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. 1) vehicle;

2. 2) MK-801 0.8 mg/kg;

3. 3) memantine 5 mg/kg;

4. 4) ketamine 25 mg/kg;

5. 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.