Major depressive disorder (MDD) is a widespread psychiatric disorder that affects millions of people worldwide and is hypothesized to occur due to impairments in several neurotransmitter systems, including the monoaminergic and glutamatergic neurotransmitter systems. Antidepressant medications targeting multiple monoamine neurotransmitters have been shown to be effective for the treatment of depression. Racemic amisulpride is an atypical antipsychotic that has been used at low doses to treat dysthymia, a mild form of depression, and functions as an antagonist at DA2/3, 5-HT2B, and 5-HT7 receptors. Recent preclinical studies have suggested that the S(+) isomer may be more critical for amisulpride’s antidepressant-like effects; however, this interpretation has not been fully characterized in comparison to the R(-) isomer. The glutamatergic system also has been shown to play a critical role in alleviating depression. Several studies have demonstrated that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces rapid and sustained antidepressant-like effects in clinical trials; however, few studies have examined the degree to which ketamine’s isomers contribute to antidepressant-like effects. Fully characterizing these differences in a preclinical model of depression may offer important insight into the role of these neurotransmitter systems on depression. The present study used a 72-sec differential-reinforcement-of-low-rate (DRL) task to assess the antidepressant-like effects of amisulpride, ketamine, and their isomers in mice. The DRL 72-sec task has shown to be a reliable and sensitive screen for drugs that possess antidepressant-like activity as reflected by an increase in the number of reinforcers, a decrease in the number of responses, and a right-ward shift in the interresponse time distributions (IRTs; i.e. the elapsed time between two successive responses). For comparison, the effects of the tricyclic antidepressant imipramine and the N-methyl-D-aspartate antagonist MK-801 as positive and negative controls, respectively, were determined. Consistent with previous findings, we hypothesized that amisulpride and S(-)-amisulpride, but not R(+)-amisulpride, would produce antidepressant-like effects, and all formulations of ketamine would produce antidepressant effects. Racemic amisulpride and S(-)-amisulpride, but not R(+)-amisulpride, produced an antidepressant-like effect, evidenced by a significant increase in the number of reinforcers and a significant decrease in the number of responses. Racemic ketamine and R(-)-ketamine significantly increased the number of reinforcers and decreased the number of responses, while S(+)-ketamine significantly increased the number of reinforcers, but did not decrease the number of responses (at the doses tested). Overall, these results indicate that the racemic formulations of amisulpride and ketamine, S(-)-amisulpride, and both ketamine isomers demonstrate antidepressant-like effects as assessed in the DRL task and may be useful in a clinical context. If either of the ketamine isomers can be shown to produce fewer psychotomimetic effects in humans, then the isomers may offer a significant clinical advantage over the parent compound ketamine. Regarding amisulpride, the present results demonstrate that the S(-) isomer, but not the R(+) isomer, possess antidepressant-like activity similar to racemic amisulpride.

Les antipsychotiques sont des antagonistes du récepteur dopaminergique de type 2 (DRD2) et constituent le principal traitement pharmacologique de la schizophrénie. Le traitement à long-terme par les antipsychotiques peut causer la tolérance au traitement et le développement de la dyskinésie tardive, dont le mécanisme est mal compris et le traitement, insatisfaisant. Il a été démontré que le traitement chronique aux antipsychotiques induit la surexpression du récepteur DRD2 et le stress oxydatif, deux mécanismes associés à la dyskinésie tardive. Le lien entre ces deux phénomènes est mal déterminé. Précédemment, il a été rapporté, dans mon laboratoire d'accueil, que le stress oxydatif, induit par le peroxyde d'hydrogène (H[indice inférieur 2]O[indice inférieur 2]), augmente le niveau du récepteur DRD2 sur la lignée cellulaire de neuroblastomes humains SH-SY5Y. L'hypothèse de recherche présentée ici est que le stress oxydatif est impliqué dans la surexpression du récepteur DRD2 induite par les antipsychotiques et que l'administration d'un antioxydant peut atténuer cette surexpression. Le projet présenté rapporte ainsi les effets des antipsychotiques sur les niveaux d'expression du récepteur DRD2 et les effets de l'inhibition du stress oxydatif par le traitement de l'acide lipoïque, un antioxydant, sur la lignée cellulaire de neuroblastomes humains SH-SY5Y. L'halopéridol, un antipsychotique de première génération, induit une augmentation des niveaux d'expression du récepteur DRD2, alors que Pamisulpride, un antipsychotique de deuxième génération, n'a pas d'effet significatif. De plus, l'halopéridol induit une plus importante augmentation des biomarqueurs du stress oxydatif (carbonylation des protéines, peroxydation lipidique et production de l'anion superoxyde) que l'amisulpride. L'acide lipoïque atténue la surexpression du récepteur DRD2 et le stress oxydatif induit par l'antipsychotique. L'inhibition de la synthèse de catécholamine par l'alpha-méthyl-DL-tyrosine (AMPT) élève l'expression du DRD2 et prévient sa surexpression par les antipsychotiques. Les résultats suggèrent que la surexpression du récepteur DRD2 induite par l'halopéridol est liée au stress oxydatif et proposent des mécanismes potentiels par lesquels l'acide lipoïque peut être considéré comme un agent thérapeutique pour la prévention et le traitement des effets secondaires reliés à l'utilisation des antipsychotiques.

Abstract ESTABLISHING THE DISCRIMINATIVE STIMULUS PROPERTIES OF THE ATYPICAL ANTIPSYCHOTIC AMISULPRIDE IN C57BL/6 MICE Antipsychotic medications are used to treat schizophrenia. The present study used the drug discrimination paradigm to measure the subjective effects of the atypical antipsychotic amisulpride and to examine the underlying neuropharmacological mechanisms responsible for the discriminative stimulus property of the drug. Male C57BL/6 mice were trained to discriminate 10 mg/kg (-)S amisulpride from vehicle in a two-lever drug discrimination task. A dose effect curve for (-)S amisulpride yielded an ED50 = 1.77 mg/kg 95% CI [1.28, 2.45 mg/kg]. Substitution testing was conducted for the isomer (+)R amisulpride, racemic (±)SR amisulpride, the atypical antipsychotics clozapine, aripiprazole and the typical antipsychotic haloperidol. There was partial substitution for (+)R amisulpride, and full substitution for (±)SR amisulpride with a significant rightward shift in the dose effect curves. Clozapine, aripiprazole, and haloperidol failed to fully substitute with significant rate suppression at the higher doses. These results demonstrated that (-)S amisulpride has a unique discriminative stimulus that differs from other antipsychotic drugs.

Amisulpride, a benzamide derivative, is an atypical antipsychotic drug used to treat both schizophrenia and depression. Amisulpride is a selective antagonist at dopamine D2 and D3 receptors and at serotonin 5-HT2B and 5-HT7 receptors and displays an atypical clinical profile with reduced extrapyramidal motor effects. The drug has a chiral center and is a mixture of two optical isomers: (S)-amisulpride and (R)-amisulpride. The present study used a two-lever drug discrimination assay to allow a direct comparison between amisulpride and its two isomers. Additionally, substitution testing was conducted with the typical antipsychotics, atypical antipsychotics, antidepressants, the anxiolytic chlordiazepoxide, several benzamide derivatives, and selective ligands with receptor mechanisms relevant to amisulpride. C57BL/6 mice were trained to discriminate 10 mg/kg rac-amisulpride from vehicle in a two-lever drug discrimination task for food reinforcement in an average of 35.7 sessions (range 6-89). The amisulpride dose-response curve (0.078 – 10.0 mg/kg) yielded an ED50 = 0.64 mg/kg, 95% CI [.47, 0.84 mg/kg]. The isomers fully substituted for amisulpride with a significant left-ward shift in the dose-response curve for (S)-amisulpride as compared to rac-amisulpride and (R)-amisulpride. The benzamide derivatives sulpiride and the (S)-sulpiride isomer fully substituted for amisulpride; tiapride produced partial substitution (76.4% DLR); none of the other tested drugs substituted for rac-amisulpride’s discriminative stimulus. These results showed that the rac-amisulpride stimulus was readily acquired in C57BL/6 mice, and that it has a unique and robust discriminative stimulus that is dose-dependent, time-dependent and stereoselective and is not shared with other antipsychotic or antidepressant drugs.