Effect of rapamycin on cue-induced drug craving in abstinent heroin addicts

Shi, Jie; Zhao, Li; Xue, Yan; Zhang, Xiang Yang; Kosten, Thomas R.; Lü, Lin

doi:10.1016/j.ejphar.2009.05.011

Cited by 30 publications

(31 citation statements)

References 36 publications

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“…These findings are significant given the recent demonstrations that mTORC1 effectively reduces alcohol-motivated behaviors in rats (Barak et al, 2013;Neasta et al, 2010) and that acute systemic rapamycin suppressed cue-induced drug craving in abstinent heroin addicts (Shi et al, 2009). Although it is important to note the need to directly test the hypothesis that the rapamycininduced reductions in mTORC1 activity and glutamate signaling molecules suppressed cocaine-seeking behavior, the present study indicates that mTORC1 inhibition can have long-lasting protective effects against drug-seeking behavior.…”

Section: Discussionmentioning

confidence: 85%

mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIα Levels

James

Quinn

Ong

et al. 2014

Neuropsychopharmacol

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The mechanistic target of rapamycin complex 1 (mTORC1) is necessary for synaptic plasticity, as it is critically involved in the translation of synaptic transmission-related proteins, such as Ca 2 þ /Calmodulin-dependent kinase II alpha (CAMKIIa) and AMPA receptor subunits (GluAs). Although recent studies have implicated mTORC1 signaling in drug-motivated behavior, the ineffectiveness of rapamycin, an mTORC1 inhibitor, in suppressing cocaine self-administration has raised questions regarding the specific role of mTORC1 in drug-related behaviors. Here, we examined mTORC1's role in three drug-related behaviors: cocaine taking, withdrawal, and reinstatement of cocaine seeking, by measuring indices of mTORC1 activity and assessing the effect of intra-cerebroventricular rapamycin on these behaviors in rats. We found that withdrawal from cocaine self-administration increased indices of mTORC1 activity in the nucleus accumbens (NAC). Intra-cerebroventricular rapamycin attenuated progressive ratio (PR) break points and reduced phospho-p70 ribosomal S6 kinase, GluA1 AMPAR, and CAMKIIa levels in the NAC shell (NACsh) and core (NACc). In a subsequent study, we treated rats with intra-NACsh infusions of rapamycin (2.5 mg/side/day for 5 days) during cocaine self-administration and then tracked the expression of addiction-relevant behaviors through to withdrawal and extinction. Rapamycin reduced drug seeking in signaled non-drug-available periods, PR responding, and cue-induced reinstatement, with these effects linked to reduced mTORC1 activity, total CAMKIIa, and GluA1 AMPAR levels in the NACsh. Together, these data highlight a role for mTORC1 in the neural processes that control the expression and maintenance of drug reward, including protracted relapse vulnerability. These effects appear to involve a role for mTORC1 in the regulation of GluA1 AMPARs and CAMKIIa in the NACsh.

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Section: Discussionmentioning

confidence: 85%

mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIα Levels

James

Quinn

Ong

et al. 2014

Neuropsychopharmacol

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“…In the present study, we found systemic rapamycin administration after memory reactivation produced a long-lasting effect on drug-related memory. It is noted that rapamycin has been used in heroin addicts, and Shi et al (2009) found that a single dose of rapamycin significantly reduced the craving. Thus, inhibition of the mTOR signaling pathway after memory reactivation maybe an effective way to prevent drug seeking and relapse.…”

Section: Discussionmentioning

confidence: 97%

“…Several studies have reported that rapamycin can inhibit drug-seeking in animals and drug-craving in humans after withdrawal. On the other hand, memory retrieval is usually completely impaired by protein synthesis inhibitors (Shi et al, 2009;Neasta et al, 2010;Wang et al, 2010;Bailey et al, 2012;Dayas et al, 2012). Rapamycin, an inhibitor of mTOR, frequently used in organ transplantation to prevent rejection via the inhibition of protein synthesis, can successfully enter the brain in rats and humans.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin prevents drug seeking via disrupting reconsolidation of reward memory in rats

Lin

Liu

Wen

et al. 2013

Int. J. Neuropsychopharm.

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The maladaptive drug memory developed between the drug-rewarding effect and environmental cues contributes to difficulty in preventing drug relapse. Established reward memories can be disrupted by pharmacologic interventions following their reactivation. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) kinase, has been proved to be involved in various memory consolidation. However, it is less well characterized in drug memory reconsolidation. Using a conditioned place preference (CPP) procedure, we examined the effects of systemically administered rapamycin on reconsolidation of drug memory in rats. We found that systemically administered rapamycin (0.1 or 10 mg/kg, i.p.) after re-exposure to drug-paired environment, dose dependently decreased the expression of CPP 1 d later, and the effect lasted for up to 14 d and could not be reversed by a priming injection of morphine. The effect of rapamycin on morphine-associated memory was specific to drug-paired context, and rapamycin had no effect on subsequent CPP expression when rats were exposed to saline-paired context or homecage. These results indicated that systemic administration of rapamycin after memory reactivation can persistently inhibit the drug seeking behaviour via disruption of morphine memory reconsolidation in rats. Additionally, the effect of rapamycin on memory reconsolidation was reproduced in cocaine CPP and alcohol CPP. Furthermore, rapamycin did not induce conditioned place aversion and had no effect on locomotor activity and anxiety behaviour. These findings suggest that rapamycin could erase the acquired drug CPP in rats, and that mTOR activity plays an important role in drug reconsolidation and is required for drug relapse.

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“…Heart rate was measured continuously with a fingertip pulse sensor connected to an SD-700 monitor (Shi et al 2009). …”

Section: Cardiovascular Measuresmentioning

confidence: 99%

“…Drug-related cues robustly increase subjective craving and, to a lesser extent, physiological indices (Bedi et al 2011;Carter and Tiffany 1999;Shi et al 2009). Craving is a predictor of relapse and treatment outcome (Gordon et al 2006;Marissen et al 2007;Paliwal et al 2008;Rohsenow et al 2007;Rohsenow et al 1994).…”

Section: Introductionmentioning

confidence: 98%

Drug-related cues exacerbate decision making and increase craving in heroin addicts at different abstinence times

et al. 2011

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Effect of rapamycin on cue-induced drug craving in abstinent heroin addicts

Cited by 30 publications

References 36 publications

mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIα Levels

mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIα Levels

Rapamycin prevents drug seeking via disrupting reconsolidation of reward memory in rats

Drug-related cues exacerbate decision making and increase craving in heroin addicts at different abstinence times

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