Attenuation of cocaine and heroin seeking by μ-opioid receptor antagonism

Abstract

Rationale: Evidence has implicated the endogenous opioids, in particular μ-opioid receptors, in emotional behavior and regulation of reward circuits, especially in the context of heroin addiction and hedonic responses to ingestive rewards. The μ-opioid receptor antagonist naltrexone (NTX) has been reported to be effective in preventing relapse to alcoholism and in reducing alcohol and cocaine craving during abstinence.

Objectives: The aim of the present experiments was to investigate the effects of a novel selective μ-opioid receptor antagonist GSK1521498 on cocaine and heroin seeking and the primary reinforcement of drug self-administration behavior.

Methods: Rats were first trained to self-administer cocaine or heroin and then to seek the drugs over prolonged periods of time under a second-order schedule of reinforcement, in which responding is maintained by contingent presentation of a drug-associated conditioned reinforcer. On a stable baseline, animals were treated with either GSK1521498 (0.1, 1, 3 mg/kg; IP) or NTX (0.1, 1, 3 mg/kg; SC) before each test session.

Results: Cocaine seeking was dose-dependently decreased following GSK1521498 treatment. However, the same treatment had no effect on cocaine self-administration under a continuous reinforcement schedule. Treatment with NTX had a less pronounced but similar effect. GSK1521498, but not NTX, dose-dependently reduced heroin seeking both before and after infusion of the drug although both increased heroin self-administration under continuous reinforcement.

Conclusions: These data suggest that GSK1521498, by reducing opioid receptor signaling at the μ-opioid receptor, may have therapeutic potential to reduce the propensity to seek cocaine or heroin and, additionally, to diminish the consequence of an initial relapse to heroin taking.

Fig. 1

Effects of GSK1521498 on cocaine seeking under a second-order schedule of reinforcement during the first drug-free interval (a, b) and after cocaine infusion (second interval) (c, d). Data shown are mean (+SEM) number of presses on the active (a, c) and inactive lever (b, d). Single asterisk (*) p < .05 compared with vehicle treated animals

Fig. 2

Effects of naltrexone on cocaine seeking under a second-order schedule of reinforcement during the first drug-free interval (a, b) and after cocaine infusion (second interval) (c, d). Data shown are mean (+SEM) number of presses on the active (a, c) and inactive lever (b, d). Double asterisk (**) p < .01 compared with vehicle treated animals

Fig. 3

Effects of GSK1521498 on heroin seeking under a second-order schedule of reinforcement during the first drug-free interval (a, b) and after heroin infusion (second interval) (c, d). Data shown are mean (±SEM) number of presses on the active (a, c) and inactive lever (b, d). Single asterisk (*) p < .05, double asterisk (**) p < .01, and triple asterisk (***) p < .001 compared with vehicle treated animals

Fig. 4

Effects of naltrexone on heroin seeking under a second-order schedule of reinforcement during the first drug-free interval (a, b) and after heroin infusion (second interval) (c, d). Data shown are mean (+SEM) number of presses on the active (a, c) and inactive lever (b, d)

Fig. 5

Top: effects of GSK1521498 (a, b) and naltrexone (b, c) on cocaine self-administration under a fixed-ratio 1 (a, c) and a fixed-ratio 10 (b, d) schedule of reinforcement. Bottom: effects of GSK1521498 (e, f) and naltrexone (g, h) on heroin self-administration under a fixed-ratio 1 (e, g) and a fixed-ratio 10 (f, h) schedule of reinforcement. Data shown are mean (+SEM) number of infusions reached per session. Double asterisk (**) p < .01 and triple asterisk (***) p < .001 compared with vehicle treated animals

Fig. 6

Differential efficacy of GSK1521498 compared to naltrexone on cocaine and heroin seeking (A) and self-administration behavior (B). Each vertical line in the plot is a 95 % confidence interval for the fold difference in effect of GSK1521498 versus NTX at each of three doses (0.1, 1, and 3 mg/kg) in log scale. Positive values indicate that GSK1521498 has a greater effect than NTX, causing greater reduction or fold decrease in cocaine- or heroin-seeking behavior; the horizontal line highlights a fold difference of 1 or equivalent efficacy of the two drugs. If a confidence interval does not include 1, that is equivalent to a statistically significant difference in efficacy of GSK1521498 compared to NTX