Rapamycin attenuates the expression of cocaine‐induced place preference and behavioral sensitization

Bailey, Jeffrey K; Ma, Dzwokai; Szumlinski, Karen K.

doi:10.1111/j.1369-1600.2010.00311.x

Cited by 54 publications

(56 citation statements)

References 46 publications

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“…Both acute systemic and intra-NAC injections of rapamycin attenuated alcohol-drinking behaviors and conditioned place preference (CPP) for alcohol (Neasta et al, 2010). Acute systemic rapamycin treatment also suppressed the expression of cocaine CPP, behavioral sensitization to cocaine (Bailey et al, 2012), and the sensitization of meth-amphetamine CPP (Narita et al, 2005). These findings indicate that mTORC1 may have a role in controlling the processes responsible for the strengthening of drug/cue associations.…”

Section: Introductionmentioning

confidence: 69%

“…rapamycin reduced lever pressing for cocaine when PR conditions were required to obtain cocaine infusions. To date, data supporting the role for mTORC1 in psychostimulant reinforcement has been limited to CPP and sensitization studies (Bailey et al, 2012;Narita et al, 2005). However, mTORC1 inhibition has been reported to reduce low-effort alcohol drinking in mice and FR1 alcohol self-administration in rats (Neasta et al, 2010).…”

Section: Intra-cerebroventricular Mtorc1 Inhibition Reduces Pr Responmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 69%

Section: Intra-cerebroventricular Mtorc1 Inhibition Reduces Pr Responmentioning

confidence: 99%

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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“…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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“…In addition to well-established roles for NMDA receptors and downstream signaling pathways (Torregrossa and Taylor, 2013), de novo protein synthesis is necessary for retrieval and/or reconsolidation of cocaine memories (Lee et al, 2006;Fuchs et al, 2009;Fan et al, 2010;Théberge et al, 2010;Bailey et al, 2012;Ren et al, 2013;Shi et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration

Werner

Milovanovic

Christian

et al. 2015

Neuropsychopharmacol

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The ubiquitin-proteasome system (UPS) has been implicated in the retrieval-induced destabilization of cocaine-and fear-related memories in Pavlovian paradigms. However, nothing is known about its role in memory retrieval after self-administration of cocaine, an operant paradigm, or how the length of withdrawal from cocaine may influence retrieval mechanisms. Here, we examined UPS activity after an extended-access cocaine self-administration regimen that leads to withdrawal-dependent incubation of cue-induced cocaine craving. Controls self-administered saline. In initial experiments, memory retrieval was elicited via a cue-induced seeking/retrieval test on withdrawal day (WD) 50-60, when craving has incubated. We found that retrieval of cocaine-and saline-associated memories produced similar increases in polyubiquitinated proteins in the nucleus accumbens (NAc), compared with rats that did not undergo a seeking/retrieval test. Measures of proteasome catalytic activity confirmed similar activation of the UPS after retrieval of saline and cocaine memories. However, in a subsequent experiment in which testing was conducted on WD1, proteasome activity in the NAc was greater after retrieval of cocaine memory than saline memory. Analysis of other brain regions confirmed that effects of cocaine memory retrieval on proteasome activity, relative to saline memory retrieval, depend on withdrawal time. These results, combined with prior studies, suggest that the relationship between UPS activity and memory retrieval depends on training paradigm, brain region, and time elapsed between training and retrieval. The observation that mechanisms underlying cocaine memory retrieval change depending on the age of the memory has implications for development of memory destabilization therapies for cue-induced relapse in cocaine addicts.

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Rapamycin attenuates the expression of cocaine‐induced place preference and behavioral sensitization

Cited by 54 publications

References 46 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

Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration

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