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Long-term effects of aripiprazole exposure on monoaminergic and glutamatergic receptor subtypes: comparison with cariprazine

  • Yong Kee Choi (a1), Nika Adham (a2), Béla Kiss (a3), István Gyertyán (a4) (a5) and Frank I. Tarazi (a1)...

Abstract

Objective

This study examined the chronic effects of aripiprazole and cariprazine on serotonin (5-HT1A and 5-HT2A) and glutamate (NMDA and AMPA) receptor subtypes. In addition, the effects of aripiprazole on D2 and D3 receptors were tested and compared with previously reported cariprazine data.

Methods

Rats received vehicle, aripiprazole (2, 5, or 15 mg/kg), or cariprazine (0.06, 0.2, or 0.6 mg/kg) for 28 days. Receptor levels were quantified using autoradiographic assays on brain sections from the medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), nucleus accumbens (NAc), caudate-putamen medial (CPu–M), caudate-putamen lateral (CPu–L), hippocampal CA1 (HIPP–CA1) and CA3 (HIPP–CA3) regions, and the entorhinal cortex (EC).

Results

Similar to previous findings with cariprazine, aripiprazole upregulated D2 receptor levels in various regions; D3 receptor changes were less than those reported with cariprazine. All aripiprazole doses and higher cariprazine doses increased 5-HT1A receptors in the MPC and DFC. Higher aripiprazole and all cariprazine doses increased 5-HT1A receptors in HIPP–CA1 and HIPP–CA3. Aripiprazole decreased 5-HT2A receptors in the MPC, DFC, HIPP–CA1, and HIPP–CA3 regions. Both compounds decreased NMDA receptors and increased AMPA receptors in select brain regions.

Conclusions

Long-term administration of aripiprazole and cariprazine had similar effects on 5-HT1A, NMDA, and AMPA receptors. However, cariprazine more profoundly increased D3 receptors while aripiprazole selectively reduced 5-HT2A receptors. These results suggest that the unique actions of cariprazine on dopamine D3 receptors, combined with its effects on serotonin and glutamate receptor subtypes, may confer the clinical benefits, safety, and tolerability of this novel compound in schizophrenia and bipolar mania.

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Copyright

This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited..

Corresponding author

*Address correspondence to: Frank I. Tarazi, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02478, USA. (Email: ftarazi@hms.harvard.edu)

Footnotes

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This study was funded by Forest Laboratories LLC, an Allergan affiliate, and Gedeon Richter Plc.

Editorial support was provided by Paul Ferguson of the Prescott Medical Communications Group (Chicago), a contractor of Allergan.

Footnotes

References

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1. Baldessarini, RJ, Tarazi, FI. Pharmacotherapy of psychosis and mania. In: Brunton LL, Lazo JS, Parker K, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill; 2005: 461500.
2. Moghaddam, B, Javitt, D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2012; 37(1): 415; Epub ahead of print Sep 28, 2011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238069/pdf/npp2011181a.pdf.
3. Eggers, AE. A serotonin hypothesis of schizophrenia. Med Hypotheses. 2013; 80(6): 791794; Epub ahead of print Apr 1.
4. Hu, W, MacDonald, ML, Elswick, DE, Sweet, RA. The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann N Y Acad Sci. 2015; 1338: 3857; Epub ahead of print Oct 14, 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363164/pdf/nihms625030.pdf.
5. Meltzer, HY, Massey, BW. The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol. 2011; 11(1): 5967; Epub ahead of print Mar 21.
6. Ellenbroek, BA, Cesura, AM. Antipsychotics and the dopamine–serotonin connection. In: Celanire S, Poli S, eds. Small Molecule Therapeutics for Schizophrenia. Cham: Springer International Publishing; 2015: 149.
7. Kiss, B, Horváth, A, Némethy, Z, et al. Cariprazine (RGH-188), a dopamine D3 receptor-preferring, D3/D2 dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010; 333(1): 328340; Epub ahead of print Jan 21. http://jpet.aspetjournals.org/content/jpet/333/1/328.full.pdf.
8. Gyertyán, I, Kiss, B, Sághy, K, et al. Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents. Neurochem Int. 2011; 59(6): 925935.
9. Slifstein, M, Abi-Dargham, A, D’Souza, DC, et al. Cariprazine demonstrates high dopamine D3 and D2 receptor occupancy in patients with schizophrenia: a clinical PET study with [11C]-(+)-PHNO. Neuropsychopharmacology. 2013; 38(Suppl 2): S520.
10. Neill, JC, Grayson, B, Kiss, B, Gyertyan, I, Ferguson, P, Adham, N. Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology. Eur Neuropsychopharmacol. 2016; 26(1): 314; Epub ahead of print Nov 19, 2015.
11. Papp, M, Gruca, P, Lason-Tyburkiewicz, M, Adham, N, Kiss, B, Gyertyán, I. Attenuation of anhedonia by cariprazine in the chronic mild stress model of depression. Behav Pharmacol. 2014; 25(5–6): 567574.
12. Zimnisky, R, Chang, G, Gyertyan, I, Kiss, B, Adham, N, Schmauss, C. Cariprazine, a dopamine D3-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse. Psychopharmacology. 2013; 226(1): 91100; Epub ahead of print Oct 19, 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572273/pdf/nihms416352.pdf.
13. Duman, RS, Duric, V, Banasr, M, Adham, N, Kiss, B, Gyertyán, I. Cariprazine exhibits dopamine D3-receptor-dependent antidepressant-like activity in the chronic unpredictable stress model of anhedonia. Neuropsychopharmacology. 2012; 38(Suppl 1): S84S85.
14. Tarazi, FI, Kiss, B, Choi, YK, Adham, N, Gyertyán, I. Effects of chronic aripiprazole administration on dopamine receptors: comparison with cariprazine. Neuropsychopharmacology. 2014; 39: S138S139.
15. Tarazi, FI, Zhang, K, Baldessarini, RJ. Long-term effects of olanzapine, risperidone, and quetiapine on serotonin 1A, 2A and 2C receptors in rat forebrain regions. Psychopharmacology. 2002; 161(3): 263270; Epub ahead of print Apr 4.
16. Tarazi, FI, Moran-Gates, T, Wong, EH, Henry, B, Shahid, M. Asenapine induces differential regional effects on serotonin receptor subtypes. J Psychopharmacol. 2010; 24(3): 341348; Epub ahead of print Aug 21, 2008.
17. Tarazi, FI, Florijn, WJ, Creese, I. Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics. Psychopharmacology. 1996; 128(4): 371379.
18. Tarazi, FI, Baldessarini, RJ, Kula, NS, Zhang, K. Long-term effects of olanzapine, risperidone, and quetiapine on ionotropic glutamate receptor types: implications for antipsychotic drug treatment. J Pharmacol Exp Ther. 2003; 306(3): 11451151; Epub ahead of print Jun 26. http://jpet.aspetjournals.org/content/jpet/306/3/1145.full.pdf.
19. Tarazi, FI, Choi, YK, Gardner, M, Wong, EH, Henry, B, Shahid, M. Asenapine exerts distinctive regional effects on ionotropic glutamate receptor subtypes in rat brain. Synapse. 2009; 63(5): 413420.
20. Gao, J, Qin, R, Li, M. Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function. J Psychopharmacol. 2015; 29(4): 390400; Epub ahead of print Jan 13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757439/pdf/nihms758943.pdf.
21. Paxinos, G, Watson, C. The Rat Brain in Stereotaxic Coordinates, 2nd ed. New York: Academic Press; 1986.
22. Florijn, WJ, Tarazi, FI, Creese, I. Dopamine receptor subtypes: differential regulation after 8 months treatment with antipsychotic drugs. J Pharmacol Exp Ther. 1997; 280(2): 561569 http://jpet.aspetjournals.org/content/jpet/280/2/561.full.pdf.
23. Tarazi, FI, Zhang, K, Baldessarini, RJ. Long-term effects of olanzapine, risperidone, and quetiapine on dopamine receptor types in regions of rat brain: implications for antipsychotic drug treatment. J Pharmacol Exp Ther. 2001; 297(2): 711717 http://jpet.aspetjournals.org/content/jpet/297/2/711.full.pdf.
24. Tarazi, FI, Yeghiayan, SK, Baldessarini, RJ, Kula, NS, Neumeyer, JL. Long-term effects of S(+)N-n-propylnorapomorphine compared with typical and atypical antipsychotics: differential increases of cerebrocortical D2-like and striatolimbic D4-like dopamine receptors. Neuropsychopharmacology. 1997; 17(3): 186196 http://www.nature.com/npp/journal/v17/n3/full/1395027a.html.
25. Greene, WH. Econometric Analysis. Upper Saddle River, NJ: Prentice Hall; 2000. http://stat.smmu.edu.cn/DOWNLOAD/ebook/econometric.pdf.
26. Winer, BJ, Brown, DR, Michels, KM. Statistical Principles in Experimental Design, 3rd ed. New York: McGraw-Hill; 1991.
27. Choi, YK, Adham, N, Kiss, B, Gyertyán, I, Tarazi, FI. Long-term effects of cariprazine exposure on dopamine receptor subtypes. CNS Spectr. 2014; 19(3): 268277; Epub ahead of print Nov 8, 2013.
28. Lammers, CH, Diaz, J, Schwartz, JC, Sokoloff, P. Selective increase of dopamine D3 receptor gene expression as a common effect of chronic antidepressant treatments. Mol Psychiatry. 2000; 5(4): 378388.
29. Newman-Tancredi, A, Assie, MB, Leduc, N, Ormiere, AM, Danty, N, Cosi, C. Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia. Int J Neuropsychopharmacol. 2005; 8(3): 341356; Epub ahead of print Feb 11.
30. Shapiro, DA, Renock, S, Arrington, E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003; 28(8): 14001411; Epub ahead of print May 21.
31. Pazos, A, Palacios, JM. Quantitative autoradiographic mapping of serotonin receptors in the rat brain, I: serotonin-1 receptors. Brain Res. 1985; 346(2): 205230.
32. Pompeiano, M, Palacios, JM, Mengod, G. Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J Neurosci. 1992; 12(2): 440453 http://www.jneurosci.org/content/jneuro/12/2/440.full.pdf.
33. Francis, PT, Pangalos, MN, Pearson, RC, Middlemiss, DN, Stratmann, GC, Bowen, DM. 5-Hydroxytryptamine1A but not 5-hydroxytryptamine2 receptors are enriched on neocortical pyramidal neurones destroyed by intrastriatal volkensin. J Pharmacol Exp Ther. 1992; 261(3): 12731281.
34. Rollema, H, Lu, Y, Schmidt, AW, Sprouse, JS, Zorn, SH. 5-HT1A receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex. Biol Psychiatry. 2000; 48(3): 229237.
35. Ichikawa, J, Ishii, H, Bonaccorso, S, Fowler, WL, O’Laughlin, IA, Meltzer, HY. 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem. 2001; 76(5): 15211531.
36. Bantick, RA, Deakin, JF, Grasby, PM. The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics? J Psychopharmacol. 2001; 15(1): 3746.
37. Christoffersen, CL, Meltzer, LT. Reversal of haloperidol-induced extrapyramidal side effects in Cebus monkeys by 8-hydroxy-2-(di-n-propylamino)tetralin and its enantiomers. Neuropsychopharmacology. 1998; 18(5): 399402 http://www.nature.com/npp/journal/v18/n5/full/1395157a.html.
38. Daniel, DG, Zimbroff, DL, Potkin, SG, Reeves, KR, Harrigan, EP, Lakshminarayanan, M. Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology. 1999; 20(5): 491505 http://www.nature.com/npp/journal/v20/n5/full/1395273a.html.
39. Millan, MJ. Improving the treatment of schizophrenia: focus on serotonin 5-HT1A receptors. J Pharmacol Exp Ther. 2000; 295(3): 853861 http://jpet.aspetjournals.org/content/jpet/295/3/853.full.pdf.
40. Celada, P, Bortolozzi, A, Artigas, F. Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research. CNS Drugs. 2013; 27(9): 703716.
41. Heckers, S, Konradi, C. GABAergic mechanisms of hippocampal hyperactivity in schizophrenia. Schizophr Res. 2015; 167(1–3): 411; Epub ahead of print Oct 18, 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402105/pdf/nihms639551.pdf.
42. O’Dell, SJ, La Hoste, GJ, Widmark, CB, Shapiro, RM, Potkin, SG, Marshall, JF. Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain. Synapse. 1990; 6(2): 146153.
43. Kuoppamaki, M, Seppala, T, Syvalahti, E, Hietala, J. Chronic clozapine treatment decreases 5-hydroxytryptamine1C receptor density in the rat choroid plexus: comparison with haloperidol. J Pharmacol Exp Ther. 1993; 264(3): 12621267.
44. Meltzer, HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology. 1999; 21(Suppl 2): 106S115S http://www.nature.com/npp/journal/v21/n1s/full/1395370a.html/.
45. Tarsy, D, Baldessarini, RJ, Tarazi, FI. Effects of newer antipsychotics on extrapyramidal function. CNS Drugs. 2002; 16(1): 2345.
46. Spurney, CF, Baca, SM, Murray, AM, Jaskiw, GE, Kleinman, JE, Hyde, TM. Differential effects of haloperidol and clozapine on ionotropic glutamate receptors in rats. Synapse. 1999; 34(4): 266276.
47. Aghajanian, GK, Marek, GJ. Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Brain Res Rev. 2000; 31(2–3): 302312.
48. Carlsson, A, Waters, N, Holm-Waters, S, Tedroff, J, Nilsson, M, Carlsson, ML. Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol. 2001; 41: 237260.
49. Tascedda, F, Blom, JM, Brunello, N, et al. Modulation of glutamate receptors in response to the novel antipsychotic olanzapine in rats. Biol Psychiatry. 2001; 50(2): 117122.
50. Tascedda, F, Lovati, E, Blom, JM, et al. Regulation of ionotropic glutamate receptors in the rat brain in response to the atypical antipsychotic Seroquel (quetiapine fumarate). Neuropsychopharmacology. 1999; 21(2): 211217.
51. Watson, DJ, King, MV, Gyertyan, I, Kiss, B, Adham, N, Fone, KC. The dopamine D3-preferring D2/D3 dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia. Eur Neuropsychopharmacol. 2016; 26(2): 208224.
52. Schmidt, WJ, Bubser, M. Anticataleptic effects of the N-methyl-d-aspartate antagonist MK-801 in rats. Pharmacol Biochem Behav. 1989; 32(3): 621623.
53. Yoshida, Y, Ono, T, Kizu, A, Fukushima, R, Miyagishi, T. Striatal N-methyl-d-aspartate receptors in haloperidol-induced catalepsy. Eur J Pharmacol. 1991; 203(2): 173180.
54. Tsai, G, Coyle, JT. Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol. 2002; 42: 165179.
55. Gao, XM, Sakai, K, Roberts, RC, Conley, RR, Dean, B, Tamminga, CA. Ionotropic glutamate receptors and expression of N-methyl-d-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. Am J Psychiatry. 2000; 157(7): 11411149 http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.157.7.1141.
56. Ariano, MA, Larson, ER, Noblett, KL, Sibley, DR, Levine, MS. Coexpression of striatal dopamine receptor subtypes and excitatory amino acid subunits. Synapse. 1997; 26(4): 400414.

Keywords

Long-term effects of aripiprazole exposure on monoaminergic and glutamatergic receptor subtypes: comparison with cariprazine

  • Yong Kee Choi (a1), Nika Adham (a2), Béla Kiss (a3), István Gyertyán (a4) (a5) and Frank I. Tarazi (a1)...

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