The reinstatement model of drug relapse: history, methodology and major findings

Shaham, Yavin; Shalev, Uri; Lü, Lin; Wit, Harriet de; Stewart, Jane

doi:10.1007/s00213-002-1224-x

Cited by 1,456 publications

(1,266 citation statements)

References 190 publications

Supporting

Mentioning

1,217

Contrasting

Unclassified

Order By: Relevance

“…Indeed, rimonabant reduced the dopamine-releasing effects of nicotine as assessed by brain microdialysis and drug discrimination. A large body of evidence has shown that dopaminergic transmission plays a role in conditioned responses associated with drugs (Everitt et al, 2001;Shaham et al, 2003). As expected, the D 1 dopamine antagonist SCH23390 (0.01 and 0.03 mg/kg) was found to reduce responding for conditioned cues.…”

Section: Discussionsupporting

confidence: 66%

“…Factors such as drug-associated environmental stimuli, stress, or drug priming can trigger craving in humans and drug-seeking behavior in laboratory animals (Shaham et al, 2003;Sinha et al, 2000;Weiss et al, 2001;Brody et al, 2002). Cue-induced drug-seeking behavior can be measured in animals using second-order schedules of drug reinforcement or extinction/reinstatement models (Markou et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

“…In the former, operant responding is maintained not only by the drug but also by drug-associated stimuli that serve as conditioned reinforcers Schindler et al, 2002). In models of relapse, extinguished drug-seeking behavior is reinstated by presentation of stimuli previously paired with the delivery of the drug Shaham et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Nicotine-Associated Cues Maintain Nicotine-Seeking Behavior in Rats Several Weeks after Nicotine Withdrawal: Reversal by the Cannabinoid (CB1) Receptor Antagonist, Rimonabant (SR141716)

Cohen

Perrault

Griebel

et al. 2004

Neuropsychopharmacol

229

176

View full text Add to dashboard Cite

Conditioned stimuli are important for nicotine dependence and may trigger craving and relapse after prolonged nicotine abstinence. However, little is known about the pharmacology of this process. Among the systems that have been shown to play a role in drugseeking behavior is the endocannabinoid transmission. Therefore, the present study examined the resistance to extinction of drugseeking behavior elicited by nicotine-associated environmental stimuli and the effects of the selective CB 1 cannabinoid antagonist rimonabant (SR141716) on the reinforcing effects of nicotine-related stimuli. Rats were trained to self-administer nicotine (0.03 mg/kg/ injection, i.v.) under conditions in which responding was reinforced jointly by response-contingent nicotine injections and stimuli (light and tone). After self-administration acquisition, nicotine was withdrawn and lever pressing was only reinforced by contingent presentation of the audiovisual stimuli. Under such a condition, responding persisted for 3 months, following which nonpresentation of the cues produced a progressive extinction of responding. As expected, rats trained to lever-press for saline injections paired with the audiovisual stimuli did not acquire the self-administration. These findings indicate that the cues required learned association with nicotine to acquire reinforcing properties and to function as conditioned reinforcers. When administered 1 month following nicotine withdrawal, rimonabant (1 mg/kg, i.p.) decreased conditioned behavior. These results showing the persistence of a nicotine-conditioned behavior are congruent with the role of nicotine-related environmental stimuli in nicotine craving in abstinent smokers. Rimonabant, which has been shown previously to reduce nicotine self-administration, may be effective not only as an aid for smoking cessation but also in the maintenance of abstinence.

show abstract

Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nicotine-Associated Cues Maintain Nicotine-Seeking Behavior in Rats Several Weeks after Nicotine Withdrawal: Reversal by the Cannabinoid (CB1) Receptor Antagonist, Rimonabant (SR141716)

Cohen

Perrault

Griebel

et al. 2004

Neuropsychopharmacol

229

176

View full text Add to dashboard Cite

show abstract

“…Recently, a clinical study with opioid-dependent patients maintained on naltrexone showed that lofexidine (at twice the daily dose used presently) decreased laboratory measures of stress-and drug cue-induced craving and decreased opioid relapse compared to placebo (Sinha et al, 2007). There is also an extensive preclinical literature showing that lofexidine decreases stress-induced drug-seeking behavior (see Shaham et al, 2003). Given that preclinical studies show that cannabis withdrawal, like opioid withdrawal, is associated with noradrenergic hyperactivity (see Introduction), lofexidine may decrease marijuana relapse in the laboratory by the same mechanism as it decreases opioid relapse: by reducing withdrawal-related noradrenergic hyperactivity.…”

Section: Discussionmentioning

confidence: 99%

Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse

et al. 2007

View full text Add to dashboard Cite

Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence.Objectives-To determine if THC, a cannabinoid agonist, and lofexidine, an α 2 -adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence.Methods-Nontreatment-seeking, male volunteers (n=8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, THC (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first 3 inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake and sleep were measured.Results-THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep, and decreased marijuana withdrawal, craving and relapse in daily marijuana smokers relative to either medication alone.Conclusions-These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence. KeywordsMarinol; Britlofex; dependence; withdrawal; treatment; cannabinoid; norepinephrine Marijuana use is prevalent in American society, and the number of individuals who currently meet DSM-IV criteria for cannabis abuse or dependence has steadily increased since the 1990s (Compton et al., 2004). Although marijuana is less likely to produce dependence than drugs such as nicotine, alcohol or heroin (Anthony et al., 1994), the sheer number of marijuana smokers combined with the increasing potency of marijuana has NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2012 June 12.Published in final edited form as:Psychopharmacology (Berl). 2008 March ; 197(1): 157-168. doi:10.1007/s00213-007-1020-8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript resulted in a significant number of individuals developing cannabis use disorders, i.e., approximately 1.5% of the U.S. population (Compton et al., 2004).A number of studies have demonstrated that there is a personal (i.e., not court-mandated) demand for marijuana treatment, particularly when marijuana-specific treatment programs are offered (Roffman et al., 1988;Stephens et al., 1993;Lang et al., 2000). Treatmentseekers report distress about their marijuana use, and repeatedly ...

show abstract

“…It has been observed that the same stimuli that reinstate self-administration are capable of inducing the reinstatement of CPP. The most important environmental events that may lead to reinstatement are re-exposure to the drug itself, presentation of drug-associated stimuli or cues and exposure to a stressful event Ribeiro Do Couto et al, 2005a, b;Ribeiro Do Couto et al, 2006; for a review, see Shalev et al, 2002;Shaham et al, 2003;Weiss, 2005).…”

Section: Introductionmentioning

confidence: 99%

Rewarding Effects and Reinstatement of MDMA-Induced CPP in Adolescent Mice

Daza-Losada

Couto

Manzanedo

et al. 2007

Neuropsychopharmacol

View full text Add to dashboard Cite

Although the rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in self-administration and conditioned place preference (CPP) procedures, its addictive potential (ie, the vulnerability to relapse, measured by its ability to induce reinstatement of an extinguished response), remains poorly understood. In this study, the effects of MDMA (5, 10, and 20 mg/kg) on the acquisition, extinction and reinstatement of CPP were evaluated in mice, using two different protocols during acquisition of CPP. In the first experiment, animals were trained using a two-session/day schedule (MDMA and saline for 4 consecutive days), whereas in the second experiment, they were trained using an alternating day schedule (MDMA and saline each 48 h). After extinction, the ability of drug priming to reinstate CPP was evaluated. In Experiment 1, MDMA did not significantly increase the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, although the preference was evident a week afterwards, lasting between 2 and 21 weeks. No reinstatement was observed after MDMA priming. In Experiment 2, all doses produced CPP in Post-C, which lasted between 1 and 4 weeks. MDMA induces reinstatement at doses up to 4 times lower than those used in conditioning. The analyses of brain monoamines revealed that the daily schedule of treatment induces a non-dose-dependent decrease in dopamine and serotonin (5-HT) in the striatum, whereas the alternating schedule produces a dose-dependent decrease of 5-HT in the cortex. These results demonstrate that MDMA produces long-lasting rewarding effects and reinstatement after extinction, suggesting the susceptibility of this drug to induce addiction.

show abstract

The reinstatement model of drug relapse: history, methodology and major findings

Cited by 1,456 publications

References 190 publications

Nicotine-Associated Cues Maintain Nicotine-Seeking Behavior in Rats Several Weeks after Nicotine Withdrawal: Reversal by the Cannabinoid (CB1) Receptor Antagonist, Rimonabant (SR141716)

Nicotine-Associated Cues Maintain Nicotine-Seeking Behavior in Rats Several Weeks after Nicotine Withdrawal: Reversal by the Cannabinoid (CB1) Receptor Antagonist, Rimonabant (SR141716)

Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse

Rewarding Effects and Reinstatement of MDMA-Induced CPP in Adolescent Mice

Contact Info

Product

Resources

About