W. Zhou , Z. Fuqiang, T. Shuien, L. Miaojun, and Y. Guodong Ningbo Addiction Research and Treatment Center, Ningbo, China
It is unclear to what extent opiate withdrawal functions as a motivational state that can explain relapse. We trained 6 groups of rats to respond to a nose-poker for a daily maximum of 25 intravenous heroin injections (0.05 mg per kg body weight). Rats were transferred daily to operant cages, response(s) on the active nose-poker were reinforced with one heroin injection paired with a 5-second stimulus light, and the response requirement was increased one step after each five injections. After 14 days of 4-hour training sessions daily, the rats came to earn 25 infusions in 166.7+6.7 minutes with 84.6+2.0 responses per session. They were withdrawn from heroin for 1, 2, and 4 weeks during which they lived in their individual feeding cages all day. Reinstatement responses induced by environmental cues were low in rats after 1 week of withdrawal when the urine test of morphine was still positive, and high in rats after 2 or 4 weeks of withdrawal. Relapse to heroin seeking induced by drug associated environmental and conditioned cues persisted over several weeks after withdrawal. A pre-session heroin injection enhanced the response induced by environmental cues at 1 or 2 weeks of withdrawal, but suppressed response induced by environmental or conditioned cues in rats that had been deprived of heroin for 4 weeks. Moreover, the resistance to extinction of responding induced by conditioned cues after repeated tests in rats at 4 weeks of withdrawal. Our results mimic the situations in humans that patients can report cravings when returning to a usual injection environment. A sensitized state of heroin priming may increase the vulnerability to environmental cues-induced drug seeking during an early phase of withdrawal. Whereby just one heroin injection has the suppressive action on relapse to drug-seeking behavior at a late phase of withdrawal, suggesting that the negative affective state of withdrawal may have motivating properties in maintaining drug-seeking behavior. In fact, the clinical data indicated that the addict is compelled to continue using heroin in order not to be sick with the protracted abstinence symptoms. We therefore propose that the substitution of socially approved reinforcers may prove to be a useful strategy to prevent relapse to heroin seeking long after detoxification.