Background: A number of studies in rodents suggest that antipsychotic drug
treatment can either alter the levels or functionality of the N-methyl-D-aspartate receptor
(NMDAR). This raises the possibility that some of the therapeutic actions or side-effects of
antipsychotic drugs could be mediated through the NMDAR.
Objective: To determine if treatments with combinations of psychotropic drugs change the levels of the
NMDAR in rat Central Nervous System (CNS).
Methods: In situ radioligand binding and autoradiography were used to quantify [3H]MK-801 binding to
NMDAR in frozen CNS sections from rats treated with vehicle, haloperidol (0.1 mg/kg/day), olanzapine (1.0
mg/kg/ day), lithium (25.5 mg/kg/day) or, at the same doses, haloperidol and lithium or olanzapine and
lithium for 28 days.
Results: There was a significant variation of [3H]MK-801 binding with treatment in the rat striatum due to
higher levels of radioligand in rats treated with haloperidol compared to those treated with olanzapine and
lithium (p < 0.01; Cohen’s d = 1.47). Levels of radioligand binding did not vary with drug treatment in the
Conclusion: These data argue for some effect of polypharmacy on NMDAR levels, possibly localized to the
striatum. Further studies of mood stabilisers with known effects on NMDAR functionality, such as valproate
and lamotrigine, with and without antipsychotic drugs could be worthwhile as they may show a greater effect
on NMDAR density in the CNS.