Diminished catalepsy and dopamine metabolism distinguish aripiprazole from haloperidol or risperidone

doi:10.1016/S0014-2999(03)01857-0

European Journal of Pharmacology

Volume 472, Issues 1–2, 4 July 2003, Pages 89-97

https://doi.org/10.1016/S0014-2999(03)01857-0 Get rights and content

Abstract

Catalepsy and changes in striatal and limbic dopamine metabolism were investigated in mice after oral administration of aripiprazole, haloperidol, and risperidone. Catalepsy duration decreased with chronic (21 day) aripiprazole compared with acute (single dose) treatment across a wide dose range, whereas catalepsy duration persisted with chronic haloperidol treatment. At the time of maximal catalepsy, acute aripiprazole did not alter neostriatal dopamine metabolite/dopamine ratios or homovanillic acid (HVA) levels, and produced small increases in dihydroxyphenylacetic acid (DOPAC). Effects were similar in the olfactory tubercle. Dopamine metabolism was essentially unchanged in both regions after chronic aripiprazole. Acute treatments with haloperidol or risperidone elevated DOPAC, HVA, and metabolite/dopamine ratios in both brain areas and these remained elevated with chronic treatment. The subtle effects of aripiprazole on striatal and limbic dopamine metabolism, and the decrease in catalepsy with chronic administration, illustrate fundamental differences in dopamine neurochemical actions and behavioral sequelae of aripiprazole compared to haloperidol or risperidone.

Introduction

Aripiprazole is a novel antipsychotic with a unique mechanism of action that differs from currently available antipsychotics Petrie et al., 1998, Kane et al., 2002. Preclinical studies have provided evidence that aripiprazole acts as a dopamine–serotonin system stabilizer, with potent partial agonist activity at dopamine D₂ receptors (Burris et al., 2002) and serotonin 5-HT_1A receptors (Jordan et al., 2002), and antagonist activity at 5-HT_2A receptors (unpublished data). Aripiprazole exhibits functional antagonist properties in animal models of dopaminergic hyperactivity (e.g. inhibition of apomorphine-induced stereotypy) and functional agonist activities in an animal model of dopaminergic hypoactivity (blockade of increased dopamine synthesis in reserpine-treated mice and rats) (Kikuchi et al., 1995). Aripiprazole induces catalepsy in mice and rats at doses higher than those at which it blocks apomorphine-induced stereotypy (Kikuchi et al., 1995). Clinical studies have shown that aripiprazole-treated subjects exhibit extrapyramidal symptoms comparable to subjects receiving placebo, while it possesses antipsychotic efficacy superior to placebo and equivalent to haloperidol (Kane et al., 2002). Based on these data, it is postulated that the decreased catalepsy and extrapyramidal symptoms observed with aripiprazole are due to its partial agonist activity at dopamine D₂ receptors.

Several well-characterized systems for evaluating the dopamine D₂ receptor agonist or antagonist properties of a drug are based on the degree to which the drug induces catalepsy or alters dopamine metabolism in mesotelencephalic dopamine neurons. The induction of catalepsy in rodents is a well-established animal model for the prediction of extrapyramidal symptoms in humans and is mediated via the nigrostriatal dopamine system (Arnt et al., 1997). Increased dopamine metabolism in the striatum is associated with increased liability for extrapyramidal symptoms whereas in the limbic region it is associated with antipsychotic activity. Dopamine D₂ receptor antagonists induce catalepsy Andersen and Kilpatrick, 1996, Barnes et al., 1990, and increase dopamine metabolism in striatal and limbic brain areas Boyar and Altar, 1987, Wood and Altar, 1988, Arnt and Skarsfeldt, 1998, Essig and Kilpatrick, 1991. Conversely, potent and full dopamine D₂ receptor agonists do not induce catalepsy and suppress brain dopamine metabolism Altar et al., 1987, Robertson et al., 1993.

Induction of catalepsy and changes in dopamine metabolism in striatal and limbic neurons have been used to evaluate the long-term effects of antipsychotic agents. For example, acute administration of typical antipsychotics such as haloperidol induces catalepsy through a blockade of postsynaptic striatal dopamine D₂ receptors, and continued treatment with haloperidol attenuates the cataleptic response Asper et al., 1973, Campbell and Baldessarini, 1981, Ezrin-Waters and Seeman, 1977. Furthermore, the increase (Karolewicz et al., 1996) and decrease (Altar et al., 1988) in dopamine metabolism produced by acute administration of dopamine D₂ receptor antagonists and agonists, respectively, is attenuated with chronic treatment.

The present study investigated whether repeated administration of aripiprazole at doses which acutely induce catalepsy in mice produces a change in cataleptic response over time, as compared with responses elicited by haloperidol or risperidone. In addition, the effects of repeated administration of aripiprazole, haloperidol, and risperidone over time on dopamine metabolism in the striatum and olfactory tubercle were evaluated.

Section snippets

Animals

Study animals were male ICR-strain mice (Japan CLEA) aged 4–5 weeks and weighing 25.7–34.6 g. The mice were housed at a temperature of 23±2 °C, a relative humidity of 60%±10%, and 12 h light/dark cycle per day (7:00–19:00). Food and water were available ad libitum. The care and handling of the animals were in accordance with “The Guidelines for Animal Experimentation in Otsuka Pharmaceutical; October 1, 1994”.

Drugs

Aripiprazole (Otsuka Pharmaceutical), haloperidol, and risperidone (Research

Catalepsy

A maximal duration of catalepsy was observed at 6 h after acute treatment with aripiprazole (day 1) and 10 h after the last chronic dose of aripiprazole (day 21; data not shown). A maximal duration of catalepsy was found 10 h after acute or chronic treatment with haloperidol, and at 6 h after acute or chronic treatment with risperidone (data not shown). The dose–response relationship for the duration of catalepsy at the peak time for each acutely or chronically administered drug is shown in

Discussion

The results of the present studies reveal that, in contrast to the typical antipsychotic haloperidol or the atypical antipsychotic risperidone, the antipsychotic aripiprazole produces relatively modest effects on striatal or limbic dopamine metabolism, even at the high doses required to elicit catalepsy. Whereas the increase in dopamine metabolism following acute haloperidol or risperidone was lessened with chronic administration, chronic administration of aripiprazole continued to produce

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¹: Present address: Research Institute of Pharmacological and Therapeutical Development.

²: Present address: Tokushima Research Institute.

³: Present address: Otsuka Maryland Research Institute.

⁴: Present address: Second Institute of New Drug Discovery.

⁵: Present address: Palatin Technologies, 4-C Cedar Brook Drive, Cedar Brook Corporate Center, Cranbury, NJ 08512, USA.

⁶: Present address: Human Resources Department, Otsuka Pharmaceutical Co. Ltd.

⁷: Present address: Gene Discovery, Psychiatric Genomics, Inc., 19 Firstfield Road, Gaithersburg, MD 20878, USA.

⁸: Present address: Therapeutic Application Development Group, Otsuka Pharmaceutical Co. Ltd.

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Diminished catalepsy and dopamine metabolism distinguish aripiprazole from haloperidol or risperidone

Abstract

Introduction

Section snippets

Animals

Drugs

Catalepsy

Discussion

Neuropsychopharmacology

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Brain Res. Bull.

Life Sci.

Neuroscience

Eur. J. Pharmacol.

Mol. Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropsychopharmacology

Neuropsychopharmacology

Life Sci.

Neurosci. Lett.

Neuropharmacology

Neuropharmacology

Neuropharmacology

Eur. J. Pharmacol.

Typical and atypical antipsychotic occupancy of D2 and S2 receptors: an autoradiographic analysis in rat brain

Brain Res. Bull.

Dopamine autoreceptor agonist including CGS 15855A decreases the in vivo release and metabolism of dopamine in mouse brain

Eur. J. Pharmacol.

Dopamine release and metabolism after chronic delivery of selective or non-selective dopamine autoreceptor agonists

Mol. Pharmacol.

Prevention by (+/-)-8-hydroxy-2-(di-n-propylamino) tertralin of both catalepsy and the rises in rat striatal dopamine metabolism caused by haloperidol

Br. J. Pharmacol.

Differentiation of classical and novel antipsychotics using animal models

Int. Clin. Psychopharmacol.

Differential modulation of in vivo dopamine release and metabolism by D1 but not D2 receptor agonist and antagonists

J. Neurochem.

Typical and atypical antipsychotic occupancy of D₂ and S₂ receptors: an autoradiographic analysis in rat brain

Differential modulation of in vivo dopamine release and metabolism by D₁ but not D₂ receptor agonist and antagonists