Reinstatement of cocaine-seeking behavior in rats is attenuated following repeated treatment with the opioid receptor antagonist naltrexone

In the present study we show that the endogenous opioid systems play a modulating role in cocaine-induced reinstatement of drug-seeking behavior in rats. We investigated the effect of blockade of opioid receptors on reinstatement of cocaine-seeking behavior by cocaine priming. Drug-naive rats were allowed to initiate self-administration behavior of cocaine (30 and 60 μg per infusion, i.v.) for 5 consecutive daily sessions, and after a 5-day extinction period during which the rats did not receive cocaine, a test for cocaine-induced (1 mg/kg, i.v.) reinstatement followed. The effect of cocaine priming was tested on days 1, 3, and 5 after extinction, while on days 2 and 4 the animals received saline priming. Before each daily reinstatement test, different groups of animals received an injection with the opioid receptor antagonist naltrexone (3 mg/kg, s.c.) or with placebo. We observed that cocaine readily reinstated extinguished responding in the rats, and that this reinstatement responding did not change over the consecutive reinstatement tests. Pretreatment with naltrexone progressively attenuates the cocaine-induced reinstatement, with a significant reduction on days 3 and 5 of reinstatement testing. Discriminative lever-pressing (active versus inactive lever) during reinstatement phase, however, remains present in animals treated with naltrexone. This implies that repeated opioid receptor blockade progressively attenuates cocaine-induced drug-seeking behavior in abstained animals, but this cannot simply be attributed to extinction of cocaine-seeking behavior.