Skip to main content
SpringerLink
Log in

Early antipsychotic exposure affects serotonin and dopamine receptor binding density differently in selected brain loci of male and female juvenile rats

  • Original article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

Antipsychotic drugs (APDs) were developed to treat schizophrenia in adults; however they have been increasingly prescribed (mostly “off-label”) for children and adolescents. This study aimed to investigate the effects of aripiprazole, olanzapine and risperidone on the binding of serotonin (5-HT) and dopamine receptors in juvenile rat brain regions that are involved in antipsychotic efficacy.

Methods

Male and female rats were treated orally with aripiprazole (1 mg/kg), olanzapine (1 mg/kg), risperidone (0.3 mg/kg) or vehicle 3 times/day starting from postnatal day 23 (±1 day) for 20 days. Quantitative autoradiography was performed to examine the receptor binding densities.

Results

Olanzapine significantly decreased 5-HT2A (5-HT2AR) and 5-HT2C receptor (5-HT2CR) binding in the prefrontal cortex (PFC), cingulate cortex (Cg) and nucleus accumbens (NAc) of both male and female rats. In the caudate putamen (CPu), olanzapine attenuated 5-HT2AR binding in both genders, and reduced 5-HT2CR binding in male rats. Olanzapine increased D2 receptor (D2R) binding in the NAcS of male rats, but decreased it in females. Olanzapine increased D1 receptor (D1R) binding in the Cg, while aripiprazole decreased D1R binding in the PFC of males. Aripiprazole significantly reduced 5-HT2AR binding in the male PFC. Risperidone decreased 5-HT2AR binding in the PFC of female rats, while attenuating D1R binding in the PFC and Cg of males. However, APDs have no effects on the binding of serotonin and dopamine transporters.

Conclusion

This study revealed that aripiprazole, olanzapine and risperidone affected 5-HT2AR, 5-HT2CR, 5-HTT, D1R and D2R bindings differently in the brains of juvenile male and female rats.

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

Similar content being viewed by others

Abbreviations

5-HT2AR:

serotonin 5-HT2A receptor

5-HT2CR:

serotonin 5-HT2C receptor

5-HTT:

serotonin 5-HT transporter

ANOVA:

analysis of variance

APDs:

antipsychotic drugs

Cg:

cingulate cortex

CPu:

caudate putamen

D1R:

dopamine D1 receptor

D2R:

dopamine D2 receptor

DFC:

dorsolateral frontal cerebral cortex

DAT:

dopamine transporter

NAc:

nucleus accumbens

NAcC:

nucleus accumbens core

NAcS:

nucleus accumbens shell

PFC:

prefrontal cortex

PD:

postnatal day

References

  1. Vitiello B, Correll C, van Zwieten-Boot B, Zuddas A, Parellada M, Arango C. Antipsychotics in children and adolescents: increasing use, evidence for efficacy and safety concerns. Eur Neuropsychopharmacol 2009;19(9):629–35.

    Article  CAS  PubMed  Google Scholar 

  2. Caccia S. Safety and pharmacokinetics of atypical antipsychotics in children and adolescents. Paediatr Drugs 2013;15(3):217–33.

    Article  PubMed  Google Scholar 

  3. Ginovart N, Kapur S. Role of dopamine D(2) receptors for anti psychotic activity. Handb Exp Pharmacol 2012;2(212):7–52.

    Google Scholar 

  4. Andersen SL, Navalta CP. Altering the course of neurodevelopment: a framework for understanding the enduring effects of psychotropic drugs. Int J Dev Neurosci 2004;22(5–6):423–40.

    Article  CAS  PubMed  Google Scholar 

  5. Moran-Gates T, Grady C, Shik Park Y, Baldessarini RJ, Tarazi FI. Effects of risperidone on dopamine receptor subtypes in developing rat brain. Eur Neuropsychopharmacol 2007; 17(6–7):448–55.

    Article  CAS  PubMed  Google Scholar 

  6. Raznahan A, Lee Y, Stidd R, Long R, Greenstein D, Clasen L. Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence. Proc Natl Acad Sci U S A 2010;107(39): 16988–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Aravagiri M, Marder SR. Brain, plasma and tissue pharmacokinetics of risperidone and 9-hydroxyrisperidone after separate oral administration to rats. Psychopharmacology (Berl) 2002;159(4):424–31.

    Article  CAS  Google Scholar 

  8. Deng C, Lian J, Pai N, Huang XF. Reducing olanzapine-induced weight gain side-effect by betahistine: a study in the rat model. J Psychopharmacol 2012;26(9):1291–379.

    Article  CAS  Google Scholar 

  9. Brenhouse HC, Andersen SL. Developmental trajectories during adolescence in males and females: a cross-species understanding of underlying brain changes. Neurosci Biobehav Rev 2011;35(8):1687–703.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lian J, Huang X-F, Pai N, Deng C. Preventing olanzapine-induced weight gain using betahistine: a study in a rat model with chronic olanzapine treatment. PLoS One 2014;9(8):e104160.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 2007;22:659–61.

    Article  PubMed  CAS  Google Scholar 

  12. FDA. Estimating the safe starting dose in clinical trials for therapeutics in adult healthy volunteers. U.S. FDA Center for Drug Evaluation and Research; 2005.

  13. Greenaway M, Elbe D. Focus on aripiprazole: a review of its use in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 2009;18(3):250–60.

    PubMed  PubMed Central  Google Scholar 

  14. Fraguas D, Correll CU, Merchan-Naranjo J, Rapado-Castro M, Parellada M, Moreno C. Efficacy and safety of second-generation antipsychotics in children and adolescents with psychotic and bipolar spectrum disorders: comprehensive review of prospective head-to-head and placebo-controlled comparisons. Eur Neuropsychopharmacol 2011;21(8):621–45.

    Article  CAS  PubMed  Google Scholar 

  15. Shimokawa Y, Akiyama H, Kashiyama E, Koga T, Miyamoto G. High performance liquid chromatographic methods for the determination of aripiprazole with ultraviolet detection in rat plasma and brain: application to the pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2005;821(1):8–14.

    Article  CAS  PubMed  Google Scholar 

  16. Aravagiri M, Teper Y, Marder SR. Pharmacokinetics and tissue distribution of olanzapine in rats. Biopharm Drug Dispos 1999;20(8):369–77.

    Article  CAS  PubMed  Google Scholar 

  17. Paxinos G, Watson C. The rat brain in sterotaxic coordinates. six edn Academic Press; 2007.

  18. Lian J, Huang XF, Pai N, Deng C. Chronic betahistine co-treatment reverses olanzapine’s effects on dopamine D2 but not 5-HT2A/2C bindings in rat brains. Prog Neuropsychopharmacol Biol Psychiatry 2015;56:75–80.

    Article  CAS  PubMed  Google Scholar 

  19. Kang K, Huang XF, Wang Q, Deng C. Decreased density of serotonin 2A receptors in the superior temporal gyrus in schizophrenia-a postmortem study. Prog Neuropsychopharmacol Biol Psychiatry 2009;33(5):867–71.

    Article  CAS  PubMed  Google Scholar 

  20. Kesby JP, O’Loan JC, Alexander S, Deng C, Huang XF, McGrath JJ, et al. Developmental vitamin D deficiency alters MK-801 -induced behaviours in adult offspring. Psychopharmacology (Berl) 2012;220(3):455–63.

    Article  CAS  Google Scholar 

  21. Han M, Huang XF, Deng C. Aripiprazole differentially affects mesolimbic and nigrostriatal dopaminergic transmission: implications for long-term drug efficacy and low extrapyramidal side-effects. Int J Neuropsychopharmcol 2009;12(7):941–52.

    Article  CAS  Google Scholar 

  22. Lian J, Huang XF, Pai N, Deng C. Chronic betahistine co-treatment reverses olanzapine’s effects on dopamine D(2) but not 5-HT2A/2C bindings in rat brains. Prog Neuropsychopharmacol Biol Psychiatry 2015;56:75–80.

    Article  CAS  PubMed  Google Scholar 

  23. Kuroki T, Nagao N, Nakahara T. Neuropharmacology of second-generation antipsychotic drugs: a validity of the serotonin-dopamine hypothesis. In: Giuseppe Di Giovann VDM, Ennio E, editors. Prog Brain Res, 172. Elsevier; 2008. p. 199–212.

  24. Meltzer H, Massey B. The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 2011;11(1):59–67.

    Article  CAS  PubMed  Google Scholar 

  25. 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 (Berl) 2002;161(3):263–70.

    Article  CAS  Google Scholar 

  26. Zhang JP, Malhotra AK. Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. Expert Opin Drug Metab Toxicol 2011;7(1):9–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Lian J, Huang X-F, Pai N, Deng C. Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density. Prog Neuropsychopharmacol Biol Psychiatry 2013;47(0):62–8.

    Article  CAS  PubMed  Google Scholar 

  28. Choi YK, Moran-Gates T, Gardner MP, Tarazi FI. Effects of repeated risperidone exposure on serotonin receptor subtypes in developing rats. Eur Neuropsychopharmacol 2010;20(3):187–94.

    Article  CAS  PubMed  Google Scholar 

  29. Armenteros JL, Lewis JE, Davalos M. Risperidone augmentation for treatment-resistant aggression in attention-deficit/hyperactivity disorder: a placebo-controlled pilot study. J Am Acad Child Adolesc Psychiatry 2007;46(5):558–65.

    Article  PubMed  Google Scholar 

  30. Huang M, Li Z, Ichikawa J, Dai J, Meltzer HY. Effects of divalproex and atypical antipsychotic drugs on dopamine and acetylcholine efflux in rat hippocampus and prefrontal cortex. Brain Res 2006;1099(1):44–55.

    Article  CAS  PubMed  Google Scholar 

  31. Moran-Gates T, Gan L, Park YS, Zhang K, Baldessarini RJ, Tarazi FI. Repeated antipsychotic drug exposure in developing rats: dopamine receptor effects. Synapse 2006;59(2):92–100.

    Article  CAS  PubMed  Google Scholar 

  32. 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):711–7.

    CAS  PubMed  Google Scholar 

  33. Kusumi I, Takahashi Y, Suzuki K, Kameda K, Koyama T. Differential effects of subchronic treatments with atypical antipsychotic drugs on dopamine D2 and serotonin 5-HT2A receptors in the rat brain. J Neural Transm 2000;107(3):295–302.

    Article  CAS  PubMed  Google Scholar 

  34. Han M, Huang XF, du Bois TM, Deng C. The effects of antipsychotic drugs administration on 5-HT1A receptor expression in the limbic system of the rat brain. Neuroscience 2009;164(4):1754–63.

    Article  CAS  PubMed  Google Scholar 

  35. Kapur S, Mamo D. Halfa century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 2003;27(7):1081–90.

    Article  CAS  PubMed  Google Scholar 

  36. Wood M, Reavill C. Aripiprazole acts as a selective dopamine D2 receptor partial agonist. Expert Opin Investig Drugs 2007;16(6):771–5.

    Article  CAS  PubMed  Google Scholar 

  37. Urban JD, Vargas GA, von Zastrow M, Mailman RB. Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways. Neuropsychopharmacology 2007;32(1):67–77.

    Article  CAS  PubMed  Google Scholar 

  38. Mailman RB, Murthy V. Ligand functional selectivity advances our understanding of drug mechanisms and drug discovery. Neuropsychopharmacology 2010;35(1):345–6.

    Article  PubMed  Google Scholar 

  39. Koener B, Focant MC, Bosier B, Maloteaux JM, Hermans E. Increasing the density of the D2L receptor and manipulating the receptor environment are required to evidence the partial agonist properties of aripiprazole. Prog Neuropsychopharmacol Biol Psychiatry 2012;36(1):60–70.

    Article  CAS  PubMed  Google Scholar 

  40. Tadokoro S, Okamura N, Sekine Y, Kanahara N, Hashimoto K, Iyo M. Chronic treatment with aripiprazole prevents development of dopamine supersensitivity and potentially supersensitivity psychosis. Schizophr Bull 2012;38(5):1012–20.

    Article  PubMed  Google Scholar 

  41. Greenaway M, Elbe D. Focus on aripiprazole: a review of its use in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 2009;18:250–60.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Varela FA, Der-Ghazarian T, Lee RJ, Charntikov S, Crawford CA, McDougall SA. Repeated aripiprazole treatment causes dopamine D2 receptor up-regulation and dopamine supersensitivity in young rats. J Psychopharmacol (Oxf) 2014;28(4):376–86.

    Article  CAS  Google Scholar 

  43. Iniguez SD, Cortez AM, Crawford CA, McDougall SA. Effects of aripiprazole and terguride on dopamine synthesis in the dorsal striatum and medial prefrontal cortex of preweanling rats. J Neural Transm 2008;115(1):97–106.

    Article  CAS  PubMed  Google Scholar 

  44. Frost D, Page S, Carroll C, Kolb B. Early exposure to haloperidol or olanzapine induces long-term alterations of dendritic form. Synapse 2010;64:191–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Farrelly LA, Dicker P, Wynne K, English J, Cagney G, Focking M. Adolescent Risperidone treatment alters protein expression associated with protein trafficking and cellular metabolism in the adult rat prefrontal cortex. Proteomics 2014;14(12):1574–8.

    Article  CAS  PubMed  Google Scholar 

  46. Vinish M, Elnabawi A, Milstein JA, Burke JS, Kallevang JK, Turek KC. Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function. Int J Neuropsychopharmacol 2013;16(7):1599–609.

    Article  CAS  PubMed  Google Scholar 

  47. Milstein JA, Elnabawi A, Vinish M, Swanson T, Enos JK, Bailey AM, et al. Olanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and function. PLoS One 2013;8(2):e57308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. De Santis M, Lian J, Huang X-F, Deng C. Early antipsychotic treatment in childhood/adolescent period has long-term effects on depressive-like, anxiety-like and locomotor behaviours in adult rats. J Psychopharmacol (Oxf) 2016;30(2):204–14.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia

    Jiamei Lian, Bo Pan & Chao Deng

  2. School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia

    Jiamei Lian, Bo Pan & Chao Deng

Authors
  1. Jiamei Lian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bo Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chao Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chao Deng.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lian, J., Pan, B. & Deng, C. Early antipsychotic exposure affects serotonin and dopamine receptor binding density differently in selected brain loci of male and female juvenile rats. Pharmacol. Rep 68, 1028–1035 (2016). https://doi.org/10.1016/j.pharep.2016.06.003

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2016.06.003

Keywords

Search

Navigation