000 C (nM) 4 AMPK-P AMPK-P 2 0 AMPK AMPK (pmole/min/mg) -AMPK activity Saline 1mg/kg 5mg/kg α2 Clozapine G H C 7 5 Saline 7 6 1mg/kg CLO 6 5 4 5 4 4 3 * 3 3 2 2 2 1 1 -AMPK activity (pmole/min/mg) AMPK activity (pmole/min/mg) AMPK activity 0 0 1 α2− α2− 1 10 100 1000 10000 1 10 100 1000 10000 Clozapine (nM) Olanzapine (pmole/min/mg) -AMPK activity 0 α2 Hypothalamus Cortex Cerebellum Fig. 1. AAPDs activate AMPK in hypothalamic slices. (A and B) Hypothalamic slices were incubated in oxygenated artificial cerebrospinal fluid buffer with D * Saline 500 nM drugs for 30 min. Phospho-AMPK (AMPK-P) and total AMPK were 8 CLO 5mg/Kg MEDICAL SCIENCES detected by Western blotting. (C and D) Hypothalamic slices were incubated ** with 500 nM clozapine or olanzapine for various times as indicated. Phospho- 6 AMPK and total AMPK were detected by Western blotting. (E and F) Hypo- thalamic slices were incubated with various concentrations of clozapine or 4 olanzapine for 30 min. (G and H) ␣2-APMK enzymatic activity was measured with SAMS peptides as a substrate. 2 0 -AMPK activity (pmole/min/mg) -AMPK activity Hypothalamus Cortex Cerebellum Relative potencies of AAPDs in blocking H1R have been α2 reported to correlate with their orexigenic potencies (21, 22), Fig. 2. AAPDs activate AMPK in intact animals. (A and B) Mice received which we confirm (Table 1). Moreover, in hypothalamic slices, clozapine (1 or 5 mg/kg) and were killed at 3 h. Hypothalami were removed the H1R antagonist triprolidine stimulates phospho-AMPK to and tissue lysates analyzed for phospho-AMPK or ␣2-AMPK activity. (C and D) the same extent as clozapine both in hypothalamic slices (Fig. Mice received clozapine (1 or 5 mg/kg) and were killed at 3 h. Various parts of brain were isolated, and ␣2-AMPK activity was assayed. Bars represent the mean Ϯ SE of three independent lysates performed in triplicate. *, Student’s Table 1. Neuroleptic affinities for the H1R correlate t test (n ϭ 5). with orexigenic actions Drugs IC50, nM Orexigenic effects 4A) and in intact animals (SI Fig. 9). Conversely, histamine Clozapine 9 ϩϩϩϩ decreases phospho-AMPK with reversal of this effect by cloza- Olanzapine 13 ϩϩϩ pine (Fig. 4B). To explore whether augmentation of phospho- Quetiapine 40 ϩϩ AMPK by drugs stems from H1R blockade, we administered Risperidone 80 ϩ/Ϫ clozapine to H1R knockout mice. Whereas the drug elicits a Ziprasidone 150 Ϫ quadrupling of phospho-AMPK in wild-type mice, no effect is Haloperidol 2,000ϩϪevident in H1R knockout animals (Fig. 4 C and D). Aripipirazole 3,000ϩϪ Discussion Receptor binding was assayed by using rat brain membranes incubated Our findings indicate that the appetite stimulation–weight gain with [3H]mepyramine and 12 concentrations of drugs ranging from 30 pM to 10 ␮ M, in triplicate.
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