Skip to main content
SpringerLink
Log in

Effects of atypical antipsychotics and haloperidol on PC12 cells: only aripiprazole phosphorylates AMP-activated protein kinase

  • Basic Neurosciences, Genetics and Immunology - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

By converting changes in intracellular energy status to changes in cell membrane polarization, ATP-sensitive K+ (KATP) channels in hypothalamic appetite-regulating neurons play a critical role in linking neuronal electrochemical function, metabolic and energy status, and feeding behavior. Most atypical antipsychotics (AAPs) increase the appetite of patients with schizophrenia and thus cause obesity. This study aimed to explain the mechanism underlying AAP-induced appetite stimulation, based on the fact that the efficiency of fatty acid uptake into mitochondria generating ATP through β-oxidation is determined by the rate of fatty acid synthesis. Using PC12 cells exposed to clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, and haloperidol, we measured intracellular ATP and mRNA and protein expression of enzymes and related substances involved in fatty acid synthesis and KATP channel function. Forty-eight-hour treatment of cells with 50 μM aripiprazole in 5.6 mM glucose decreased intracellular ATP. Only 50 μM aripiprazole phosphorylated AMP-activated protein kinase (AMPK); none of the other antipsychotics did so to a detectable level. Expression of carnitine palmitoyltransferase 1a, uncoupling protein 2, and sulfonylurea receptor 1 was unaffected by the antipsychotics, although expression of their mRNA was affected by AAPs. Pyrilamine (H1 receptor antagonist), ketanserin (5HT2 receptor antagonist), and raclopride (D2 receptor antagonist) alone or in combination had no effect on expression of the aforementioned proteins. Therefore, although this study did not differentiate orexigenic and non-orexigenic AAPs, it suggests that aripiprazole is unique in its ability to activate AMPK.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AAP:

Atypical antipsychotic

ACC:

Acetyl-CoA carboxylase

AMPK:

AMP-activated protein kinase

ANOVA:

Analysis of variance

CaMKKβ:

Ca2+/calmodulin-dependent protein kinase β

cAMP:

Cyclic AMP

CoA:

Coenzyme A

CPT1:

Carnitine palmitoyltransferase 1

DMEM:

Dulbecco’s modified Eagle’s medium

FAS:

Fatty acid synthase

GLUT3:

Glucose transporter 3

HPRT:

Hypoxanthine–guanine phosphoribosyltransferase

Ig:

Immunoglobulin

KATP channels:

ATP-sensitive K+ channels

LKB1:

Liver kinase B1

MCD:

Malonyl-CoA decarboxylase

PCR:

Polymerase chain reaction

PGC1α:

PPARγ coactivator 1α

PKA:

Protein kinase A

POMC:

Proopiomelanocortin

PPARα:

Peroxisome proliferator-activated receptor α

PVDF:

Polyvinylidene fluoride

SUR:

Sulfonylurea receptor

UCP2:

Uncoupling protein 2

References

  • Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ (1999) Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156:1686–1696

    CAS  PubMed  Google Scholar 

  • Anand BK, Chhina GS, Sharma KN, Dua S, Singh B (1964) Activity of single neurons in the hypothalamic feeding centers: effect of glucose. Am J Physiol 207:1146–1154

    CAS  PubMed  Google Scholar 

  • Andrews ZB, Liu Z-W, Walllingford N, Erion DM, Borok E, Friedman JM, Tschöp MH, Shanabrough M, Cline G, Shulman GI, Coppola A, Gao X-B, Horvath TL, Diano S (2008) UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals. Nature 454:846–851

    Article  CAS  PubMed  Google Scholar 

  • Bolonna AA, Kerwin RW (2005) Partial agonism and schizophrenia. Br J Psychiatry 186:7–10

    Article  CAS  PubMed  Google Scholar 

  • Brandt JM, Djouadi F, Kelly DP (1998) Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor α. J Biol Chem 273:23786–23792

    Article  CAS  PubMed  Google Scholar 

  • Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB (2002) Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302:381–389

    Article  CAS  PubMed  Google Scholar 

  • Djouder N, Tuerk RD, Suter M, Salvioni P, Thali RF, Scholz R, Vaahtomeri K, Auchli Y, Rechsteiner H, Brunisholz RA, Viollet B, Mäkelä TP, Wallimann T, Neumann D, Krek W (2010) PKA phosphorylates and inactivates AMPKα to promote efficient lipolysis. EMBO J 29:469–481

    Article  CAS  PubMed  Google Scholar 

  • Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, Harper JA, Roebuck SJ, Morrison A, Pickering S, Clapham JC, Brand MD (2002) Superoxide activates mitochondrial uncoupling proteins. Nature 415:96–99

    Article  CAS  PubMed  Google Scholar 

  • Girgis RR, Javitch JA, Lieberman JA (2008) Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway. Mol Psychiatry 13:918–929

    Article  CAS  PubMed  Google Scholar 

  • Hao W, Chang C-PB, Tsao C-C, Xu J (2010) Oligomycin-induced bioenergetic adaptation in cancer cells with heterogeneous bioenergetic organization. J Biol Chem 285:12647–12654

    Article  CAS  PubMed  Google Scholar 

  • Hardie DG, Carling D (1997) The AMP-activated protein kinase—fuel gauge of the mammalian cell? Eur J Biochem 246:259–273

    Article  CAS  PubMed  Google Scholar 

  • Hardie DG, Carling D, Carlson M (1998) The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu Rev Biochem 67:821–855

    Article  CAS  PubMed  Google Scholar 

  • Hardie DG, Scott JW, Pan DA, Hudson ER (2003) Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546:113–120

    Article  CAS  PubMed  Google Scholar 

  • Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG (2005) Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2:9–19

    Article  CAS  PubMed  Google Scholar 

  • He W, Lam TK, Obici S, Rossetti L (2006) Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat Neurosci 9:227–233

    Article  CAS  PubMed  Google Scholar 

  • Heiser P, Enning F, Krieg JC, Vedder H (2007) Effects of haloperidol, clozapine and olanzapine on the survival of human neuronal and immune cells in vitro. J Psychopharmacol 21:851–856

    Article  CAS  PubMed  Google Scholar 

  • Jo Y-H, Su Y, Gutierrez-Juarez R, Chua S Jr (2009) Oleic acid directly regulates POMC neuron excitability in the hypothalamus. J Neurophysiol 101:2305–2316

    Article  CAS  PubMed  Google Scholar 

  • Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA (2002) The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur J Pharmacol 441:137–140

    Article  CAS  PubMed  Google Scholar 

  • Kato T, Mizoguchi Y, Monji A, Horikawa H, Suzuki SO, Seki Y, Iwaki T, Hashioka S, Kanba S (2008) Inhibitory effects of aripiprazole on interferon-γ-induced microglial activation via intracellular Ca2+ regulation in vitro. J Neurochem 106:815–825

    Article  CAS  PubMed  Google Scholar 

  • Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH (2007) Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci USA 104:3456–3459

    Article  CAS  PubMed  Google Scholar 

  • Krauss S, Zhang CY, Lowell BB (2002) A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP2. Proc Natl Acad Sci USA 99:118–122

    Article  CAS  PubMed  Google Scholar 

  • Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL (2003) H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28:519–526

    Article  CAS  PubMed  Google Scholar 

  • Lamberti JS, Olson D, Crilly JF, Olivares T, Williams GC, Tu X, Tang W, Wiener K, Dvorin S, Dietz MB (2006) Prevalence of the metabolic syndrome among patients receiving clozapine. Am J Psychiatry 163:1273–1276

    Article  PubMed  Google Scholar 

  • Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR, Mailman RB (1999) Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 20:612–627

    Article  CAS  PubMed  Google Scholar 

  • Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, Kuhajda FP (2000) Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288:2379–2381

    Article  CAS  PubMed  Google Scholar 

  • López M, Lage R, Saha AK, Pérez-Tilve D, Vázquez MJ, Varela L, Sangiao-Alvarellos S, Tovar S, Raghay K, Rodríguez-Cuenca S, Deoliveira RM, Castañeda T, Datta R, Dong JZ, Culler M, Sleeman MW, Álvarez CV, Gallego R, Lelliott CJ, Carling D, Tschöp MH, Diéguez C, Vidal-Puig A (2008) Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab 7:388–399

    Article  Google Scholar 

  • Mascaró C, Acosta E, Ortiz JA, Marrero PF, Hegardt FG, Haro D (1998) Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferators-activated receptor. J Biol Chem 273:8560–8563

    Article  PubMed  Google Scholar 

  • Matsui-Sakata A, Ohtani H, Sawada Y (2005) Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus. Drug Metab Pharmacokinet 20:368–378

    Article  CAS  PubMed  Google Scholar 

  • Mayer J (1953a) Glucostatic mechanism of regulation of food intake. New Engl J Med 249:13–16

    Article  CAS  PubMed  Google Scholar 

  • Mayer J (1953b) Genetic, traumatic and environmental factors in the etiology of obesity. Physiol Rev 33:472–508

    CAS  PubMed  Google Scholar 

  • Mayer J (1955) Regulation of energy intake and the body weight: the glucostatic theory and the lipostatic hypothesis. Ann N Y Acad Sci 63:15–43

    Article  CAS  PubMed  Google Scholar 

  • McGarry JD, Foster DW (1979) In support of the roles of malonyl-CoA and carnitine acyltransferase I in the regulation of hepatic fatty acid oxidation and ketogenesis. J Biol Chem 254:8163–8168

    CAS  PubMed  Google Scholar 

  • McGarry JD, Leatherman GF, Foster DW (1978) Carnitine palmitoyltransferase I: the site of inhibition of hepatic fatty acid oxidation by malonyl-CoA. J Biol Chem 253:4128–4136

    CAS  PubMed  Google Scholar 

  • Moore ML, Park EA, McMillin JB (2003) Upstream stimulatory factor represses the induction of carnitine palmitoyltransferase-Iβ expression by PGC-1. J Biol Chem 278:17263–17268

    Article  CAS  PubMed  Google Scholar 

  • Mountjoy PD, Rutter GA (2007) Glucose sensing by hypothalamic neurones and pancreatic islet cells: AMPle evidence for common mechanisms? Exp Physiol 92:311–319

    Article  CAS  PubMed  Google Scholar 

  • Nasrallah HA (2008) Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 13:27–35

    Article  CAS  PubMed  Google Scholar 

  • Nichols CG (2006) KATP channels as molecular sensors of cellular metabolism. Nature 440:470–476

    Article  CAS  PubMed  Google Scholar 

  • Obici S, Feng Z, Arduini A, Conti R, Rossetti L (2003) Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 9:756–761

    Article  CAS  PubMed  Google Scholar 

  • Oomura Y, Ono T, Ooyama H, Wayner MJ (1969) Glucose and osmosensitive neurones of the rat hypothalamus. Nature 222:282–284

    Article  CAS  PubMed  Google Scholar 

  • Ota M, Nakashima A, Kaneko YS, Mori K, Takami G, Ota A (2007) Risperidone reduces mRNA expression levels of Sulfonylurea Receptor 1 and TASK1 in PC12 cells. Neurosci Lett 412:254–258

    Article  CAS  PubMed  Google Scholar 

  • Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang C-Y, Xu C, Vianna CR, Balthasar N, Lee CE, Elmquist JK, Cowley MA, Lowell BB (2007) Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449:228–232

    Article  CAS  PubMed  Google Scholar 

  • Pothos EN, Przedborski S, Davila V, Schmitz Y, Sulzer D (1998) D2-like dopamine autoreceptor activation reduces quantal size in PC12 cells. J Neurosci 18:5575–5585

    CAS  PubMed  Google Scholar 

  • Quinn JC, Johnson-Farley NN, Yoon J, Cowen DS (2002) Activation of extracellular-regulated kinase by 5-hydroxytryptamine2A receptors in PC12 cells is protein kinase C-independent and requires calmodulin and tyrosine kinases. J Pharmacol Exp Ther 303:746–752

    Article  CAS  PubMed  Google Scholar 

  • Ronnett GV, Ramamurthy S, Kleman AM, Landree LE, Aja S (2009) AMPK in the brain: its roles in energy balance and neuroprotection. J Neurochem 109(Suppl 1):17–23

    Article  CAS  PubMed  Google Scholar 

  • Ruderman NB, Saha AK, Vavvas D, Witters LA (1999) Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol 276:E1–E18

    CAS  PubMed  Google Scholar 

  • Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R (2003) Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 28:1400–1411

    Article  CAS  PubMed  Google Scholar 

  • Shen Y, Fan Y, Dai H, Fu Q, Hu W, Chen Z (2007) Neuroprotective effect of carnosine on necrotic cell death in PC12 cells. Neurosci Lett 414:145–149

    Article  CAS  PubMed  Google Scholar 

  • Stahmann N, Woods A, Carling D, Heller R (2006) Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase β. Mol Cell Biol 26:5933–5945

    Article  CAS  PubMed  Google Scholar 

  • Stark AD, Jordan S, Allers KA, Bertekap RL, Chen R, Mistry Kannan T, Molski TF, Yocca FD, Sharp T, Kikuchi T, Burris KD (2007) Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT2A receptors: functional receptor-binding and in vivo electrophysiological studies. Psychopharmacology (Berl) 190:373–382

    Article  CAS  Google Scholar 

  • Tamás P, Hawley SA, Clarke RG, Mustard KJ, Green K, Hardie DG, Cantrell DA (2006) Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med 203:1665–1670

    Article  PubMed  Google Scholar 

  • Urban JD, Vargas GA, von Zastrow M, Mailman RB (2007) Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways. Neuropsychopharmacology 32:67–77

    Article  CAS  PubMed  Google Scholar 

  • van den Top M, Lyons DJ, Lee K, Coderre E, Renaud LP, Spanswick D (2007) Pharmacological and molecular characterization of ATP-sensitive K+ conductances in CART and NPY/AgRP expressing neurons of the hypothalamic arcuate nucleus. Neuroscience 144:815–824

    Article  PubMed  Google Scholar 

  • Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    Article  CAS  PubMed  Google Scholar 

  • Wang G-L, Moore ML, McMillin JB (2002) A region in the first exon/intron of rat carnitine palmitoyltransferase Iβ is involved in enhancement of basal transcription. Biochem J 362:609–618

    Article  CAS  PubMed  Google Scholar 

  • Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    Article  CAS  PubMed  Google Scholar 

  • Wirshing DA, Boyd JA, Meng LR, Ballon JS, Marder SR, Wirshing WC (2002) The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry 63:856–865

    CAS  PubMed  Google Scholar 

  • Yang NC, Ho WM, Chen YH, Hu ML (2002) A convenient one-step extraction of cellular ATP using boiling water for the luciferin-luciferase assay of ATP. Anal Biochem 306:323–327

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    Article  CAS  PubMed  Google Scholar 

  • Zhang C-Y, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig AJ, Boss O, Kim Y-B, Zheng XX, Wheeler MB, Shulman GI, Chan CB, Lowell BB (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and type 2 diabetes. Cell 105:745–755

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants-in-aid from Fujita Health University to AO. We thank Pfizer (New York, NY, USA) for the generous supply of ziprasidone.

Author information

Authors and Affiliations

  1. Department of Physiology, School of Medicine, Fujita Health University, Toyoake, 470-1192, Japan

    Goro Takami, Akira Nakashima, Yoko S. Kaneko, Keiji Mori & Akira Ota

  2. Irigaike Mental Clinic, Nagakute, Japan

    Goro Takami

  3. Department of Neuropsychiatry, Tosei General Hospital, Seto, Japan

    Miyuki Ota

  4. Department of Psychiatry, Nagoya City University Medical School, Nagoya, Japan

    Miyuki Ota

  5. Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Japan

    Toshiharu Nagatsu

Authors
  1. Goro Takami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miyuki Ota
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akira Nakashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoko S. Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keiji Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Toshiharu Nagatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akira Ota
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akira Ota.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig.

 Addendum Intracellular cAMP in PC12 cells treated with the AAPs or haloperidol. Cells were incubated with AAPs or haloperidol at final concentrations of 20 nM, 1μM, or 50 μM for 24 h in DMEM containing 25 or 5.6 mM glucose. The basal amount of intracellular cAMP in PC12 cells was 0.16–0.35 pmol/106 cells. Each group comprised 6 to 8 samples. Values normalized (=1.0) to those of vehicle are shown as means (columns) ± SEM (bars). Clo, clozapine; Ola, olanzapine; Ris, risperidone; Quet, quetiapine; Zip, ziprasidone; Arip, aripiprazole; Hal, haloperidol (PPT 63 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takami, G., Ota, M., Nakashima, A. et al. Effects of atypical antipsychotics and haloperidol on PC12 cells: only aripiprazole phosphorylates AMP-activated protein kinase. J Neural Transm 117, 1139–1153 (2010). https://doi.org/10.1007/s00702-010-0457-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-010-0457-9

Keywords

Search

Navigation