Skip to main content
SpringerLink
Log in

Developmental vitamin D deficiency alters dopamine-mediated behaviors and dopamine transporter function in adult female rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. DVD deficiency in neonatal rats is associated with alterations in cellular development, dopamine metabolism, and brain morphology. DVD-deficient adult rats show novelty-induced hyperlocomotion and an enhanced locomotor response to MK-801, which can be ameliorated by pretreatment with the antipsychotic drug haloperidol.

Objectives

In this study, we examined locomotor responses of male and female juvenile and adult rats to a dose range of amphetamine. We also measured dopamine receptor and monoamine transporter densities in adult brain.

Results

Female DVD-deficient adult rats displayed an enhanced sensitivity to amphetamine-induced locomotion, an increased dopamine transporter density in the caudate–putamen and increased affinity in the nucleus accumbens compared with control females. By contrast, there were no differences between control and DVD-deficient male rats.

Discussion

Taken together, this suggests an alteration in the development of the dopamine system and on dopamine-mediated behaviors in female DVD-deficient rats, and this may be relevant to the underlying neurobiology of schizophrenia.

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

Similar content being viewed by others

References

  • Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M (1998) Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiat 155:761–767

    CAS  PubMed  Google Scholar 

  • Andreasen NC (1995) Symptoms, signs, and diagnosis of schizophrenia. Lancet 346:477–481

    Article  CAS  PubMed  Google Scholar 

  • Angrist B, Vankammen DP (1984) CNS stimulants as tools in the study of schizophrenia. Trends Neurosci 7:388–390

    Article  Google Scholar 

  • Baksi SN, Hughes MJ (1982) Chronic vitamin D deficiency in the weanling rat alters catecholamine metabolism in the cortex. Brain Res 242:387–390

    Article  CAS  PubMed  Google Scholar 

  • Bardo MT, Bowling SL, Pierce RC (1990) Changes in locomotion and dopamine neurotransmission following amphetamine, haloperidol, and exposure to novel environmental stimuli. Psychopharmacology 101:338–343

    Article  CAS  PubMed  Google Scholar 

  • Bauer RH (1980) The effects of L-amphetamine, D-amphetamine, and parahydroxy-amphetamine on locomotor-activity and wall climbing in rats of different ages. Pharmacol Biochem Behav 13:155–165

    Article  CAS  PubMed  Google Scholar 

  • Bauer RH (1982) Ontogenetic differences in response to D-amphetamine - 2-way avoidance, inter-trial responses, and locomotor-activity. Pharmacol Biochem Behav 16:217–223

    Article  CAS  PubMed  Google Scholar 

  • Becker JB, Robinson TE, Lorenz KA (1982) Sex differences and estrous cycle variations in amphetamine-elicited rotational behavior. Eur J Pharmacol 80:65–72

    Article  CAS  PubMed  Google Scholar 

  • Becker A, Eyles DW, McGrath JJ, Grecksch G (2005) Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats. Behav Brain Res 161:306–312

    Article  CAS  PubMed  Google Scholar 

  • Bhatt SD, Dluzen DE (2005) Dopamine transporter function differences between male and female CD-1 mice. Brain Res 1035:188–195

    Article  CAS  PubMed  Google Scholar 

  • Boksa P (2004) Animal models of obstetric complications in relation to schizophrenia. Brain Res Brain Res Rev 45:1–17

    Article  PubMed  Google Scholar 

  • Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, deBartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D (1997) Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 94:2569–2574

    Article  CAS  PubMed  Google Scholar 

  • Burne TH, O’Loan J, McGrath JJ, Eyles DW (2006) Hyperlocomotion associated with transient prenatal vitamin D deficiency is ameliorated by acute restraint. Behav Brain Res 174:119–124

    Article  CAS  PubMed  Google Scholar 

  • Cannon M, Jones PB, Murray RM (2002) Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiat 159:1080–1092

    Article  PubMed  Google Scholar 

  • Cantor-Graae E, Selten JP (2005) Schizophrenia and migration: a meta-analysis and review. Am J Psychiat 162:12–24

    Article  PubMed  Google Scholar 

  • Concannon JT, Schechter MD (1981) Hyperactivity in developing rats - sex-differences in 6-hydroxydopamine and amphetamine effects. Pharmacol Biochem Behav 14:5–10

    Article  CAS  PubMed  Google Scholar 

  • Cui XY, McGrath JJ, Burne THJ, Mackay-Sim A, Eyles DW (2007) Maternal vitamin D depletion alters neurogenesis in the developing rat brain. Int J Dev Neurosci 25:227–232

    Article  CAS  PubMed  Google Scholar 

  • Davies G, Welham J, Chant D, Torrey EF, McGrath J (2003) A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. Schizophr Bull 29:587–593

    PubMed  Google Scholar 

  • El-Khodor BF, Boksa P (1998) Birth insult increases amphetamine-induced behavioral responses in the adult rat. Neuroscience 87:893–904

    Article  CAS  PubMed  Google Scholar 

  • El-Khodor BF, Boksa P (2002) Birth insult and stress interact to alter dopamine transporter binding in rat brain. Neuroreport 13:201–206

    Article  CAS  PubMed  Google Scholar 

  • Eyles D, Brown J, Mackay-Sim A, McGrath J, Feron F (2003) Vitamin D-3 and brain development. Neuroscience 118:641–653

    Article  CAS  PubMed  Google Scholar 

  • Feron F, Burne THJ, Brown J, Smith E, McGrath JJ, Mackay-Sim A, Eyles DW (2005) Developmental Vitamin D-3 deficiency alters the adult rat brain. Brain Res Bull 65:141–148

    Article  CAS  PubMed  Google Scholar 

  • Ghisi V, Ramsey AJ, Masri B, Gainetdinov RR, Caron MG, Salahpour A (2009) Reduced D2-mediated signaling activity and trans-synaptic upregulation of D1 and D2 dopamine receptors in mice overexpressing the dopamine transporter. Cell Signal 21:87–94

    Article  CAS  PubMed  Google Scholar 

  • Giros B, Jaber M, Jones SR, Wightman RM, Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612

    Article  CAS  PubMed  Google Scholar 

  • Hietala J, Syvalahti E, Vuorio K, Rakkolainen V, Bergman J, Haaparanta M, Solin O, Kuoppamaki M, Kirvela O, Ruotsalainen U, Salokangas RKR (1995) Presynaptic dopamine function in striatum of neuroleptic–naive schizophrenic-patients. Lancet 346:1130–1131

    Article  CAS  PubMed  Google Scholar 

  • Holick MF (1995) Environmental factors that influence the cutaneous production of vitamin D. Am J Clin Nutr 61:638S–645S

    CAS  PubMed  Google Scholar 

  • Hughes RN (2007) Sex does matter: comments on the prevalence of male-only investigations of drug effects on rodent behaviour. Behav Pharmacol 18:583–589

    Article  PubMed  Google Scholar 

  • Ji J, Dluzen DE (2008) Sex differences in striatal dopaminergic function within heterozygous mutant dopamine transporter knock-out mice. J Neural Transm 115:809–817

    Article  CAS  PubMed  Google Scholar 

  • Jones SR, Gainetdinov RR, Wightman RM, Caron MG (1998) Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J Neurosci 18:1979–1986

    CAS  PubMed  Google Scholar 

  • Kesby JP, Burne THJ, McGrath JJ, Eyles DW (2006) Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: an animal model of schizophrenia. Biol Psychiatry 60:591–596

    Article  CAS  PubMed  Google Scholar 

  • Kesby JP, Cui X, Ko P, McGrath JJ, Burne TH, Eyles DW (2009) Developmental vitamin D deficiency alters dopamine turnover in neonatal rat forebrain. Neurosci Lett 461:155–158

    Article  CAS  PubMed  Google Scholar 

  • Ko P, Burkert R, McGrath J, Eyles D (2004) Matemal vitamin D-3 deprivation and the regulation of apoptosis and cell cycle during rat brain development. Brain Res Dev Brain Res 153:61–68

    Article  CAS  PubMed  Google Scholar 

  • Kuczenski R, Segal DS (1999) Sensitization of amphetamine-induced stereotyped behaviors during the acute response. J Pharmacol Exp Ther 288:699–709

    CAS  PubMed  Google Scholar 

  • Lanier LP, Isaacson RL (1977) Early developmental-changes in locomotor response to amphetamine and their relation to hippocampal function. Brain Res 126:567–575

    Article  CAS  PubMed  Google Scholar 

  • Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 93:9235–9240

    Article  CAS  PubMed  Google Scholar 

  • Leung A, Chue P (2000) Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand 101:3–38

    Article  Google Scholar 

  • Lindstrom LH, Gefvert O, Hagberg G, Lundberg T, Bergstrom M, Hartvig P, Langstrom B (1999) Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-C-11) DOPA and PET. Biol Psychiat 46:681–688

    Article  CAS  PubMed  Google Scholar 

  • McGrath J (1999) Hypotheses: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophr Res 40:173–177

    Article  CAS  PubMed  Google Scholar 

  • McGrath J, Selten JP, Chant D (2002) Long-term trends in sunshine duration and its association with schizophrenia birth rates and age at first registration—data from Australia and The Netherlands. Schizophr Res 54:199–212

    Article  PubMed  Google Scholar 

  • McGrath J, Eyles D, Mowry B, Yolken R, Buka S (2003) Low maternal vitamin D as a risk factor for schizophrenia: a pilot study using banked sera. Schizophr Res 63:73–78

    Article  PubMed  Google Scholar 

  • McGrath JJ, Saari K, Hakko H, Jokelainen J, Jones PB, Jarvelin MR, Chant DC, Isohanni M (2004) Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth-cohort study. Schizophr Res 67:237–245

    Article  PubMed  Google Scholar 

  • McGrath J, Saha S, Chant D, Welham J (2008) Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 30:67–76

    Article  PubMed  Google Scholar 

  • Meyer U, Engler A, Weber L, Schedlowskic M, Feldon J (2008a) Preliminary evidence for a modulation of fetal dopaminergic development by maternal immune activation during pregnancy. Neuroscience 154:701–709

    Article  CAS  PubMed  Google Scholar 

  • Meyer U, Nyffeler M, Schwendener S, Knuesel I, Yee BK, Feldon J (2008b) Relative prenatal and postnatal maternal contributions to schizophrenia-related neurochemical dysfunction after in utero immune challenge. Neuropsychopharmacology 33:441–456

    Article  PubMed  Google Scholar 

  • Neal-Beliveau BS, Joyce JN (1993) D(1) and D(2) dopamine-receptors do not up-regulate in response to neonatal intrastriatal 6-hydroxydopamine lesions. Neurosci Lett 160:77–80

    Article  CAS  PubMed  Google Scholar 

  • Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007

    CAS  PubMed  Google Scholar 

  • O’Loan J, Eyles DW, Kesby J, Ko P, McGrath JJ, Burne TH (2007) Vitamin D deficiency during various stages of pregnancy in the rat; its impact on development and behaviour in adult offspring. Psychoneuroendocrinology 32:227–234

    Article  PubMed  Google Scholar 

  • O’Neill MF, Shaw G (1999) Comparison of dopamine receptor antagonists on hyperlocomotion induced by cocaine, amphetamine, MK-801 and the dopamine D-1 agonist C-APB in mice. Psychopharmacology 145:237–250

    Article  PubMed  Google Scholar 

  • Patterson PH (2007) Maternal effects on schizophrenia risk. Science 318:576–577

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (2005) The Rat Brain in Stereotaxic Coordinates. Academic Press, San Diego

  • Puchacz E, Stumpf WE, Stachowiak EK, Stachowiak MK (1996) Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells. Brain Res Mol Brain Res 36:193–196

    Article  CAS  PubMed  Google Scholar 

  • Salahpour A, Ramsey AJ, Medvedev IO, Kile B, Sotnikova TD, Holmstrand E, Ghisi V, Nicholls PJ, Wong L, Murphy K, Sesack SR, Wightman RM, Gainetdinov RR, Caron MG (2008) Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter. Proc Natl Acad Sci USA 105:4405–4410

    Article  CAS  PubMed  Google Scholar 

  • Selten JP, Cantor-Graae E, Kahn RS (2007) Migration and schizophrenia. Curr Opin Psychiatr 20:111–115

    Article  Google Scholar 

  • Sharp T, Zetterstrom T, Ljungberg T, Ungerstedt U (1987) A direct comparison of amphetamine-induced behaviours and regional brain dopamine release in the rat using intracerebral dialysis. Brain Res 401:322–330

    Article  CAS  PubMed  Google Scholar 

  • Sulzer D, Maidment NT, Rayport S (1993) Amphetamine and other weak bases act to promote reverse transport of dopamine in ventral midbrain neurons. J. Neurochem. 60:527–535

    Article  CAS  PubMed  Google Scholar 

  • Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A (1995) Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci 15:4102–4108

    CAS  PubMed  Google Scholar 

  • Tekes K, Gyenge M, Folyovich A, Csaba G (2009) Influence of neonatal vitamin A or vitamin D treatment on the concentration of biogenic amines and their metabolites in the adult rat brain. Horm Metab Res 41:277–280

    Article  CAS  PubMed  Google Scholar 

  • Tenenhouse A, Warner M, Commissiong JW (1991) Neurotransmitters in the CNS of the vitamin-D deficient, hypocalcemic rat. Neurochem Int 18:249–255

    Article  CAS  Google Scholar 

  • Toda M, Abi-Dargham A (2007) Dopamine hypothesis of schizophrenia: making sense of it all. Curr Psychiatry Rep 9:329–336

    Article  PubMed  Google Scholar 

  • Torrey EF, Miller J, Rawlings R, Yolken RH (1997) Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res 28:1–38

    Article  CAS  PubMed  Google Scholar 

  • Vasilev V, Vestov R, Janac B, Rakic LJ, Stojiljkovic M (2003) Age-related differences in MK-801-and amphetamine-induced locomotor and stereotypic activities of rats. Neurobiol Aging 24:715–723

    Article  CAS  PubMed  Google Scholar 

  • Walker QD, Rooney MB, Wightman RM, Kuhn CM (2000) Dopamine release and uptake are greater in female than male rat striatum as measured by fast cyclic voltammetry. Neuroscience 95:1061–1070

    Article  CAS  PubMed  Google Scholar 

  • Walker QD, Ray R, Kuhn CM (2006) Sex differences in neurochemical effects of dopaminergic drugs in rat striatum. Neuropsychopharmacology 31:1193–1202

    CAS  PubMed  Google Scholar 

  • Wang JY, Wu JN, Cherng TL, Hoffer BJ, Chen HH, Borlongan CV, Wang Y (2001) Vitamin D-3 attenuates 6-hydroxydopamine-induced neurotoxicity in rats. Brain Res 904:67–75

    Article  CAS  PubMed  Google Scholar 

  • Wieczorek WJ, Kruk ZL (1994) Differential action of (+)-amphetamine on electrically-evoked dopamine overflow in rat-brain slices containing corpus striatum and nucleus-accumbens. Brit J Pharmacol 111:829–836

    CAS  Google Scholar 

  • Zhuang XX, Oosting RS, Jones SR, Gainetdinov RR, Miller GW, Caron MG, Hen R (2001) Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci USA 98:1982–1987

    Article  CAS  PubMed  Google Scholar 

  • Zorrilla EP (1997) Multiparous species present problems (and possibilities) to developmentalists. Dev Psychobiol 30:141–150

    Article  CAS  PubMed  Google Scholar 

  • Zuckerman L, Rehavi M, Nachman R, Weiner I (2003) Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology 28:1778–1789

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Health and Medical Research Council of Australia.

Disclosure/conflicts of interest

The authors have no conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. School of Biomedical Science, University of Queensland, Brisbane, QLD, 4072, Australia

    James P. Kesby

  2. Queensland Brain Institute, University of Queensland, Brisbane, QLD, 4072, Australia

    Xiaoying Cui, John J. McGrath, Thomas H. J. Burne & Darryl W. Eyles

  3. Queensland Centre for Mental Health Research, Wacol, QLD, 4076, Australia

    Jonathan O’Loan, John J. McGrath, Thomas H. J. Burne & Darryl W. Eyles

  4. Department of Psychiatry, University of Queensland, Brisbane, QLD, 4072, Australia

    John J. McGrath

Authors
  1. James P. Kesby
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoying Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan O’Loan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John J. McGrath
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas H. J. Burne
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Darryl W. Eyles
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Darryl W. Eyles.

Additional information

Kesby and Cui contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kesby, J.P., Cui, X., O’Loan, J. et al. Developmental vitamin D deficiency alters dopamine-mediated behaviors and dopamine transporter function in adult female rats. Psychopharmacology 208, 159–168 (2010). https://doi.org/10.1007/s00213-009-1717-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-009-1717-y

Keywords

Search

Navigation