Discriminative stimulus properties of atypical and typical antipsychotic drugs: a review of preclinical studies

Abstract

Background Drug discrimination is an increasingly valuable behavioral assay for the preclinical development of antipsychotic drugs. The majority of studies have used the atypical antipsychotic clozapine because it displays robust discriminative stimulus properties and is the "prototypical" or "gold standard" atypical antipsychotic against which other antipsychotics will undoubtedly be compared for many years. Objectives Pharmacological mechanisms mediating the discriminative stimulus properties of antipsychotics used as training drugs and the usefulness of drug discrimination for distinguishing typical and atypical antipsychotics were reviewed. Results Clozapine appears to have a compound cue involving antagonism of two or more receptors. While muscarinic receptor antagonism is a prominent factor for mediation of clozapine's cue in rats with a 5.0-mg/kg training dose, there are differences in clozapine's cue with a low training dose and in pigeons and mice. With a low training dose, clozapine has consistently produced full or partial generalization to atypical but not to typical antipsychotics. Although not evaluated as extensively, the atypical antipsychotics quetiapine and ziprasidone also appear to generalize to atypical but not typical antipsychotics. This has not been the case for other antipsychotic drugs (olanzapine, chlorpromazine, haloperidol) used as training drugs. Conclusions There are important differences in discriminative stimulus properties both between and within atypical and typical antipsychotics and across species. While lowdose clozapine discrimination in rats appears to provide a more sensitive behavioral assay for distinguishing atypical from typical antipsychotics, the extent to which clozapine's discriminative stimulus properties are predictive of its antipsychotic effects remains to be determined.

Long-term impacts of adolescent risperidone treatment on behavioral responsiveness to olanzapine and clozapine in adulthood

“…Recently, we further demonstrated a cross-sensitization from asenapine to olanzapine (Qin et al, 2013). These findings, together with many from drug discrimination studies (Porter and Prus, 2009), suggest that there is a common mechanism underlying sensitization effects induced by various antipsychotics despite their different chemical structures and receptor binding profiles.…”

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

“…Drug discrimination is a widely used behavioral paradigm where a subject, typically a rat, is first trained to respond to a drug, then subsequently other drugs are tested for their ability to generalize to, or "substitute" for, the training drug (for review, see Porter and Prus, 2009). In one of the earliest studies, Butelman et al (2004) tested the ability of systemically administered (subcutaneous) salvinorin A to substitute for U69,593 in rhesus monkeys.…”

Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats

“…Training doses, efficacy and selectivity of the training drugs are some crucial determinants of the discriminative stimulus properties of drugs (Colpaert, 1988; Comer et al, 1991; Lelas et al, 2000; Porter and Prus, 2009). Regarding the discriminative stimulus effects of imidazoline I 2 receptor ligands, little is known of the roles these parameters play in determining their stimulus properties.…”