Neurochemical evidence for antagonism by olanzapine of dopamine, serotonin, α1-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.

In Vivo Olanzapine Occupancy of Muscarinic Acetylcholine Receptors in Patients with Schizophrenia

“…However, the estimates we have made of the effective in vivo dissociation constant K d Ј (1.5 nM to 2.8 nM) agree fairly well with the low range of K i values (1.9 nM to 2.5 nM) found by Bymaster et al (1996a). In another study by the same group, treatment with olanzapine also resulted in an inhibition of ex vivo binding of [H-3]pirenzepine, (Bymaster et al 1996b). Yet, unpublished experiments by this group suggest that the previous study may have overestimated the affinity of olanzapine to the muscarinic receptor and that the true affinity may be 10-fold weaker .…”

“…In vitro , olanzapine antagonizes various dopamine, serotonin, histamine, norepinephrine and muscarinic receptors. The in vitro K i values for the muscarinic receptor subtypes range between 2 and 25 nM, similar to the K i value of 11 nM for olanzapine at the dopamine D 2 receptor (Bymaster et al 1996b).…”

Erythropoietin Prevents Haloperidol Treatment-Induced Neuronal Apoptosis through Regulation of BDNF

“…The HAL dose (2.0 mg/kg/ day) was selected based on previous studies where this dose was found to establish clinically relevant (Baldessarini et al, 1988) steady-state plasma levels in the rat . This dose is also comparable to the optimal dose to cause pharmacological effects (Skarsfeldt, 1996;Didriksen, 1995;Bymaster et al, 1996). The schedule of HAL administration was selected based on several studies by us and others in which differences in behavioral as well as pharmacological effects were seen after 45 days of treatment in rats (Parikh et al, 2004a, b, c;Terry et al, 2004;Pillai et al, 2005;Angelucci et al, 2000;Dawson et al, 2001).…”

The Comparative Peripheral Anticholinergic-Like Adverse Event Profiles of Olanzapine and Risperidone

“…These data are further supported by Chengappa et al, 10 who suggest that olanzapine in vivo (patient-reported adverse events) is much less anticholinergic than would have been predicted from the originally published in vitro data. 2,6,11 The objective of the present analysis was to characterize the extent of olanzapine's in vivo anticholinergic activity by comparing solicited anticholinergic treatmentemergent adverse events as reported in a randomized, double-blind clinical trial of olanzapine and risperidone in patients not taking adjunctive anticholinergic medication. Risperidone was specifically selected owing to the expectation, based on in vitro assay data, that this commonly used agent had very low in vivo (in humans) affinity for muscarinic receptors.…”

“…Risperidone was specifically selected owing to the expectation, based on in vitro assay data, that this commonly used agent had very low in vivo (in humans) affinity for muscarinic receptors. 6,11 The hypothesis tested was whether olanzapine and risperidone differed substantially in clinical, peripheral, anticholinergic-associated adverse events as indexed by the Association de Méthodologie et de Documentation en Psychiatrie (AMDP-5)-solicited adverse event symptom list.…”