Alterations in prefrontal glutamatergic and noradrenergic systems following MK-801 administration in rats prenatally exposed to methylazoxymethanol at gestational day 17.
BACKGROUND
Prenatal methylazoxymethanol (MAM) administration at gestational day 17 has been shown to induce in adult rats schizophrenia-like behaviours as well as morphological and/or functional abnormalities in structures such as the hippocampus, medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), consistent with human data.


OBJECTIVE
The aim of the present study was to further characterize the neurochemical alterations associated with this neurodevelopmental animal model of schizophrenia.


METHODS
We performed simultaneous measurements of locomotor activity and extracellular concentrations of glutamate, dopamine and noradrenaline in the mPFC and the NAcc of adult rats prenatally exposed to MAM or saline after acute systemic injection of a noncompetitive NMDA antagonist, MK-801 (0.1 mg/kg s.c.).


RESULTS
A significant attenuation of the MK-801-induced increase in glutamate levels associated with a potentiation of the increase in noradrenaline concentrations was found in the mPFC of MAM-exposed rats, whereas no significant change was observed in the NAcc. MAM-exposed rats also exhibited an exaggerated locomotor hyperactivity, in line with the exacerbation of symptoms reported in schizophrenic patients after administration of noncompetitive NMDA antagonists.


CONCLUSIONS
Given the importance of the mPFC in regulating the hyperlocomotor effect of NMDA antagonists, our results suggest that the prefrontal neurochemical alterations induced by MK-801 may sustain the exaggerated locomotor response in MAM-exposed rats.
Léna
Isabelle
I
INSERM Equipe Avenir, JE 2441, Laboratoire de Neurobiologie et Psychopathologie, Université de Nice-Sophia Antipolis, Parc Valrose, 06108, Nice cedex 2, France. lena@unice.fr
Chessel
Aline
A
Le Pen
Gwenaëlle
G
Krebs
Marie-Odile
MO
Garcia
René
R
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012559:Schizophrenia / Q000503:physiopathology*
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D008746:Methylazoxymethanol Acetate; D016291:Dizocilpine Maleate; C030667:methylazoxymethanol; D004298:Dopamine; D009638:Norepinephrine