Assessment of the kappa opioid agonist, salvinorin A, as a punisher of drug self-administration in monkeys

Abstract

Rationale: Drugs can function as punishers. However, work on the study of drugs as punishers is limited, as is the range of compounds known to function as punishers. Kappa opioid agonists, which have received much experimental attention as potential therapeutics for drug abuse, reportedly produce aversive effects. However, kappa agonists have yet to be tested as punishers of behavior.

Objective: The goal of the current study was to determine if a kappa agonist could function as a punisher of drug self-administration.

Method: In separate experiments, monkeys were allowed to choose in a two-lever choice design between intravenous injections of equal doses of either cocaine (0.1 mg/kg/injection on each lever) or remifentanil (0.1 μg/kg/injection on each lever) when one of the two options was mixed with various doses of the kappa agonist, salvinorin A.

Results: Choice for the cocaine and remifentanil options that were combined with salvinorin A decreased as a function of salvinorin A dose in all monkeys. However, operant response rates were not systematically affected by salvinorin A administration.

Conclusion: The present findings demonstrate that the kappa agonist, salvinorin A, can punish self-administration of a psychotimulant, cocaine, and a mu opioid, remifentanil. In consideration of these findings, it may be possible to curtail the abuse of some drugs by contingently delivering kappa agonists (e.g., as combination formularies for prescription medications).

Fig 1

Session blocks of stable cocaine choice for each choice condition and its reversal in each of three monkeys (CJ82, DJ9J, and R02050). The ordinate represents percent choice for the conditions associated with responding on the left and right levers (solid circles and open circles, respectively). For each monkey, adjacent panels separated by solid lines represent various salvinorin A dose conditions (mg/kg/inj). Hatched lines within these panels represent reversals for the lever response contingencies within each condition. For each reversal within a condition, the lever on which responding results in the delivery of cocaine (0.1 mg/kg/inj) mixed with salvinorin A is indicated by a “+” sign. Alternatively, the “−” sign indicates that responding on the indicated lever results in an injection of cocaine alone (0.1 mg/kg/inj). SVA = salvinorin A; L = left lever; R = right lever

Fig 2

Session blocks of stable remifentanil choice for each choice condition and its reversal in each of three monkeys (CJ82, DJ9J, and R02050). The ordinate represents percent choice for the conditions associated with responding on the left and right levers (solid circles and open circles, respectively). For each monkey, adjacent panels separated by solid lines represent various salvinorin A dose conditions (mg/kg/inj). Hatched lines within these panels represent reversals for the lever response contingencies within each condition. For each reversal within a condition, the lever on which responding results in the delivery of remifentanil (0.1 μg/kg/inj) mixed with salvinorin A is indicated by a “+” sign. Alternatively, the “−” sign indicates that responding on the indicated lever results in an injection of remifentanil alone (0.1 μg/kg/inj). SVA = salvinorin A; L = left lever; R = right lever

Fig 3

The top row illustrates the percentage of choice trials that monkeys chose a drug reinforcer (0.1 mg/kg cocaine, left; 0.1 μg/kg/inj remifentanil, right) mixed with various doses of salvinorin A when that same drug reinforcer was offered at the same dose without salvinorin A on the opposite lever. The bottom row illustrates response rates averaged across sessions for each choice condition. Symbols and legend codes represent individual monkeys. Remi = remifentanil; Coc = cocaine