Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist properties

Wood, Martyn; Scott, Claire M.; Clarke, Kirsten; Westaway, Julie; Davies, Ceri H.; Reavill, Charlie; Hill, M. J.; Rourke, Colin; Newson, Michael J F; Jones, Declan N.C.; Forbes, Ian J.; Gribble, Andrew D.

doi:10.1016/j.ejphar.2006.07.008

Cited by 44 publications

(22 citation statements)

References 17 publications

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“…This study is confined by the selection of only two time points and doses of APZ and the lack of drug monitoring, including metabolites (Wood et al 2006), rendering the translation to human psychopharmacology difficult. The doses were extrapolated from the dose relationship between haloperidol and APZ as used in clinical practice and in previous animal trials with haloperidol and clozapine (Fitzgerald et al 1995;Schmitt et al 2003b).…”

Section: Discussionmentioning

confidence: 99%

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

et al. 2011

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Section: Discussionmentioning

confidence: 99%

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

et al. 2011

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“…Aripiprazole is reported to have an affinity for dopamine D 2 receptors only slightly lower than haloperidol (pK i ϭ 8.59 versus 9.01, respectively) (Newman-Tancredi et al, 2005). Aripiprazole is a partial agonist at these receptors (Burris et al, 2002;Shapiro et al, 2003), whereas in rats, it is metabolized in vivo to a full D 2 receptor antagonist (Wood et al, 2006). Thus, the effect of aripiprazole could be explained by its blocking action on dopamine D 2 receptors as well as or rather than an action on 5-HT 1A receptors.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Antipsychotic Drugs on Serotonin-1A Receptor-Mediated Disruption of Prepulse Inhibition

Buuse¹,

Gogos²

2006

J Pharmacol Exp Ther

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Serotonin-1A (5-HT 1A ) receptors have been implicated in the symptoms of schizophrenia. However, there is limited in vivo evidence for an interaction of antipsychotic drugs with 5-HT 1A receptor-mediated behavioral effects. We therefore investigated in rats the action of several antipsychotic drugs on prepulse inhibition (PPI), a measure of sensorimotor gating that is deficient in schizophrenia. Disruption of PPI at the 100-ms interstimulus interval (ISI), but not the 30-ms ISI, was induced by treatment with 0.5 mg/kg 8-hydroxy-di-propylaminotetralin

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“…Thus, it is conceivable that the rat metabolite is responsible for a fraction of the aripiprazole-induced prolactin secretion in rats. It should be mentioned in this context that the rat metabolite is reported to have only minor effects on behaviour, possibly due to a low propensity to cross the blood-brain barrier (Wood et al 2006). As for OSU6162 and ACR16, there appears not to be any known active metabolites which could interfere with the outcome of this study.…”

Section: Discussionmentioning

confidence: 93%

Effects of the dopamine stabilizers (S)-(-)-OSU6162 and ACR16 on prolactin secretion in drug-naive and monoamine-depleted rats

Rung

Johansson

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.

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Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist properties

Cited by 44 publications

References 17 publications

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

Differential Effects of Antipsychotic Drugs on Serotonin-1A Receptor-Mediated Disruption of Prepulse Inhibition

Effects of the dopamine stabilizers (S)-(-)-OSU6162 and ACR16 on prolactin secretion in drug-naive and monoamine-depleted rats

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