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Discriminative stimulus properties of the atypical antipsychotic amisulpride: comparison to its isomers and to other benzamide derivatives, antipsychotic, antidepressant, and antianxiety drugs in C57BL/6 mice

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Abstract

Rationale

Racemic (RS)-amisulpride (Solian®) is an atypical antipsychotic drug used to treat schizophrenia and dysthymia. Blockade of dopamine D2/D3 and/or serotonin 5-HT7 receptors is implicated in its pharmacological effects. While the (S)-amisulpride isomer possesses a robust discriminative cue, discriminative stimulus properties of (RS)-amisulpride have not been evaluated.

Objectives

The present study established (RS)-amisulpride as a discriminative stimulus and assessed amisulpride-like effects of amisulpride stereoisomers, other benzamide derivatives, and antipsychotic, antidepressant, and anxiolytic drugs.

Methods

Adult, male C57BL/6 mice were trained to discriminate 10 mg/kg (RS)-amisulpride from vehicle in a two-lever food-reinforced operant conditioning task.

Results

(RS)-Amisulpride’s discriminative stimulus was dose-related, time-dependent, and stereoselective. (S)-Amisulpride (an effective dose of 50% (ED50) = 0.21 mg/kg) was three times more potent than (RS)-amisulpride (ED50 = 0.60 mg/kg) or (R)-amisulpride (ED50 = 0.68 mg/kg). (RS)-Amisulpride generalized fully to the structurally related atypical antipsychotic/antidysthymia drug sulpiride (Sulpor®; ED50 = 7.29 mg/kg) and its (S)-enantiomer (ED50 = 9.12 mg/kg); moderate to high partial generalization [60–75% drug lever responding (%DLR)] occurred to the benzamide analogs tiapride (Tiapridal®) and raclopride, but less than 60% DLR to metoclopramide (Reglan®), nemonapride (Emilace®), and zacopride. Antipsychotic, antidepressant, and antianxiety drugs from other chemical classes (chlorpromazine, quetiapine, risperidone, and mianserin) produced 35–55% amisulpride lever responding. Lastly, less than 35% DLR occurred for clozapine, olanzapine, aripiprazole imipramine, chlordiazepoxide, and bupropion.

Conclusions

(RS)-Amisulpride generalized to some, but not all benzamide derivatives, and it failed to generalize to any other antipsychotic, antidepressant, or antianxiety drugs tested. Interestingly, the (R)-isomer shared very strong stimulus properties with (RS)-amisulpride. This finding was in contrast to findings from Donahue et al. (Eur J Pharmacol 734:15–22, 2014), which found that the (R)-isomer did not share very strong stimulus properties when the (S)-isomer was the training drug.

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Acknowledgments

This research was supported in part by Grant T32DA07268 from the National Institute of Drug Abuse of the National Institutes of Health (T.M.H.). The authors are grateful to Dr. Milton L. Brown, Director of the Center for Drug Discovery at Georgetown University, for making the material and analytical resources at his center available for the execution of this project.

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Authors and Affiliations

  1. Department of Psychology, Virginia Commonwealth University, 806 West Franklin Street, PO Box 842018, Richmond, VA, 23284-2018, USA

    Timothy J. Donahue, Kevin A. Webster & Joseph H. Porter

  2. Department of Psychology, Weber State University, Ogden, UT, USA

    Todd M. Hillhouse

  3. Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA

    Richard Young

  4. Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, USA

    Eliseu O. De Oliveira

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  1. Timothy J. Donahue
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  2. Todd M. Hillhouse
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  6. Joseph H. Porter
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Correspondence to Joseph H. Porter.

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The research reported here was reviewed and approved by the Institutional Animal Care and Use Committees (IACUC) at Virginia Commonwealth University and is in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council 2011).

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Donahue, T.J., Hillhouse, T.M., Webster, K.A. et al. Discriminative stimulus properties of the atypical antipsychotic amisulpride: comparison to its isomers and to other benzamide derivatives, antipsychotic, antidepressant, and antianxiety drugs in C57BL/6 mice. Psychopharmacology 234, 3507–3520 (2017). https://doi.org/10.1007/s00213-017-4738-y

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