, Volume 181, Issue 1, pp 90–100 | Cite as

Role of withdrawal in reinstatement of morphine-conditioned place preference

  • Lin Lu
  • Hai Chen
  • Wenjuan Su
  • Xin Ge
  • Wen Yue
  • Fen Su
  • Lan Ma
Original Investigation



Relapse is a major characteristic of drug addiction and the primary problem in treating drug abuse. Based on the negative reinforcement view of addiction, in which the motivation to take drugs is thought to result from the desire to avoid the aversive effect of drug withdrawal, it has been theorized that withdrawal symptoms play a major role in the maintenance of and relapse to drug taking. However, the role of withdrawal in relapse has not yet been systemically investigated in the reinstatement model.


Using a conditioned place preference (CPP) paradigm, we examined the role of different morphine withdrawal states (spontaneous withdrawal, naloxone-precipitated withdrawal, and conditioned withdrawal) in relapse to drug seeking.


Rats alternately received morphine (10 mg/kg, s.c.) and saline for 8 days to acquire the CPP. The morphine CPP disappeared after a 2-week extinction phase of saline-paired training. Rats were then chronically administered morphine to induce physical dependence. The different withdrawal states were induced and their roles in the reinstatement of extinguished CPP were assessed. During conditioned withdrawal, trunk blood samples were taken and the corticosterone level was measured by radioimmunoassay. To examine the role of corticotropin-releasing factor (CRF) receptor antagonist on conditioned-withdrawal-induced reinstatement of CPP, different doses of α-helical CRF (0.1 and 1 μg, i.c.v.) were administered 30 min prior to the CPP testing.


The results show that morphine spontaneous withdrawal and naloxone-precipitated morphine withdrawal were ineffective in reinstating morphine CPP. However, the withdrawal cues significantly elicited the reinstatement of CPP and increased corticosterone level. Moreover, pretreatment with the CRF receptor antagonist α-helical CRF (1 μg, i.c.v.) significantly attenuated the effects of withdrawal cues on reinstatement of CPP and corticosterone levels.


These findings demonstrate that the cues associated with previous drug withdrawal play a major role in drug relapse and that activation of the CRF receptor is involved in conditioned-withdrawal-induced reinstatement. The present study suggests that CRF receptor antagonists might be of value in the treatment and prevention of relapse to drug seeking after long-term abstinence.


Conditioned place preference Drug-seeking Withdrawal Cue conditioning Morphine Relapse 



This work was supported in part by grants from the National Natural Science Foundation of China (30000050 to Lin Lu and 30230130 to Lan Ma). We thank Yavin Shaham for helpful comments and Emily Wentzell for editorial assistance.


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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Lin Lu
    • 1
    • 2
  • Hai Chen
    • 1
  • Wenjuan Su
    • 1
  • Xin Ge
    • 1
  • Wen Yue
    • 1
  • Fen Su
    • 1
  • Lan Ma
    • 1
  1. 1.National Laboratory of Medical Neurobiology and Pharmacology Research CenterFudan UniversityShanghaiChina
  2. 2.Behavioral Neuroscience BranchIRP/NIDA/NIHBaltimoreUSA

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