Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring

Kesby, James P., O'Loan, Jonathan C., Alexander, Suzanne, Deng, Chao, Huang, Xu-Feng, McGrath, John J., Eyles, Darryl W. and Burne, Thomas H. J. (2012) Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring. Psychopharmacology, 220 3: 455-463. doi:10.1007/s00213-011-2492-0

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Author Kesby, James P.
O'Loan, Jonathan C.
Alexander, Suzanne
Deng, Chao
Huang, Xu-Feng
McGrath, John J.
Eyles, Darryl W.
Burne, Thomas H. J.
Title Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring
Journal name Psychopharmacology   Check publisher's open access policy
ISSN 0033-3158
Publication date 2012-04-01
Year available 2011
Sub-type Article (original research)
DOI 10.1007/s00213-011-2492-0
Open Access Status File (Author Post-print)
Volume 220
Issue 3
Start page 455
End page 463
Total pages 9
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Abstract Stress is known to modulate sensitisation to repeated psychostimulant exposure. However, there is no direct evidence linking glucocorticoids and sensitisation achieved by repeated administration of the NMDA receptor antagonist MK-801. We tested the hypothesis that co-administration of RU486, a glucocorticoid receptor (GR) antagonist, prior to repeated daily MK-801 injections would block the expression of locomotor sensitisation due to its dual effects on corticosterone and dopamine. We employed a repeated MK-801 administration locomotor sensitisation paradigm in male Sprague Dawley rats. RU486 or a dimethyl sulfoxide (DMSO) vehicle was co-administered with MK-801 or saline during the induction phase. Subsequent to withdrawal, rats were challenged with MK-801 alone to test for the expression of sensitisation. In a separate cohort of rats, plasma corticosterone levels were quantified from blood samples taken on the 1st, 4th and 7th day of induction and at expression. One day after challenge, nucleus accumbens tissue levels of dopamine and its metabolites DOPAC and HVA were measured. During the induction phase, RU486 progressively enhanced locomotor sensitisation to MK-801. RU486 and MK-801 both showed stimulatory effects on corticosterone levels and this was further augmented when given in combination. Contrary to our hypothesis, RU486 did not block the expression of locomotor sensitisation to MK-801 and actually increased levels of dopamine, DOPAC and HVA in nucleus accumbens tissue. Our results showed that RU486 has augmentative rather than inhibitory effects on MK-801-induced sensitisation. This study indicates a divergent role for glucocorticoids in sensitisation to MK-801 compared to sensitisation with other psychostimulants.
Formatted abstract
Rationale Developmental vitamin D (DVD) deficiency is a candidate risk factor for developing schizophrenia in humans. In rodents DVD deficiency induces subtle changes in the way the brain develops. This early developmental insult leads to select behavioural changes in the adult, such as an enhanced response to amphetamine-induced locomotion in female DVD-deficient rats but not in male DVDdeficient rats and an enhanced locomotor response to the Nmethyl-D-aspartate (NMDA) receptor antagonist, MK-801, in male DVD-deficient rats. However, the response to MK-801-induced locomotion in female DVD-deficient rats is unknown. Therefore, the aim of the current study was to further examine this behavioural finding in male and female rats and assess NMDA receptor density. Methods DVD-deficient Sprague Dawley rats were assessed for locomotion, ataxia, acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR to multiple doses of MK-801. The NMDA receptor density in relevant brain regions was assessed in a drug-naive cohort. Results DVD deficiency increased locomotion in response to MK-801 in both sexes. DVD-deficient rats also showed an enhanced ASR compared with control rats, but PPI was normal. Moreover, DVD deficiency decreased NMDA receptor density in the caudate putamen of both sexes. Conclusions These results suggest that a transient prenatal vitamin D  deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders.
Keyword Schizophrenia
Vitamin D
Prepulse inhibition
Animal model
NMDA receptor
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID APP 1024239
Institutional Status UQ
Additional Notes Published online: 21 September 2011

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2012 Collection
School of Psychology Publications
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Citation counts: TR Web of Science Citation Count  Cited 32 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 34 times in Scopus Article | Citations
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Created: Sat, 10 Mar 2012, 02:53:45 EST by Debra McMurtrie on behalf of Queensland Brain Institute