Abstract
Rationale
Cariprazine is an atypical antipsychotic that acts as a D3/D2 receptor partial agonist. In addition to treating positive symptoms of schizophrenia, cariprazine may have utility for treating negative symptoms. Rodent studies have focused on the effects of cariprazine on cognitive functions and behaviors thought to be related to anhedonia. Avolition, which is characterized by reduced initiation and persistence of goal-directed behavior, is another important negative symptom.
Objectives
Effort-related choice tasks have been used as animal models of avolition. In these studies, cariprazine was assessed for its effects on effort-based choice in both rats and mice. Previous work has shown that D2 antagonists such as haloperidol and eticlopride produce a low-effort bias in rodents tested on effort-based choice tasks.
Results
Low doses of cariprazine produced a low-effort bias in rats tested on the fixed ratio 5/chow feeding choice task, decreasing lever pressing for high carbohydrate pellets but increasing chow intake. Cariprazine did not alter preference or intake of these foods in free-feeding tests. The effort-related effects of cariprazine were reversed by co-administration of the adenosine A2A antagonist istradefylline, and cariprazine failed to reverse the effort-related effects of the dopamine-depleting agent tetrabenazine. In mouse touchscreen choice tests, low doses of cariprazine also produced a low-effort bias, shifting behavior away from panel pressing.
Conclusions
These results demonstrate that with these rodent models of avolition, cariprazine appears to act like a D2-family antagonist even at very low doses. Furthermore, the pharmacological regulation of avolition may differ from that of other negative symptoms.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Data are available on request.
References
Artaloytia JF, Arango C, Lahti A et al (2006) Negative signs and symptoms secondary to antipsychotics: a double-blind, randomized trial of a single dose of placebo, haloperidol, and risperidone in healthy volunteers. Am J Psychiatry 163(3):488–493. https://doi.org/10.1176/appi.ajp.163.3.488
Bailey MR, Chun E, Schipani E, Balsam PD, Simpson EH (2020) Dissociating the effects of dopamine D2 receptors on effort-based versus value-based decision making using a novel behavioral approach. Behav Neurosci 134(2):101–118. https://doi.org/10.1037/bne0000361
Collins LE, Sager TN, Sams AG, Pennarola A, Port RG, Shahriari M, Salamone JD (2012) The novel adenosine A2A antagonist Lu AA47070 reverses the motor and motivational effects produced by dopamine D2 receptor blockade. Pharmacol Biochem Behav 100(3):498–505. https://doi.org/10.1016/j.pbb.2011.10.015
Culbreth AJ, Moran EK, Barch DM (2018) Effort-based decision-making in schizophrenia. Curr Opin Behav Sci 22:1–6. https://doi.org/10.1016/j.cobeha.2017.12.003
Culbreth AJ, Moran EK, Kandala S, Westbrook A, Barch DM (2020) Effort, avolition and motivational experience in schizophrenia: analysis of behavioral and neuroimaging data with relationships to daily motivational experience. Clin Psychol Sci 8(3):555–568. https://doi.org/10.1177/2167702620901558
Duric V, Banasr M, Franklin T, Lepack A, Adham N, Kiss B, Gyertyán I, Duman RS (2017) Cariprazine exhibits anxiolytic and dopamine D3 receptor-dependent antidepressant effects in the chronic stress model. Int J Neuropsychopharmacol 20(10):788–796. https://doi.org/10.1093/ijnp/pyx038
Errante EL, Chakkalamuri M, Akinbo OI, Yohn SE, Salamone JD, Matuszewich L (2021) Sex differences in effort-related decision-making: role of dopamine D2 receptor antagonism. Psychopharmacology 238(6):1609–1619. https://doi.org/10.1007/s00213-021-05795-x
Farrar AM, Pereira M, Velasco F, Hockemeyer J, Müller CE, Salamone JD (2007) Adenosine A(2A) receptor antagonism reverses the effects of dopamine receptor antagonism on instrumental output and effort-related choice in the rat: implications for studies of psychomotor slowing. Psychopharmacology 191(3):579–586. https://doi.org/10.1007/s00213-006-0554-5
Farrar AM, Segovia KN, Randall PA, Nunes EJ, Collins LE, Stopper CM, Port RG, Hockemeyer J, Müller CE, Correa M, Salamone JD (2010) Nucleus accumbens and effort-related functions: behavioral and neural markers of the interactions between adenosine A2A and dopamine D2 receptors. Neuroscience 166(4):1056–1067. https://doi.org/10.1016/j.neuroscience.2009.12.056
Ferré S, Fredholm BB, Morelli M, Popoli P, Fuxe K (1997) Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci 20(10):482–487. https://doi.org/10.1016/s0166-2236(97)01096-5
Fraser KM, Haight JL, Gardner EL, Flagel SB (2016) Examining the role of dopamine D2 and D3 receptors in Pavlovian conditioned approach behaviors. Behav Brain Res 305:87–99. https://doi.org/10.1016/j.bbr.2016.02.022
Garnock-Jones KP (2017) Cariprazine: A Review in Schizophrenia. CNS Drugs 31(6):513–525. https://doi.org/10.1007/s40263-017-0442-z
Gold JM, Strauss GP, Waltz JA, Robinson BM, Brown JK, Frank MJ (2013) Negative symptoms of schizophrenia are associated with abnormal effort-cost computations. Biol Psychiat 74(2):130–136. https://doi.org/10.1016/j.biopsych.2012.12.022
Gyertyán I, Kiss B, Sághy K, Laszy J, Szabó G, Szabados T, Gémesi LI, Pásztor G, Zájer-Balázs M, Kapás M, Csongor ÉÁ, Domány G, Tihanyi K, Szombathelyi Z (2011) 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 59(6):925–935. https://doi.org/10.1016/j.neuint.2011.07.002
Huang M, He W, Kiss B, Farkas B, Adham N, Meltzer HY (2019) The role of dopamine D3 Receptor partial agonism in cariprazine-induced neurotransmitter efflux in rat hippocampus and nucleus accumbens. J Pharmacol Exp Ther 371(2):517–525. https://doi.org/10.1124/jpet.119.259879
Keppel G (1991) Design and analysis a researcher’s handbook, 3rd edn. Prentice Hall, Englewood Clifts
Kiss B, Horváth A, Némethy Z, Schmidt É, Laszlovszky I, Bugovics G, Fazekas K, Hornok K, Orosz S, Gyertyán I, Ágai-Csongor É, Domány G, Tihanyi K, Adham N, Szombathelyi Z (2010) Cariprazine (RGH-188), a dopamine D3 receptor-preferring, D 3/D2 dopamine receptor antagonist-partial agonist antipsychotic candidate: In vitro and neurochemical profile. J Pharmacol Exp Ther 333(1):328–340. https://doi.org/10.1124/jpet.109.160432
Kiss B, Laszlovszky I, Krámos B, Visegrády A, Bobok A, Lévay G, Lendvai B, Román V (2021) Neuronal dopamine D3 receptors: translational implications for preclinical research and cns disorders. Biomolecules 11(1):1–39. https://doi.org/10.3390/biom11010104
Kondej M, Stępnicki P, Kaczor AA (2018) Multi-target approach for drug discovery against Schizophrenia. Int J Mol Sci 19(10):3105. https://doi.org/10.3390/ijms19103105
Laszlovszky I, Barabássy Á, Németh G (2021) Cariprazine, a broad-spectrum antipsychotic for the treatment of schizophrenia: pharmacology, efficacy, and safety. Adv Ther 38(7):3652–3673. https://doi.org/10.1007/s12325-021-01797-5
Mas S, Gassó P, Fernández de Bobadilla R, Arnaiz JA, Bernardo M, Lafuente A (2013) Secondary nonmotor negative symptoms in healthy volunteers after single doses of haloperidol and risperidone: a double-blind, crossover, placebo-controlled trial. Hum Psychopharmacol 28(6):586–593. https://doi.org/10.1002/hup.2350
Merchant JT, Moran EK, Strube MJ, Barch DM (2021) Correlates of real-world goal-directed behavior in schizophrenia. Psychol Med 12:1–9. https://doi.org/10.1017/S0033291721004281
Neill JC, Grayson B, Kiss B, Gyertyán I, Ferguson P, Adham N (2016) Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology. Eur Neuropsychopharmacol 26(1):3–14. https://doi.org/10.1016/j.euroneuro.2015.11.016
Nunes EJ, Randall PA, Santerre JL, Given AB, Sager TN, Correa M, Salamone JD (2010) Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism. Neuroscience 170(1):268–280. https://doi.org/10.1016/j.neuroscience.2010.05.068
Nunes EJ, Randall PA, Hart EE, Freeland C, Yohn SE, Baqi Y, Müller CE, López-Cruz L, Correa M, Salamone JD (2013) Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine: implications for animal models of the motivational symptoms of depression. J Neurosci 33(49):19120–19130. https://doi.org/10.1523/JNEUROSCI.2730-13.2013
Papp M, Gruca P, Lason-Tyburkiewicz M, Adham N, Kiss B, Gyertyan I (2014) Attenuation of anhedonia by cariprazine in the chronic mild stress model of depression. Behav Pharmacol 25(5–6):567–574. https://doi.org/10.1097/FBP.0000000000000070
Pettibone DJ, Totaro JA, Pflueger AB (1984) Tetrabenazine-induced depletion of brain monoamines: characterization and interaction with selected antidepressants. Eur J Pharmacol 102:425–430. https://doi.org/10.1016/0014-2999(84)90562-4
Presby RE, Rotolo RA, Hurley EM, Ferrigno SM, Murphy CE, McMullen HP, Desai PA, Zorda EM, Kuperwasser FB, Carratala-Ros C, Correa M, Salamone JD (2021) Sex differences in lever pressing and running wheel tasks of effort-based choice behavior in rats: suppression of high effort activity by the serotonin transport inhibitor fluoxetine. Pharmacol Biochem Behav 202:173115. https://doi.org/10.1016/j.pbb.2021.173115
Randall PA, Lee CA, Nunes EJ, Yohn SE, Nowak V, Khan B, Shah P, Pandit S, Vemuri VK, Makriyannis A, Baqi Y, Müller CE, Correa M, Salamone JD (2014) The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs. PLoS ONE 9(6):e99320
Reddy LF, Horan WP, Barch DM, Buchanan RW, Dunayevich E, Gold JM, Lyons N, Marder SR, Treadway MT, Wynn JK, Young JW, Green MF (2015) Effort-based decision-making paradigms for clinical trials in schizophrenia: part 1-psychometric characteristics of 5 paradigms. Schizophr Bull 41(5):1045–1054. https://doi.org/10.1093/schbul/sbv089
Rotolo RA, Dragacevic V, Kalaba P, Urban K, Zehl M, Roller A, Wackerlig J, Langer T, Pistis M, De Luca MA, Caria F, Schwartz R, Presby RE, Yang JH, Samels S, Correa M, Lubec G, Salamone JD (2019) The novel atypical dopamine uptake inhibitor (S)-CE-123 partially reverses the effort-related effects of the dopamine depleting agent tetrabenazine and increases progressive ratio responding. Front Pharm 10:682. https://doi.org/10.3389/fphar.2019.00682
Rotolo RA, Kalaba P, Dragacevic V, Presby RE, Neri J, Robertson E, Yang JH, Correa M, Bakulev V, Volkova NN, Pifl C, Lubec G, Salamone JD (2020) Behavioral and dopamine transporter binding properties of the modafinil analog (S, S)-CE-158: reversal of the motivational effects of tetrabenazine and enhancement of progressive ratio responding. Psychopharmacology 237(11):3459–3470. https://doi.org/10.1007/s00213-020-05625-6
Rotolo RA, Presby RE, Tracey O, Asar S, Yang J-H, Correa M, Murray F, Salamone JD (2021) The novel atypical dopamine transport inhibitor CT-005404 reverses the effort-related motivational effects of tetrabenazine and interleukin-1β and increases progressive ratio responding. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2020.108325
Salamone JD, Steinpreis RE, McCullough LD, Smith P, Grebel D, Mahan K (1991) Haloperidol and nucleus accumbens dopamine depletion suppress lever pressing for food but increase free food consumption in a novel food choice procedure. Psychopharmacology 104(4):515–521. https://doi.org/10.1007/BF02245659
Salamone JD, Correa M (2002) Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine. Behav Brain Res 137:3–25
Salamone JD, Arizzi MN, Sandoval MD, Cervone KM, Aberman JE (2002) Dopamine antagonists alter response allocation but do not suppress appetite for food in rats: contrast between the effects of SKF 83566, raclopride, and fenfluramine on a concurrent choice task. Psychopharmacology 160(4):371–380. https://doi.org/10.1007/s00213-001-0994-x
Salamone JD, Correa M (2012) The mysterious motivational functions of mesolimbic dopamine. Neuron 76:470–485
Salamone JD, Yohn SE, Lopez-Cruz L, San Miguel N, Correa M (2016) Activational aspects of motivation: neural mechanisms and implications for psychopathology. Brain 139:1325–1347
Salamone JD, Correa M (2022) Critical review of RDoC approaches to the study of motivation with animal models: effort valuation/willingness to work. Emerg Top Life Sci. https://doi.org/10.1042/ETLS20220008
Salamone JD, Ecevitoglu A, Carratala-Ros C, Presby RE, Edelstein GA, Fleeher R, Rotolo RA, Meka N, Srinath S, Masthay JC, Correa M (2022a) Complexities and paradoxes in understanding the role of dopamine in incentive motivation and instrumental action: Exertion of effort vs. anhedonia. Brain Res Bull 182:57–66. https://doi.org/10.1016/j.brainresbull.2022.01.019
Salamone JD, Srynath S, Evevitoglu A, Edelstein GA, Meka N, Pietrorazio D, Dwy CJ, Correa M (2022b) Exploring possible sex differences in the effort-related motivational effects of dopamine antagonists and dopamine depletion with tetrabenazine. Program No. 730.01. 2022b Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2022. Online
Santerre JL, Nunes EJ, Kovner R, Leser CE, Randall PA, Collins-Praino LE, Lopez Cruz L, Correa M, Baqi Y, Müller CE, Salamone JD (2012) The novel adenosine A(2A) antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions. Pharmacol Biochem Behav 102(4):477–487. https://doi.org/10.1016/j.pbb.2012.06.009
Shaffer JJ, Peterson MJ, McMahon MA, Bizzell J, Calhoun V, van Erp TG, Ford JM, Lauriello J, Lim KO, Manoach DS, McEwen SC, Mathalon DH, O’Leary D, Potkin SG, Preda A, Turner J, Voyvodic J, Wible CG, Belger A (2015) Neural correlates of schizophrenia negative symptoms: distinct subtypes impact dissociable brain circuits. Mol Neuropsychiat 1(4):191–200. https://doi.org/10.1159/000440979
Simpson EH, Kellendonk C, Ward RD, Richards V, Lipatova O, Fairhurst S, Kandel ER, Balsam PD (2011) Pharmacologic rescue of motivational deficit in an animal model of the negative symptoms of schizophrenia. Biol Psychiat 69(10):928–935. https://doi.org/10.1016/j.biopsych.2011.01.012
Sink KS, Vemuri VK, Olszewska T, Makriyannis A, Salamone JD (2008) Cannabinoid CB1 antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior. Psychopharmacology 196(4):565–574. https://doi.org/10.1007/s00213-007-0988-4
Sommer S, Danysz W, Russ H, Valastro B, Flik G, Hauber W (2014) The dopamine reuptake inhibitor MRZ-9547 increases progressive ratio responding in rats. Int J Neuropsychopharmacol 17:2045–2056. https://doi.org/10.1017/S1461145714000996
Strauss GP, Bartolomeo LA, Harvey PD (2021) Avolition as the core negative symptom in schizophrenia: relevance to pharmacological treatment development. NPJ Schizophr 7(1):16. https://doi.org/10.1038/s41537-021-00145-4
Torvinen M, Marcellino D, Canals M, Agnati LF, Lluis C, Franco R, Fuxe K (2005) Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/D3 heteromeric complexes. Mol Pharmacol 67(2):400–407. https://doi.org/10.1124/mol.104.003376
Treadway MT, Peterman JS, Zald DH, Park S (2015) Impaired effort allocation in patients with schizophrenia. Schizophr Res 161(2–3):382–385. https://doi.org/10.1016/j.schres.2014.11.024
Worden LT, Shahriari M, Farrar AM, Sink KS, Hockemeyer J, Müller CE, Salamone JD (2009) The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists. Psychopharmacology 203:489–499
World Health Organization (2022) Schizophrenia. World Health Organization. Retrieved February 12, 2023, from https://www.who.int/news-room/fact-sheets/detail/schizophrenia#:~:text=Schizophrenia%20affects%20approximately%2024%20million,as%20many%20other%20mental%20disorders
Yang JH, Presby RE, Jarvie AA, Rotolo RA, Fitch RH, Correa M, Salamone JD (2020a) Pharmacological studies of effort-related decision making using mouse touchscreen procedures: effects of dopamine antagonism do not resemble reinforcer devaluation by removal of food restriction. Psychopharmacology 237:33–43. https://doi.org/10.1007/s00213-019-05343-8
Yang JH, Presby RE, Cayer S, Rotolo RA, Perrino PA, Fitch RH, Correa M, Chesler EJ, Salamone JD (2020b) Effort-related decision making in humanized COMT mice: effects of Val158Met polymorphisms and possible implications for negative symptoms in humans. Pharmacol Biochem Behav 196:172975. https://doi.org/10.1016/j.pbb.2020.172975
Yang JH, Presby RE, Rotolo RA, Quiles T, Okifo K, Zorda E, Fitch RH, Correa M, Salamone JD (2020c) The dopamine depleting agent tetrabenazine alters effort-related decision making as assessed by mouse touchscreen procedures. Psychopharmacology 237(9):2845–2854. https://doi.org/10.1007/s00213-020-05578-w
Yohn SE, Santerre JL, Nunes EJ, Kozak R, Podurgiel SJ, Correa M, Salamone JD (2015) The role of dopamine D1 receptor transmission in effort-related choice behavior: effects of D1 agonists. Pharmacol Biochem Behav 135:217–226. https://doi.org/10.1016/j.pbb.2015.05.003
Yohn SE, Lopez-Cruz L, Hutson PH, Correa M, Salamone JD (2016) Effects of lisdexamfetamine and s-citalopram, alone and in combination, on effort-related choice behavior in the rat. Psychopharmacology 233(6):949–960. https://doi.org/10.1007/s00213-015-4176-7
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interests/Competing interests
This research was supported by funds from the University of Connecticut Research Foundation. We would like to thank Arsal Shah for his dedicated work on this research. JS has received grants from, and done consulting work for Chronos, Blackthorn, Acadia, Otsuka, and Lundbeck. On behalf of all authors, the corresponding author states that there is no conflict of interest.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Ecevitoglu, A., Edelstein, G.A., Presby, R.E. et al. Effects of the atypical antipsychotic and D3/D2 dopamine partial agonist cariprazine on effort-based choice behavior: implications for modeling avolition. Psychopharmacology 240, 1747–1757 (2023). https://doi.org/10.1007/s00213-023-06405-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-023-06405-8