The discriminative effects of the kappa-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects

Abstract

Rationale: The widely available hallucinogen salvinorin A is a unique example of a plant-derived compound selective for kappa-opioid receptors and may produce effects distinct from those of other compounds with classic hallucinogenic or dissociative properties which are also abused in humans.

Objectives: The objective of this study is to characterize the salvinorin A discriminative cue in nonhuman primates with high kappa-receptor genetic homology to humans.

Methods: Adult rhesus monkeys (n = 3) were trained to discriminate salvinorin A (0.015 mg/kg, s.c.) from vehicle, in a food-reinforced operant discrimination assay. Parallel studies, using unconditioned behavioral endpoints (facial relaxation and ptosis) also evaluated the kappa-opioid receptor mediation of salvinorin A in vivo function.

Results: Monkeys trained to discriminate salvinorin A generalized structurally diverse, centrally penetrating kappa-agonists (bremazocine, U69,593, and U50,488). By contrast, mu- and delta-opioid agonists (fentanyl and SNC80, respectively) were not generalized, nor were the serotonergic 5HT2 hallucinogen psilocybin or the dissociative N-methyl-D-aspartic acid antagonist, ketamine. The discriminative effects of salvinorin A were blocked by the opioid antagonist quadazocine (0.32 mg/kg), but not by the 5HT2 antagonist ketanserin (0.1 mg/kg). Consistent with these findings, salvinorin and kappa-agonists (e.g., U69,593) produce effects in the unconditioned endpoints (e.g., ptosis), whereas psilocybin was inactive.

Conclusions: These findings support the conclusion that the interoceptive/discriminative cue produced by salvinorin A is mediated by agonism at kappa-receptors and is mechanistically distinct from that produced by a classic serotonergic hallucinogen.

Fig. 1

Discriminative effects of salvinorin A and other ligands in subjects trained to discriminate salvinorin A (0.015 mg/kg; n=3) from vehicle. Upper panel: percent salvinorin A-appropriate responding; lower panel: rate of responding. Abscissae: cumulative dose after s.c. administration (milligrams per kilogram). Ordinate (upper panel): percent salvinorin A-appropriate responding; ordinate (lower panel): rate of responding expressed as percentage of control rates (control rate was the mean rate of responding for the three prior vehicle-training cycles for each subject). Data are mean±SEM, selected SEM omitted for clarity

Fig. 2

Antagonism of the discriminative effects of salvinorin A, after pretreatment with either quadazocine (0.32 mg/kg) or ketanserin (0.1 mg/kg). Other details as in Fig. 1

Fig. 3

Timecourse of salvinorin A (0.032 mg/kg, n=4) by the intravenous or subcutaneous route, on facial relaxation (upper panel) and ptosis (lower panel). Abscissae: time from the end of injection (minutes). Ordinates: behavioral score for each behavior, within a 1-min bin (scores could therefore range from 0 to 60 s). Data are mean±SEM

Fig. 4

Effects of salvinorin A and other ligands on facial relaxation (upper panel) and ptosis (lower panel). Abscissae: cumulative dose after i.v. administration (milligrams per kilogram). Ordinates: behavioral score for each behavior, within a 1-min bin, measured 14–15 min after each injection. Data are mean±SEM

Fig. 5

Antagonism of the effects of salvinorin A on ptosis, after pretreatment with either quadazocine (0.32 mg/kg) or naltrexone (0.1 mg/kg). Abscissa: cumulative salvinorin A dose after i.v. administration (milligrams per kilogram). Ordinate: ptosis score. Other details as in Fig. 4