BACKGROUND: Drug-associated conditioned stimuli are a key factor to induce morphine relapse. To date, limited evidence is available regarding the impact of drug history on propensity or vulnerability to relapse after long-term abstinence.OBJECTIVE: To determine the effect of morphine pre-exposure on acquisition, maintenance and reinstatement of morphine-induced conditioned place preference (CPP) in rats.DESIGN, TIME AND SETTING: A randomized, controlled, animal experiment was performed at the Laboratory of Behavior Pharmacology, Institute of Psychology, the Chinese Academy of Sciences, from March to September, 2006.MATERIALS: Morphine hydrochloride was purchased from Qinghai Pharmaceutical, China; CPP software was designed and developed by Taiji Software Company, Beijing, China.METHODS: A total of 64 Sprague Dawley rats were randomly assigned to eight groups (n = 8). Four morphine pretreatment regimens were used (subcutaneous injections, twice daily for 5 consecutive days and a total of 10 times): (1) intensive (morphine injections with doses escalating from 10 to 60 mg/kg; (2) moderate (one morphine injection at 5 mg/kg dose and one saline injection at 1 mL/kg daily for 5 days); and (3) single (nine saline injections at 1 mL/kg followed by one morphine injection at 5 mg/kg; (4) control (ten saline injections at 1 mL/kg). At 5 days after morphine pretreatment, animals were divided into two subgroups that underwent morphine conditioned or saline conditioned training. The test for acquisition of CPP was performed 24 hours after CPP training. The retention of morphine CPP was measured by repeated tests performed weekly for 1 month after the initial test of place preference. After extinction by pairing each chamber with saline, the reinstatement of place preference by low doses of morphine (0.05, 0.15, 0.45 mg/kg) was tested. MAIN OUTCOME MEASURES: Acquisition, maintenance, and recovery response of CPP behavior.RESULTS: The acquisition magnitude of morphine-induced CPP was not affected by prior morphine exposure (F3, 56=0.17, P > 0.05). However, rats treated with moderate or intensive morphine pretreatment showed a less persistent CPP (t = -1.36, P > 0.05; t = -1.18, P > 0.05), but their place preference was reinstated by a low dose of morphine priming (t = -2.55, P < 0.05; t = -2.54, P < 0.05). The retention and reinstatement of morphine-induced CPP did not differ between rats with single morphine pre-exposure and control rats.CONCLUSION: Morphine pretreatment enhanced reinstatement of morphine-induced CPP but with less persistence. Individuals with heavy drug exposure are more susceptible to drug relapse when re-exposed to addictive drugs.