Translational Value of Drug Discrimination with Typical and Atypical Antipsychotic Drugs

Abstract

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., training dose and species, for drug discrimination studies with the atypical antipsychotic clozapine is examined. Serotonin receptors appear to be an important pharmacological mechanism mediating clozapine's discriminative cue in both rats and mice, although differences are clearly evident as antagonism of cholinergic muscarinic receptors is important in rats at a higher training dose (5.0 mg/kg) of clozapine, but not at a lower training dose (1.25 mg/kg). Antagonism of α adrenoceptors is a sufficient mechanism in C57BL/6 and 129S2 mice to mimic clozapine's cue, but not in DBA/2 and B6129S mice, and only produces partial substitution in low-dose clozapine discrimination in rats. Dopamine antagonism produces partial substitution for clozapine in DBA/2, 129S2, and B6129S mice, but not in C57BL/6 mice, and partial substitution is seen with D antagonism in low-dose clozapine drug discrimination in rats. Thus, it is evident that clozapine has a complex mixture of receptor contributions towards its discriminative cue based on the data from the four mouse strains that have been tested that is similar to the results from rat studies. A further examination of antipsychotic stimulus properties in humans, particularly in patients with schizophrenia, would go far in evaluating the translational value of the drug discrimination paradigm for antipsychotic drugs.

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

“…Thus, it is tempting to speculate that amisulpride’s discriminative cue may be related to its antipsychotic properties and/or adverse effects (that are mediated by dopamine activity), but clearly this conclusion may be premature. For example, numerous drug discrimination studies with the atypical antipsychotic clozapine have failed to conclusively demonstrate such a relationship (Porter and Prus, 2009; Porter et al ., 2017). As these articles summarize, clozapine has a complex (or compound) discriminative stimulus in which multiple receptors appear to play a role and these can differ between both species and strains of rats and mice.…”