N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking

Abstract

Background: Previous studies show that the acute administration of N-acetylcysteine (NAC) inhibits the desire for cocaine in addicts and cocaine-seeking in animals.

Methods: Rats were trained to self-administer heroin, and the reinstatement model of drug seeking was used to determine whether chronic NAC treatment inhibited heroin-seeking.

Results: Daily NAC administration inhibited cue- and heroin-induced seeking. Moreover, repeated NAC administration during extinction training reduced extinction-responding and inhibited cue- and heroin-induced reinstatement for up to 40 days after discontinuing daily NAC injection.

Conclusions: These data show that daily NAC inhibits heroin-induced reinstatement and produces an enduring reduction in cue- and heroin-induced drug seeking for over 1 month after the last injection of NAC. Both the inhibitory effect of NAC on the reinstatement of heroin-seeking and the ability of NAC to reduce extinction-responding support clinical evaluation of repeated NAC administration to decrease in drug-seeking in heroin addicts.

Figures

Figure 1. Daily NAC administration facilitates extinction training and produces enduring inhibition of cue- and heroin-induced reinstatement

A) NAC (100 mg/kg, ip) or vehicle was administered 2.5 h before each 3 h extinction training session. All animals were extinguished for 7 days (NAC, n= 24; Vehicle, n= 23), and for days 8–10 all but 3 rats in each group continued to receive extinction training. Regardless of the extinction training period, on days 1–10 all animals received respective pretreatments with NAC or vehicle. B) Daily NAC and vehicle injections continued for 5 more days. On day 11 animals were presented with a light cue, and on day 15 received an injection of heroin (0.25 mg/kg, sc). C) Animals were returned to the home cage for 40 days without any drug treatments. On day 55 they were exposed to light cues without any drug treatments. After an additional 4 days in the home cage, all animals were administered heroin without NAC or vehicle pretreatment. D) Inactive lever presses during all reinstatement trials. All data are shown as mean ± sem lever presses. E) Data from one replication (n= 10 in each group) was analyzed in hourly intervals indicating that the effect of NAC treatment on Day 1 extinction responding occurred primarily in the first h. F) Photocell counts showing that chronic NAC did not alter behavioral responding in a novel open field environment compared with chronic vehicle treatment (n= 7 in both groups). *p