Neurochemical evidence for antagonism by olanzapine of dopamine, serotonin, alpha 1-adrenergic and muscarinic receptors in vivo in rats

Abstract

The ability of the atypical antipsychotic drug candidate olanzapine to antagonize dopamine, serotonin, alpha-adrenergic and muscarinic receptors in vivo was assessed by various neurochemical measurements in rat brain. Olanzapine increased the concentrations of the dopamine metabolites DOPAC and HVA in striatum and nucleus accumbens. Olanzapine antagonized the pergolide-induced decrease of striatal DOPA concentrations in rats treated with gammabutyrolactone and NSD1015 and increased striatal 3-methoxytyramine concentrations in nomifensine-treated rats (but not after gammabutyrolactone administration), suggesting that olanzapine blocked terminal and somatodendritic autoreceptors on dopamine neurons. Inactivation of dopamine D1 and D2 receptors by EEDQ was antagonized by olanzapine. The ex vivo binding of the 5HT2 radioligand [3H]-ketanserin was inhibited by olanzapine treatment, as was quipazine-induced increases in MHPG-SO4, evidence suggesting that olanzapine antagonized 5HT2 receptors. At higher doses, olanzapine increased the concentrations of the norepinephrine metabolite, MHPG-SO4, probably by blocking alpha 1-adrenergic receptors. Olanzapine inhibited ex vivo binding of the muscarinic antagonist radioligand [3H]-pirenzepine and lowered concentrations of striatal, but not hippocampal, acetylcholine levels. The findings provide evidence that olanzapine antagonized dopamine, serotonin, alpha-adrenergic and muscarinic receptors in vivo, consistent with its high affinity for these receptor sites in vitro.