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An ionotropic but not a metabotropic glutamate agonist potentiates the pharmacological effects of olanzapine in the rat

This study aimed to evaluate the possible potentiating action of ionotropic or metabotropic (metabotropic glutamate receptor type 5) glutamate agonists on pharmacological effects induced in rats by the atypical antipsychotic olanzapine. The administration of doses of olanzapine, which did not affect spontaneous motility, inhibited behaviors induced by the selective stimulation of 5HT2A and D2 receptors. In particular, 0.03 or 0.06 mg/kg of olanzapine was sufficient to reduce, respectively, head shakes induced by the 5HT2A agonist 1-2,5-dimethoxy-4-iodophenyl-2-aminopropane (1 mg/kg) or hypermotility elicited by the D2 stimulant quinpirole (0.15 mg/kg). Behavioral responses to a D1/D2 agonist (apomorphine-induced stereotypies) were inhibited by doses of olanzapine that also influenced spontaneous behavior. The concomitant administration of D-cycloserine, an agonist at the glycine site on the N-methyl-D-aspartate receptor complex, given at a dose (3 mg/kg) that did not affect behavior, increased the inhibitory effect of olanzapine on the responses produced by 5HT2A, D2 and D1/D2 receptor stimulation. The concomitant administration of 2-chloro-5-hydroxyphenylglycine, an agonist of metabotropic glutamate receptor type 5, increased the inhibitory effect of olanzapine on the behaviors induced by the stimulation of D2, but not 5HT2A or D1/D2 receptors. As the effect on the serotonergic system seems important for the unusual pharmacological profile of atypical antipsychotics, the present results suggest that N-methyl-D-aspartate, but not metabotropic glutamate receptor type 5 agonists could be seen as promising therapeutic agents for increasing the pharmacological effects of olanzapine.