Examination of the mechanisms underlying the discriminative stimulus properties of the atypical antipsychotic amisulpride.

Amisulpride is an atypical benzamide antipsychotic/antidepressant, whose mechanism of action is thought to depend mainly on dopamine D2/3 receptor activity, but also with some serotonin 5-HT2B/7 effects. The present study examined the role of D2/3 receptors and 5-HT2B/7 receptors in amisulpride's discriminative stimulus. Selective agonists and antagonists of the above receptors were tested in adult, male C57BL/6 mice trained to discriminate 10 mg/kg amisulpride from vehicle in a two-lever drug discrimination assay.

Discriminative stimulus properties of the typical antipsychotic haloperidol compared to other antipsychotic drugs in C57BL/6 mice.

Haloperidol (HAL) was developed in 1958 for the treatment of schizophrenia and is classified as a typical antipsychotic drug (APD). Effective in treating positive symptoms of schizophrenia, it does not treat negative symptoms and produces extrapyramidal motor side-effects. Atypical APDs like clozapine treat both positive and negative symptoms of schizophrenia, have reduced extrapyramidal motor side-effects and possess other clinical advantages.

The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice.

Clozapine-N-oxide (CNO) has long been the ligand of choice for selectively activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). However, recent studies have challenged the long-held assertion that CNO is otherwise pharmacologically inert. The present study aimed to 1) determine whether CNO is reverse-metabolized to its parent compound clozapine in mice (as has recently been reported in rats), and 2) determine whether CNO exerts clozapine-like interoceptive stimulus effects in rats and/or mice.

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.

Rationale: Racemic (RS)-amisulpride (Solian) is an atypical antipsychotic drug used to treat schizophrenia and dysthymia. Blockade of dopamine D/D and/or serotonin 5-HT 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.

Translational Value of Drug Discrimination with Typical and Atypical Antipsychotic Drugs.

This chapter focuses on the translational value of drug discrimination as a preclinical assay for drug development. In particular, the importance of two factors, i.e.

(S)-amisulpride as a discriminative stimulus in C57BL/6 mice and its comparison to the stimulus effects of typical and atypical antipsychotics.

Amisulpride, a substituted benzamide derivative, exerts atypical antipsychotic and antidepressant clinical effects and its (S)-stereoisomer is thought to underlie these actions. In the present study, male C57BL/6 mice were trained to discriminate (S)-amisulpride (10mg/kg, s.c.

The metabolites N-desmethylclozapine and N-desmethylolanzapine produce cross-tolerance to the discriminative stimulus of the atypical antipsychotic clozapine in C57BL/6 mice.

It has been previously shown that cross-tolerance to the discriminative stimulus properties of clozapine can be demonstrated with the drug discrimination paradigm. This study examined the ability of N-desmethylclozapine and N-desmethylolanzapine (metabolites of the atypical antipsychotic drugs clozapine and olanzapine, respectively) to induce cross-tolerance to the discriminative stimulus effects of clozapine. After C57BL/6 mice were trained to reliably discriminate 2.