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

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.

Keywords: Amisulpride; Antidepressants; Antipsychotics; Anxiolytics; Benzamides; C57BL/6 mice; Discriminative stimulus; Drug discrimination; Isomers; Schizophrenia.