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Aripiprazole (OPC-14597) fully substitutes for the 5-HT1A receptor agonist LY293284 in the drug discrimination assay in rats

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Abstract

Rationale

Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug with a low incidence of side effects. The therapeutic action of aripiprazole has been attributed to its unique agonist/antagonist effects at D2 dopamine receptors; however, aripiprazole also has significant in vitro affinity at 5-HT1A receptors.

Objectives

The 5-HT1A agonist property of aripiprazole has so far not been evaluated in any in vivo assay.

Methods

Thirteen male Sprague Dawley rats trained to discriminate the 5-HT1A agonist LY 293284 (75 nmol/kg) from saline, using a fixed ratio (FR) 50 schedule of food-reinforcement in a two-lever operant-conditioning task, were used to evaluate the behavioral effect of aripiprazole at 5-HT1A receptors.

Results

Aripiprazole fully mimicked LY 293284 in a drug-discrimination assay with an ED50 of 1.39 μmol/kg (0.62 mg/kg). In combination tests, aripiprazole did not block the LY 293284 cue but at 8.92 μmol/kg (4 mg/kg) significantly reduced the response rate by lowering the threshold for induction of the 5-HT syndrome produced by the training dose of LY 293284. Moreover, the selective 5HT1A receptor antagonist WAY 100635 was able to block the substitution of aripiprazole in LY-293284 trained rats.

Conclusion

Although the efficacy of aripiprazole against the positive symptoms of schizophrenia may be related to its dopamine receptor interactions, it seems possible that its atypical profile may derive, at least in part, from its 5-HT1A agonist effect, rather than from unusual D2 receptor properties.

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Acknowledgement

These studies were supported by grant DA-02189 from NIDA.

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  1. Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy—RHPH, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907-2091, USA

    Danuta Marona-Lewicka & David E. Nichols

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  1. Danuta Marona-Lewicka
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  2. David E. Nichols
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Correspondence to David E. Nichols.

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Marona-Lewicka, D., Nichols, D.E. Aripiprazole (OPC-14597) fully substitutes for the 5-HT1A receptor agonist LY293284 in the drug discrimination assay in rats. Psychopharmacology 172, 415–421 (2004). https://doi.org/10.1007/s00213-003-1677-6

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