Involvement of mitogen-stimulated p70-S6 kinase in the development of sensitization to the methamphetamine-induced rewarding effect in rats

Akai, Hiroyuki; Kita, Taizo; Nagumo, Yoko; Narita, Minoru; Sunagawa, Norio; Hara, Chiaki; Hasebe, Ko; Nagase, Hiroshi; Suzuki, Tsutomu

doi:10.1016/j.neuroscience.2004.12.050

Cited by 28 publications

(24 citation statements)

References 24 publications

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“…The mTOR inhibitor rapamycin prevented both the induction and the expression of sensitization, suggesting that the mTOR pathway is engaged during multiple stages of the sensitization process, and/or mTOR activation in both VTA and NAc contributes to cocaine sensitization. Our findings are also consistent with recently reported observations that rapamycin reduces craving in heroin addicts (Shi et al, 2009) and methamphetamine sensitization in rodents (Narita et al, 2005). …”

Section: Discussionsupporting

confidence: 93%

Inhibition of the mammalian target of rapamycin pathway by rapamycin blocks cocaine-induced locomotor sensitization

McCallum

Glick

et al. 2011

Neuroscience

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Section: Discussionsupporting

confidence: 93%

Inhibition of the mammalian target of rapamycin pathway by rapamycin blocks cocaine-induced locomotor sensitization

McCallum

Glick

et al. 2011

Neuroscience

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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: 89%

“…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%

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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“…These authors also showed that methamphetamine administration activated the downstream target of mTOR, p70S6K in the NAC (Narita et al, 2005). Consistent with the methamphetamine findings, Szumlinski et al recently showed that systemic rapamycin (10 mg/kg) suppressed the expression of cocaine-induced place preference (cpp) in C57/B6 mice (see Box 1; Bailey et al, 2011).…”

Section: Signaling Molecules Upstream Of Mtorc1 That Are Implicated Imentioning

confidence: 97%

“…The first evidence that mTORC1 signaling might play a role in addiction came from the demonstration that rapamycin infused into the NAC of male Sprague Dawley rats prevented psychostimulant-induced sensitization of methamphetamine place preference – a behavior shown to require structural plasticity in the striatum (Narita et al, 2005). These authors also showed that methamphetamine administration activated the downstream target of mTOR, p70S6K in the NAC (Narita et al, 2005).…”

Section: Signaling Molecules Upstream Of Mtorc1 That Are Implicated Imentioning

confidence: 99%

An Emerging Role for the Mammalian Target of Rapamycin in “Pathological” Protein Translation: Relevance to Cocaine Addiction

Dayas¹,

Dw²,

Dunkley³

2012

Front. Pharmacol.

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Complex neuroadaptations within key nodes of the brain’s “reward circuitry” are thought to underpin long-term vulnerability to relapse. A more comprehensive understanding of the molecular and cellular signaling events that subserve relapse vulnerability may lead to pharmacological treatments that could improve treatment outcomes for psychostimulant-addicted individuals. Recent advances in this regard include findings that drug-induced perturbations to neurotrophin, metabotropic glutamate receptor, and dopamine receptor signaling pathways perpetuate plasticity impairments at excitatory glutamatergic synapses on ventral tegmental area and nucleus accumbens neurons. In the context of addiction, much previous work, in terms of downstream effectors to these receptor systems, has centered on the extracellular-regulated MAP kinase signaling pathway. The purpose of the present review is to highlight the evidence of an emerging role for another downstream effector of these addiction-relevant receptor systems – the mammalian target of rapamycin complex 1 (mTORC1). mTORC1 functions to regulate synaptic protein translation and is a potential critical link in our understanding of the neurobiological processes that drive addiction and relapse behavior. The precise cellular and molecular changes that are regulated by mTORC1 and contribute to relapse vulnerability are only just coming to light. Therefore, we aim to highlight evidence that mTORC1 signaling may be dysregulated by drug exposure and that these changes may contribute to aberrant translation of synaptic proteins that appear critical to increased relapse vulnerability, including AMPARs. The importance of understanding the role of this signaling pathway in the development of addiction vulnerability is underscored by the fact that the mTORC1 inhibitor rapamycin reduces drug-seeking in pre-clinical models and preliminary evidence indicating that rapamycin suppresses drug craving in humans.

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Involvement of mitogen-stimulated p70-S6 kinase in the development of sensitization to the methamphetamine-induced rewarding effect in rats

Cited by 28 publications

References 24 publications

Inhibition of the mammalian target of rapamycin pathway by rapamycin blocks cocaine-induced locomotor sensitization

Inhibition of the mammalian target of rapamycin pathway by rapamycin blocks cocaine-induced locomotor sensitization

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

An Emerging Role for the Mammalian Target of Rapamycin in “Pathological” Protein Translation: Relevance to Cocaine Addiction

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