Abstract
Background
Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors.
Materials and methods
This study examined aripiprazole’s interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic properties.
Results
Aripiprazole produced increases in [35S]GTPγS binding to rat hippocampal membranes. Its potency (pEC50 = 7.2) was similar to that of ziprasidone (7.1) and greater than that of 5-HT (6.7) and buspirone (6.4), a 5-HT1A-receptor partial agonist, whereas its intrinsic activity was similar to that of ziprasidone and buspirone. The stimulatory effect of aripiprazole was blocked by WAY-100635, a 5-HT1A-receptor antagonist. In in vivo electrophysiology studies, aripiprazole produced a dose-related reduction in the firing rate of 5-HT-containing dorsal raphe neurons in rats, which was both prevented and reversed by WAY-100635 administration. Aripiprazole showed a high affinity for human 5-HT1A receptors (K i = 4.2 nM) using parietal cortex membrane preparations. In membranes from cells expressing human recombinant receptors, aripiprazole bound with high affinity to 5-HT2A receptors (K i = 3.4 nM), moderate affinity to 5-HT2C (K i = 15 nM) and 5-HT7 (K i = 39 nM) receptors, and low affinity to 5-HT6 receptors (K i = 214 nM) and 5-HT transporter (K i = 98 nM). In addition, aripiprazole potently blocked 5-HT2A-receptor-mediated increases in intracellular Ca2+ levels in a rat pituitary cell line (IC50 = 11 nM).
Discussion
These results support a partial agonist activity for aripiprazole at 5-HT1A receptors in vitro and in vivo, and suggest important interactions with other 5-HT-receptor subtypes. This receptor activity profile may contribute to the antipsychotic activity of aripiprazole in humans.
Similar content being viewed by others
References
Andrade R (1998) Regulation of membrane excitability in the central nervous system by serotonin receptor subtypes. Ann N Y Acad Sci 861:190–203
Bardin L, Kleven MS, Barret-Grevoz C, Depoortere R, Newman-Tancredi A (2005) Antipsychotic-like vs cataleptogenic actions in mice of novel antipsychotics having D(2) antagonist and 5-HT(1A) agonist properties. Neuropsychopharmacology 31:1869–1879
Blier P, de Montigny C (1987) Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain. Synapse 1:470–480
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72:248–254
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
Ceci A, Baschirotto A, Borsini F (1994) The inhibitory effect of 8-OH-DPAT on the firing activity of dorsal raphe serotoninergic neurons in rats is attenuated by lesion of the frontal cortex. Neuropharmacology 33:709–713
Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108
Cosi C, Waget A, Rollet K, Tesori V, Newman-Tancredi A (2005) Clozapine, ziprasidone and aripiprazole but not haloperidol protect against kainic acid-induced lesion of the striatum in mice, in vivo: role of 5-HT1A receptor activation. Brain Res 1043(1–2):32–41
Davies M, Sheffler D, Roth B (2004) Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology. CNS Drug Rev 10:317–336
Hajos M, Hajos-Korcsok E, Sharp T (1999) Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat. Br J Pharmacol 126:1741–1750
Hirose T, Uwahodo Y, Yamada S, Miwa T, Kikuchi T, Kitagawa H, Burris KD, Altar CA, Nabeshima T (2004) Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile. J Psychopharmacol 18:335–343
Inoue T, Domae M, Yamada K, Furukawa T (1996) Effects of the novel antipsychotic agent 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597) on prolactin release from the rat anterior pituitary gland. J Pharmacol Exp Ther 277:137–143
Ivins KJ, Molinoff PB (1990) Serotonin-2 receptors coupled to phosphoinositide hydrolysis in a clonal cell line. Mol Pharmacol 37:622–630
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-HT(1A) receptor. Eur J Pharmacol 441:137–140
Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, Ali MW (2002) Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 63:763–771
Keck PE Jr, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G (2003) A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry 160:1651–1658
Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro Y, Morita S (1995) 7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J Pharmacol Exp Ther 274:329–336
Lieberman JA, Mailman RB, Duncan G, Sikich L, Chakos M, Nichols DE, Kraus JE (1998) Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychiatry 44:1099–1117
Marder SR, McQuade RD, Stock E, Kaplita S, Marcus R, Safferman AZ, Saha A, Ali M, Iwamoto T (2003) Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr Res 61:123–136
McQuade RD, Burris KD, Jordan S, Tottori K, Kurahashi N, Kikuchi T (2002) Aripiprazole: a dopamine-serotonin system stabilizer. Int J Neuropsychopharmacol 5:S176
Meller E, Goldstein M, Bohmaker K (1990) Receptor reserve for 5-hydroxytryptamine1A-mediated inhibition of serotonin synthesis: possible relationship to anxiolytic properties of 5-hydroxytryptamine1A agonists. Mol Pharmacol 37:231–237
Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21:106S–115S
Millan MJ (2000) Improving the treatment of schizophrenia: focus on serotonin (5-HT)(1A) receptors. J Pharmacol Exp Ther 295:853–861
Miyamoto S, Duncan GE, Mailman RB, Lieberman JA (2000) Developing novel antipsychotic drugs: strategies and goals. Curr Opin CPNS Invest Drugs 2:25–39
Newman-Tancredi A, Gavaudan S, Conte C, Chaput C, Touzard M, Verriele L, Audinot V, Millan MJ (1998) Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study. Eur J Pharmacol 355:245–256
O’Neill C, Cowburn RF, Wiehager B, Alafuzoff I, Winblad B, Fowler CJ (1991) Preservation of 5-hydroxytryptamine1A receptor-G protein interactions in the cerebral cortex of patients with Alzheimer’s disease. Neurosci Lett 133:15–19
Papakostas GI, Petersen TJ, Kinrys G, Burns AM, Worthington JJ, Alpert JE, Fava M, Nierenberg AA (2005) Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J Clin Psychiatry 66:1326–1330
Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, Stringfellow J, Ingenito G, Marder SR (2003) Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 60:681–690
Roth BL, Meltzer HY (1995) The role of serotonin in schizophrenia. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven Press, New York, NY, pp 1215–1227
Scatchard G (1949) The attractions of proteins for small molecules and ions. Ann N Y Acad Sci 51:660–672
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
Simon JS, Nemeroff CB (2005) Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. J Clin Psychiatry 66:1216–1220
Stockmeier CA, DiCarlo JJ, Zhang Y, Thompson P, Meltzer HY (1993) Characterization of typical and atypical antipsychotic drugs based on in vivo occupancy of serotonin2 and dopamine2 receptors. J Pharmacol Exp Ther 266:1374–1384
Van der Maelen C, Matheson G, Wilderman R, Patterson L (1986) Inhibition of serotonergic dorsal raphe neurons by systemic and iontophoretic administration of buspirone, a non-benzodiazepine anxiolytic drug. Eur J Pharmacol 129:123–130
Varty GB, Bakshi VP, Geyer MA (1999) M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague–Dawley and Wistar rats. Neuropsychopharmacology 20:311–321
Wohlpart KL, Molinoff PB (1998) Characterization of 5-HT- and ionomycin-stimulated changes in levels of intracellular calcium and PI hydrolysis in P11 cells. Ann N Y Acad Sci 861:240–241
Yocca FD, Hyslop DK, Smith DW, Maayani S (1987) BMY 7378, a buspirone analog with high affinity, selectivity and low intrinsic activity at the 5-HT1A receptor in rat and guinea pig hippocampal membranes. Eur J Pharmacol 137:293–294
Zhang JY, Kowal DM, Nawoschik SP, Lou Z, Dunlop J (2006) Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms. Biochem Pharmacol 71:521–529
Acknowledgements
This study was supported by Bristol-Myers Squibb Company (Princeton, NJ, USA) and Otsuka Pharmaceutical (Tokyo, Japan). Editorial support for the preparation of this manuscript was provided by Ogilvy Healthworld Medical Education; funding was provided by Bristol-Myers Squibb Company.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Stark, A.D., Jordan, S., Allers, K.A. et al. Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT2A receptors: functional receptor-binding and in vivo electrophysiological studies. Psychopharmacology 190, 373–382 (2007). https://doi.org/10.1007/s00213-006-0621-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-006-0621-y