Assessment of the effects of contingent histamine injections on the reinforcing effectiveness of cocaine using behavioral economic and progressive-ratio designs

Abstract

Rationale: Recent research has demonstrated that the drug, histamine, can function as a punisher of cocaine self-administration. However, little is known about how drug punishers affect the maximum reinforcing effectiveness of drugs as reinforcers.

Objective: The goal of the present study was to determine if histamine, when self-administered as a mixture with cocaine, could reduce cocaine's maximum reinforcing effectiveness using two procedures designed for measuring reinforcing effectiveness.

Methods: In the first experiment, rhesus monkeys were allowed to self-administer cocaine (0.1 mg/kg/inj) alone or as a mixture with histamine (0.012-0.05 mg/kg/inj) in a behavioral economic design. In the second experiment, monkeys were allowed to self-administer cocaine alone (0.006-0.56 mg/kg/inj) or as a mixture with histamine (0.025-0.1 mg/kg/inj) under a progressive-ratio schedule of reinforcement.

Results: In Experiment 1, histamine decreased the reinforcing effectiveness of cocaine in a dose-dependent manner as evidenced by increases in cocaine's demand elasticity with increases in histamine dose. In Experiment 2, histamine decreased cocaine's potency and effectiveness as a reinforcer in a dose-dependent manner as indicated by rightward and downward shifts, respectively, in the dose-response functions.

Conclusion: The reinforcing effectiveness of cocaine can be reduced by contingent self-administration of histamine. These results indicate that combining drug punishers with drug reinforcers reduces the maximum reinforcing effect of the drug reinforcer, which suggests a use for drug punishers as a deterrent to drug abuse (e.g., as mixtures with prescription medications with abuse potential).

Fig. 1

Number of injections of 0.1 mg/kg/inj cocaine alone (solid line) and as a mixture with various doses of histamine (hatched lines) self-administered per session as a function of response requirement. Each panel represents an individual monkey, and each point represents the mean of three stable sessions.

Fig. 2

Panel A: Aggregated mean demand curves of all sessions from all monkeys for 0.1 mg/kg/inj of cocaine alone (solid line) and cocaine mixed with various doses of histamine (hatched lines). Panel B: Mean + SEM baseline consumption (i.e., at FR10) of all monkeys for cocaine alone and cocaine mixed with various doses of histamine. Panel C: "Essential Value" (inverse demand elasticity [1/α]) of the aggregated mean demand curves in Panel A for cocaine alone and cocaine mixed with various doses of histamine. * p ≤ 0.05.

Fig. 3

Dose-response functions for self-administration of cocaine alone or cocaine mixed with various doses of histamine under a progressive ratio schedule of reinforcement. Each panel represents an individual monkey, and each data point is the mean value for two test sessions at each dose or dose combination of cocaine and histamine.