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2251 – Cortical And Subcortical Gene-expression Imaging By Different n-methyl-daspartate Receptor (nmda-r) Antagonists At Glutammatergic Synapses: Implications For Dopamine-glutamate Interplay In Psychoses
Published online by Cambridge University Press: 15 April 2020
Abstract
According to the NMDA-R hypofunction hypothesis of psychosis, the administration of certain antagonists at NMDA-R, such as ketamine, may exacerbate psychotic symptoms in humans and provide a preclinical model of psychosis. Both ketamine and antipsychotic drugs induce molecular changes in genes of the post-synaptic density (PSD), involved in glutamate signaling and dopamine-glutamate interplay.
Memantine, an antagonist/partial agonist at NMDA-Rs with procognitive properties, has been proposed as an adjunctive treatment for schizophrenia.
We tested the hypothesis that memantine and propsychotic NMDA-Rs antagonists (ketamine and MK-801) may elicit divergent molecular changes at glutamatergic synapses.
Sprague-Dawley rats were treated by:
1) vehicle;
2) MK-801 0.8 mg/kg;
3) memantine 5 mg/kg;
4) ketamine 25 mg/kg;
5) ketamine 50 mg/kg.
We compared, by in situ hybridization histochemistry, the expression of PSD genes in cortical and striatal brain regions.
Homer1a expression was significantly induced by ketamine 25 mg/kg and reduced by MK-801 in striatum and cortex. Arc expression was significantly induced by ketamine and memantine in the cortex and by MK-801 in nucleus accumbens. Homer1b/c expression was significantly decreased by ketamine compared to vehicle in motor cortex and dorsolateral striatum. PSD-95 expression was significantly decreased by MK-801 compared to vehicle in all striatal regions and by ketamine in dorsomedial striatum.
These results demonstrate that NMDA-Rs antagonists with different pharmacological properties trigger different molecular changes at glutamatergic synapses. These results are consistent with the different clinical profiles of these compounds and with the observation that NMDA-R blockade is not necessarily associated to psychosis exacerbation.
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- Abstract
- Information
- European Psychiatry , Volume 28 , Issue S1: Abstracts of the 21th European Congress of Psychiatry , 2013 , 28-E1403
- Copyright
- Copyright © European Psychiatric Association 2012
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