Timothy J Donahue1, Todd M Hillhouse2, Kevin A Webster1, Richard Young3, Eliseu O De Oliveira4, Joseph H Porter5. 1. Department of Psychology, Virginia Commonwealth University, 806 West Franklin Street, PO Box 842018, Richmond, VA, 23284-2018, USA. 2. Department of Psychology, Weber State University, Ogden, UT, USA. 3. Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA. 4. Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, USA. 5. Department of Psychology, Virginia Commonwealth University, 806 West Franklin Street, PO Box 842018, Richmond, VA, 23284-2018, USA. jporter@vcu.edu.
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.
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.
Authors: L Toll; I P Berzetei-Gurske; W E Polgar; S R Brandt; I D Adapa; L Rodriguez; R W Schwartz; D Haggart; A O'Brien; A White; J M Kennedy; K Craymer; L Farrington; J S Auh Journal: NIDA Res Monogr Date: 1998-03
Authors: Scott D Philibin; D Matthew Walentiny; Sarah A Vunck; Adam J Prus; Herbert Y Meltzer; Joseph H Porter Journal: Psychopharmacology (Berl) Date: 2008-11-07 Impact factor: 4.530