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.
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
Andreasen NC (1995) Symptoms, signs, and diagnosis of schizophrenia. Lancet 346:477–481
Angrist B, Vankammen DP (1984) CNS stimulants as tools in the study of schizophrenia. Trends Neurosci 7:388–390
Baksi SN, Hughes MJ (1982) Chronic vitamin D deficiency in the weanling rat alters catecholamine metabolism in the cortex. Brain Res 242:387–390
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
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
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
Becker JB, Robinson TE, Lorenz KA (1982) Sex differences and estrous cycle variations in amphetamine-elicited rotational behavior. Eur J Pharmacol 80:65–72
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
Bhatt SD, Dluzen DE (2005) Dopamine transporter function differences between male and female CD-1 mice. Brain Res 1035:188–195
Boksa P (2004) Animal models of obstetric complications in relation to schizophrenia. Brain Res Brain Res Rev 45:1–17
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
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
Cannon M, Jones PB, Murray RM (2002) Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiat 159:1080–1092
Cantor-Graae E, Selten JP (2005) Schizophrenia and migration: a meta-analysis and review. Am J Psychiat 162:12–24
Concannon JT, Schechter MD (1981) Hyperactivity in developing rats - sex-differences in 6-hydroxydopamine and amphetamine effects. Pharmacol Biochem Behav 14:5–10
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
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
El-Khodor BF, Boksa P (1998) Birth insult increases amphetamine-induced behavioral responses in the adult rat. Neuroscience 87:893–904
El-Khodor BF, Boksa P (2002) Birth insult and stress interact to alter dopamine transporter binding in rat brain. Neuroreport 13:201–206
Eyles D, Brown J, Mackay-Sim A, McGrath J, Feron F (2003) Vitamin D-3 and brain development. Neuroscience 118:641–653
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
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
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
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
Holick MF (1995) Environmental factors that influence the cutaneous production of vitamin D. Am J Clin Nutr 61:638S–645S
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
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
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
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
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
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
Kuczenski R, Segal DS (1999) Sensitization of amphetamine-induced stereotyped behaviors during the acute response. J Pharmacol Exp Ther 288:699–709
Lanier LP, Isaacson RL (1977) Early developmental-changes in locomotor response to amphetamine and their relation to hippocampal function. Brain Res 126:567–575
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
Leung A, Chue P (2000) Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand 101:3–38
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
McGrath J (1999) Hypotheses: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophr Res 40:173–177
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
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
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
McGrath J, Saha S, Chant D, Welham J (2008) Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 30:67–76
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
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
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
Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007
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
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
Patterson PH (2007) Maternal effects on schizophrenia risk. Science 318:576–577
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
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
Selten JP, Cantor-Graae E, Kahn RS (2007) Migration and schizophrenia. Curr Opin Psychiatr 20:111–115
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
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
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
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
Tenenhouse A, Warner M, Commissiong JW (1991) Neurotransmitters in the CNS of the vitamin-D deficient, hypocalcemic rat. Neurochem Int 18:249–255
Toda M, Abi-Dargham A (2007) Dopamine hypothesis of schizophrenia: making sense of it all. Curr Psychiatry Rep 9:329–336
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
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
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
Walker QD, Ray R, Kuhn CM (2006) Sex differences in neurochemical effects of dopaminergic drugs in rat striatum. Neuropsychopharmacology 31:1193–1202
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
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
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
Zorrilla EP (1997) Multiparous species present problems (and possibilities) to developmentalists. Dev Psychobiol 30:141–150
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
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
Corresponding author
Additional information
Kesby and Cui contributed equally to this work.
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-009-1717-y