Repeated administration of the novel antipsychotic olanzapine does not modulate NMDA-sensitive glutamate and 5HT2 serotonin receptors in rats.
Antipsychotic drugs reportedly show a common property in facilitating glutamatergic transmission in rat cerebral cortex. Since the binding of the radiolabelled channel blocker [3H]-MK801 is generally considered an affordable index of N-methyl-d-aspartate (NMDA)-sensitive glutamate receptor activation, we examined the effects of clinically effective treatment (3 weeks, daily administration) of the atypical antipsychotic drug olanzapine (32 micromol/kg/5 ml) on the specific binding of [3H]-MK801 specific binding and on the strychnine-insensitive glycine sites (glycine B) in synaptic plasma membranes (SPM) prepared from the medial prefrontal cortex (mPFC) of rats sacrificed after different (24, 60, 120 h) washout periods. We studied also the effects of repeated olanzapine administration on [3H]-ketanserin binding to 5HT2A receptors to verify whether, consistent with previously reported paradoxical effects of repeated administration of 5HT2A antagonists, this drug decreases 5HT2A receptor density without changing the apparent affinity. Neither single nor repeated olanzapine administration changed the kinetic characteristics of [3H]-MK801 or [3H]-glycine specific binding. When rats were sacrificed 120 h after the last olanzapine administration, both single or repeated treatment had failed to change the kinetic characteristics of [3H]-ketanserin binding, while the apparent affinity of 5HT2A receptors was increased in animals sacrificed at shorter (60 h) washout periods. Owing to the long half-life of olanzapine (24 h), and since the drug concentrations in mPFC of rats sacrificed 60 h after a single olanzapine administration (about 50 nM) are high enough to induce changes in 5HT2A receptor affinity, it is concluded that this modification, probably unrelated to the therapeutic efficacy, could be due to some drug still present in the brain at the time of the sacrifice.
Gandolfi
Ottavio
O
Dept. of Pharmacology, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy. gandolfi@biocfarm.unibo.it
Voltattorni
Manuela
M
Gaggi
Renato
R
Dall'Olio
Rossella
R
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001569:Benzodiazepines / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity*; D000077152:Olanzapine; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism*; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists
D014150:Antipsychotic Agents; D017470:Receptors, Glutamate; D044348:Receptors, Serotonin, 5-HT2; D058826:Serotonin 5-HT2 Receptor Agonists; D001569:Benzodiazepines; D016202:N-Methylaspartate; D000077152:Olanzapine