Skip to main content
SpringerLink
Log in

The dissociation of heroin-seeking patterns induced by contextual, discriminative, or discrete conditioned cues in a model of relapse to heroin in rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The role of heroin-related stimuli in motivating the resumption of heroin use is not fully understood.

Objectives

The objective was to characterize the relative importance of drug-related contextual stimuli, discriminative stimuli (DS), or discrete conditioned stimuli (CSs) on drug seeking when rats were reintroduced into the operant context after withdrawal.

Methods

Nose-poke responding by male rats was reinforced with intravenous heroin (0.05 mg/kg per infusion, 4-h session daily) under a progressive ratio schedule of reinforcement for 14 days. Each session began with the illumination of a green light in the active hole that served as DS. Each earned heroin injection was paired with a 5-s compound cue light and the sound of the infusion pump that served as the discrete CSs.

Results

Response rates of heroin seeking induced by the contextual stimuli were comparable to the average rates of responding during self-administration training, but rates induced by either DS or CSs were greater than those induced by the contextual stimuli alone (P<0.05). The responding induced by contingent presentations of CSs was higher than that of DS after extinction of instrumental behavior. The drug seeking induced by CSs can be maintained after 3 days extinction with DS in the original context, although the responding elicited by DS cannot be recovered after 3 days of extinction with CSs.

Conclusions

The relapse to drug seeking can be elicited separately by environmental cues, heroin-predictive DS, or discrete CSs in the same rat after withdrawal.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Anagnostaras SG, Schllert T, Robinson TE (2002) Memory processes governing amphetamine-induced psychomotor sensitization. Neuropsychopharmacology 26:703–715

    Article  PubMed  CAS  Google Scholar 

  • Arroyo M, Markou A, Robbins TW, Everitt BJ (1998) Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine. Psychopharmacology (Berl) 140:331–344

    Article  CAS  Google Scholar 

  • Bouton ME (2002) Context, ambiguity, and unlearning: source of relapse after behavioral extinction. Biol Psychiatry 52:976–986

    Article  PubMed  Google Scholar 

  • Childress AR, McLellan AT, O’Brien CP (1986) Abstinent opiate abuses exhibit conditioned craving, conditioned withdrawal and reduction in both through extinction. Br J Addict 81:655–660

    Article  PubMed  CAS  Google Scholar 

  • Childress AR, Hole AV, Ehrman RN, Robbins SJ, McLellan AT, O’Brien CP (1993) Cue reactivity and cue reactivity interventions in drug dependence. NIDA Res Monogr 137:73–95

    PubMed  CAS  Google Scholar 

  • Ciccocioppo R, Martin-Fardon R, Weiss F (2004) Stimuli associated with a single cocaine experience elicit long-lasting cocaine-seeking. Nat Neurosci 7:1–2

    Article  PubMed  CAS  Google Scholar 

  • Crombag HS, Shaham Y (2002) Renewal of drug seeking by contextual cues after prolonged extinction in rats. Behav Neurosci 116:169–173

    Article  PubMed  CAS  Google Scholar 

  • Deroche-Gamonet V, Piat F, Le Moal M, Piazza PV (2002) Influence of cue-conditioning on acquisition, maintenance and relapse of cocaine intravenous self-administration. Eur J Neurosci 15:1363–1370

    Article  PubMed  Google Scholar 

  • Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017

    Article  PubMed  CAS  Google Scholar 

  • de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology (Berl) 75:134–143

    Article  Google Scholar 

  • de Wit H, Stewart J (1983) Drug reinstatement of heroin-reinforced responding in the rat. Psychopharmacology (Berl) 79:29–31

    Article  Google Scholar 

  • Di Ciano P, Everitt BJ (2001) Dissociable effect of antagonism of NMDA and AMPA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior. Neuropsychopharmacology 25:341–360

    Article  PubMed  Google Scholar 

  • Di Ciano P, Everitt BJ (2002) Reinstatement and spontaneous recovery of cocaine-seeking following extinction and different durations of withdrawal. Behav Pharmacol 13:397–405

    PubMed  Google Scholar 

  • Di Ciano P, Everitt BJ (2003) Differential control over drug-seeking behavior by drug-associated conditioned reinforcers and discriminative stimuli predictive of drug availability. Behav Neurosci 117:952–960

    Article  PubMed  Google Scholar 

  • Di Ciano P, Everitt BJ (2004) Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour. Neuropharmacology 47:202–213

    Article  PubMed  Google Scholar 

  • Di Ciano P, Blaha CD, Phillips AG (2001) Changes in dopamine efflux associated with extinction, CS-induced and d-amphetamine-induced reinstatement of drug seeking behavior by rats. Behav Brain Res 120:147–158

    Article  PubMed  Google Scholar 

  • Goldberg SR (1976) Stimuli associated with drug injections as events that control behavior. Pharmacol Rev 27:325–340

    Google Scholar 

  • Goldberg SR, Gardner ML (1981) Second-order schedules: extended sequences of behavior controlled by brief environmental stimuli associated with drug self-administration. NIDA Res Monogr 37:241–270

    PubMed  CAS  Google Scholar 

  • Gracy KN, Dankiewicz LA, Weiss F, Koob GF (2000) Heroin-specific stimuli reinstate operant heroin-seeking behavior in rats after prolonged extinction. Pharmacol Biochem Behav 65:489–494

    Article  PubMed  CAS  Google Scholar 

  • Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, Phillips RL, Kimwa AS, Margolin A (1996) Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci U S A 93:4130–4146

    Article  Google Scholar 

  • Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Incubation of cocaine craving after withdrawal. Nature 412:141–142

    Article  PubMed  CAS  Google Scholar 

  • Hutcheson DM, Everitt BJ, Robbins TW, Dickinson A (2001) The role of withdrawal in heroin addiction: enhances reward or promotes avoidance? Nat Neurosci 4:943–947

    Article  PubMed  CAS  Google Scholar 

  • Ito R, Dalley JW, Howes SR, Robbins TW, Everitt BJ (2000) Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats. J Neurosci 20:7489–7495

    PubMed  CAS  Google Scholar 

  • Kalivas PW, McFarland K (2003) Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl) 168:44–56

    Article  CAS  Google Scholar 

  • Koob GF, Weiss F, Tiffany ST, Zieglgansbenger W, Spanagel R (1999) Animal models of craving: a roundtable discussion. Alcohol Res Health 23:233–236

    PubMed  CAS  Google Scholar 

  • Kozlowski LT, Wilkinson DA (1987) Use and misuse of the concept of craving by alcohol, tobacco and drug researchers. Br J Addict 82:31–36

    Article  PubMed  CAS  Google Scholar 

  • Kruzich PJ, Congleton KM, See RE (2001) Conditioned reinstatement of drug-seeking behavior with a discrete compound stimulus classically conditioned with intravenous cocaine. Behav Neurosci 115:1086–1092

    Article  PubMed  CAS  Google Scholar 

  • Leri F, Stewart J (2002) Consequences of different “lapses” on relapse to heroin seeking in rats. Exp Clin Psychopharmacol 10:339–349

    Article  PubMed  CAS  Google Scholar 

  • Lu L, Grimm JW, Hope B, Shaham Y (2004) Incubation of cocaine seeking after withdrawal in rats: a review. Neuropharmacology 47:214–226

    Article  PubMed  CAS  Google Scholar 

  • Markou A, Weiss F, Gold LH, Caine SB, Schulteis G, Koob GF (1993) Animal models of drug craving. Psychopharmacology (Berl) 112:163–182

    Article  CAS  Google Scholar 

  • McFarland K, Ettenberg A (1997) Reinstatement of drug-seeking behavior produced by heroin-predictive environmental stimuli. Psychopharmacology (Berl) 131:86–92

    Article  CAS  Google Scholar 

  • Neisewander JL, O’Dell LE, Tran-Nguyen LT, Castaneda E, Fuchs RA (1996) Dopamine overflow in the nucleus accumbens during extinction and reinstatement of cocaine self-administration behavior. Neuropsychopharmacology 15:506–514

    Article  PubMed  CAS  Google Scholar 

  • O’Brien CP (1997) A range of research-based pharmacotherapies for addiction. Science 278:66–70

    Article  PubMed  CAS  Google Scholar 

  • Panlilio LV, Weiss SJ, Schindler CW (1998) Motivational effects of compounding discriminative stimuli associated with food and cocaine. Psychopharmacology (Berl) 136:70–74

    Article  CAS  Google Scholar 

  • Powell J, Gray JA, Bradley BP, Kasvikis Y, Strang J, Barratt L, Marks I (1990) Effects of exposure to drug-related cues in detoxified opiate addicts: a theoretical review and some new data. Addict Behav 15:339–354

    Article  PubMed  CAS  Google Scholar 

  • Robbins TW, Everitt BJ (1999) Drug addiction: bad habits add up. Nature 398:567–570

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE (2004) Addicted rats. Science 305:951–953

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291

    Article  PubMed  CAS  Google Scholar 

  • Schindler CW, Panlilio LV, Goldberg SR (2002) Second-order schedules of drug-administration in animals. Psychopharmacology (Berl) 163:327–344

    Article  CAS  Google Scholar 

  • Schmajuk NA, Lamoureux JA, Holland PC (1998) Occasion setting: a neural network approach. Psychol Rev 105:3–32

    Article  PubMed  CAS  Google Scholar 

  • See RE (2002) Neural substrates of conditioned-cued relapse to drug-seeking behavior. Pharmacol Biochem Behav 71:517–529

    Article  PubMed  CAS  Google Scholar 

  • See RE, Grimm JW, Kruzich PJ, Rustay N (1999) The importance of a compound stimulus in conditioned drug-seeking behavior following one week of extinction from self-administered cocaine in rats. Drug Alcohol Depend 57:41–49

    Article  PubMed  CAS  Google Scholar 

  • Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168:3–20

    Article  CAS  Google Scholar 

  • Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–37

    Article  PubMed  CAS  Google Scholar 

  • Sherman JE, Zinser MC, Sideroff SI, Baker TB (1989) Subjective dimensions of heroin urges: influence of heroin-related and affectively negative stimuli. Addict Behav 14:611–623

    Article  PubMed  CAS  Google Scholar 

  • Stafford D, LeSage MG, Glowa JR (1998) Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review. Psychopharmacology (Berl) 139:169–184

    Article  CAS  Google Scholar 

  • Stewart J, Wise RA (1992) Reinstatement of heroin self-administration habits: morphine prompts and naltrexone discourages renewed responding after extinction. Psychopharmacology (Berl) 108:79–84

    Article  CAS  Google Scholar 

  • Sutton MA, Karanian DA, Self DW (2000) Factors that determine a propensity for cocaine-seeking behavior during abstinence in rats. Neuropsychopharmacology 22:626–641

    Article  PubMed  CAS  Google Scholar 

  • Sutton MA, Schmidt EF, Chol K, Schad CA, Whisler K, Simmons D, Karanian DA, Menteggia LM, Neve RL, Self DW (2003) Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour. Nature 421:70–75

    Article  PubMed  CAS  Google Scholar 

  • Tiffany ST, Carter BL (1998) Is craving the source of compulsive drug use? J Psychopharmacol 12:23–30

    Article  PubMed  CAS  Google Scholar 

  • Tran-Nguyen LT, Fuchs RA, Coffey GP, Baker DA, O’Dell LE, Neisewander JL (1998) Time-dependent changes in cocaine-seeking behavior and extracellular dopamine levels in the amygdala during cocaine withdrawal. Neuropsychopharmacology 19:48–59

    Article  PubMed  CAS  Google Scholar 

  • Vanderschuren LJMJ, Everitt BJ (2004) Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305:1017–1019

    Article  PubMed  CAS  Google Scholar 

  • Weiss F (2005) Neurobiology of craving, conditioned reward and relapse. Curr Opin Pharmacol 5:9–19

    Article  PubMed  CAS  Google Scholar 

  • Weiss F, Maldonado-Vlaar CS, Parsons LH, Kerr TM, Smith DL, Ben-Shahar O (2000) Control of cocaine-seeking behavior by drug-associated stimuli in rats: effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens. Proc Natl Acad Sci U S A 97:4321–4326

    Article  PubMed  CAS  Google Scholar 

  • Weiss F, Martin-Fardon R, Ciccocioppo R, Kerr TM, Smith DL, Ben-Shahar O (2001) Enduring resistance to extinction of cocaine-seeking behavior induced by drug-related cues. Neuropsychopharmacology 25:361–372

    Article  PubMed  CAS  Google Scholar 

  • Yun IA, Nicola SM, Fields HL (2004) Contrasting effects of dopamine and glutamate receptor antagonist injection in the nucleus accumbens suggest a neural mechanism underlying cue-evoked goal-directed behavior. Eur J Neurosci 20:249–263

    Article  PubMed  Google Scholar 

  • Zhang F, Zhou W, Tang S, Liu H, Lai M, Zhu H, Yang G (2004) Motivation of heroin-seeking elicited by drug-associated cues is related to total amount of heroin exposure during self-administration in rats. Pharmacol Biochem Behav 79:291–298

    Article  PubMed  CAS  Google Scholar 

  • Zhou W, Zhang F, Tang S, Liu H, Lai M, Yang G (2004) Low dose of heroin inhibits drug-seeking elicited by cues after prolonged withdrawal from heroin self-administration in rats. NeuroReport 15:727–730

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Dr. Charles Schindler and Dr. Tatia Lee for comments on the manuscript. The valuable comments and suggestions of the reviewers are kindly acknowledged. This work was supported by National Basic Research Program of China (No. 2003CB515404) and National Nature Science Foundation of China (No. 30100051, No. 30470554).

Author information

Authors and Affiliations

  1. Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, 42 Xibei Str., Ningbo, 315010, People’s Republic of China

    Wenhua Zhou, Fuqiang Zhang, Shuaien Tang, Huifen Liu, Jun Gu & Guodong Yang

Authors
  1. Wenhua Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fuqiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuaien Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huifen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guodong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wenhua Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, W., Zhang, F., Tang, S. et al. The dissociation of heroin-seeking patterns induced by contextual, discriminative, or discrete conditioned cues in a model of relapse to heroin in rats. Psychopharmacology 181, 197–206 (2005). https://doi.org/10.1007/s00213-005-2262-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-005-2262-y

Keywords

Search

Navigation