mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIa Levels
Article
James, Morgan H., Quinn, Rikki K., Ong, Lin Kooi, Levi, Emily M., Charnley, Janine L., Smith, Doug W., Dickson, Phillip W. and Dayas, Christopher V.. 2014. "mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIa Levels." Neuropsychopharmacology. 39 (7), pp. 1694-1702. https://doi.org/10.1038/npp.2014.16
| Article Title | mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIa Levels |
|---|---|
| ERA Journal ID | 40224 |
| Article Category | Article |
| Authors | James, Morgan H., Quinn, Rikki K., Ong, Lin Kooi, Levi, Emily M., Charnley, Janine L., Smith, Doug W., Dickson, Phillip W. and Dayas, Christopher V. |
| Journal Title | Neuropsychopharmacology |
| Journal Citation | 39 (7), pp. 1694-1702 |
| Number of Pages | 9 |
| Year | Jun 2014 |
| Place of Publication | United States |
| ISSN | 0893-133X |
| 1740-634X | |
| Digital Object Identifier (DOI) | https://doi.org/10.1038/npp.2014.16 |
| Web Address (URL) | https://www.nature.com/articles/npp201416 |
| Abstract | 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+/Calmodulin-dependent kinase II alpha (CAMKII) 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 CAMKII levels in the NAC shell (NACsh) and core (NACc). In a subsequent study, we treated rats with intra-NACsh infusions of rapamycin (2.5 μg/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 CAMKII, 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 CAMKII in the NACsh. |
| Keywords | mechanistic target of rapamycin (mTOR); rapamycin; nucleus accumbens; GluAI; CAMKII alpha; cocaine |
| Public Notes | There are no files associated with this item. |
| Byline Affiliations | University of Newcastle |
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Ong, L. K., Guan, L., Stutz, B., Dickson, P. W., Dunkley, P. R. and Bobrovskaya, L.. 2011. "The effects of footshock and immobilization stress on tyrosine hydroxylase phosphorylation in the rat locus coeruleus and adrenal gland." Neuroscience. 192, pp. 20-27. https://doi.org/10.1016/j.neuroscience.2011.06.087Epigenetic Inheritance of Anxiety-Like Behaviour in Rats - Role of Early Life Exposure to a Bacterial Mimetic
Sominsky, L., Walker, A. K., Ong, L., Tynan, R. J., Walker, F. R. and Hodgson, D. M.. 2011. "Epigenetic Inheritance of Anxiety-Like Behaviour in Rats - Role of Early Life Exposure to a Bacterial Mimetic." Journal of Developmental Origins of Health and Disease. 2, pp. S109-S109.Neonatal respiratory infection and adult re-infection: Effect on glucocorticoid and mineralocorticoid receptors in the hippocampus in BALB/c mice
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Ong, L. K., Sominsky, L., Walker, A. K., Hodgson, D. M., Goodchild, A. K., Bobrovskaya, L., Dickson, P. W. and Dunkley, P. R.. 2011. "Sustained Phosphorylation of Tyrosine Hydroxylase at Serine 40 in VIVO." 23rd Biennial Meeting of the International Society for Neurochemistry (2011). Athen, Greece 28 Aug - 01 Sep 2011 United Kingdom.The Effect of Social Defeat on Tyrosine Hydroxylase Phosphorylation in the Rat Brain and Adrenal Gland
Ong, Lin Kooi, Bobrovskaya, Larisa, Walker, Frederick R., Day, Trevor A., Dickson, Phillip W. and Dunkley, Peter R.. 2011. "The Effect of Social Defeat on Tyrosine Hydroxylase Phosphorylation in the Rat Brain and Adrenal Gland." Neurochemical Research. 36 (1), pp. 27-33. https://doi.org/10.1007/s11064-010-0255-7Tyrosine hydroxylase phosphorylation in response to footshock and restraint stress
Ong, L., Guan, L., Stutz, B., Dickson, P., Dunkley, P. and Bobrovskaya, L.. 2010. "Tyrosine hydroxylase phosphorylation in response to footshock and restraint stress." Journal of Neurochemistry. 115, pp. 77-77.Signal transduction pathways and tyrosine hydroxylase regulation in the adrenal medulla following glucoprivation: An in vivo analysis
Bobrovskaya, Larisa, Damanhuri, Hanafi A., Ong, Lin Kooi, Schneider, Jennifer J., Dickson, Phillip W., Dunkley, Peter R. and Goodchild, Ann K.. 2010. "Signal transduction pathways and tyrosine hydroxylase regulation in the adrenal medulla following glucoprivation: An in vivo analysis." Neurochemistry International: the journal for the publication of cellular and molecular aspects of neurochemistry. 57 (2), pp. 162-167. https://doi.org/10.1016/j.neuint.2010.05.009The effect of social conflict on tyrosine hydroxylase phosphorylation in catecholamine-producing cells from sprague-dawley rats
Ong, L., Bobrovskaya, L., Walker, F., Day, Trevor, Dickson, P. and Dunkley, P.. 2009. "The effect of social conflict on tyrosine hydroxylase phosphorylation in catecholamine-producing cells from sprague-dawley rats." 22nd Biennial Meeting of the International Society for Neurochemistry & Asian Pacific Society for Neurochemistry (2009). South Korea 23 - 29 Aug 2009 United Kingdom.Cross-neutralisation of Australian brown and tiger snake venoms with commercial antivenoms: Cross-reactivity or antivenom mixtures?
O’Leary, Margaret A., Schneider, Jennifer J., Prakash Krishnan, Brian, Lavis, Christopher, McKendry, Amy, Ong, Lin Kooi and Isbister, Geoffrey K.. 2007. "Cross-neutralisation of Australian brown and tiger snake venoms with commercial antivenoms: Cross-reactivity or antivenom mixtures?" Toxicon. 50 (2), pp. 206-213. https://doi.org/10.1016/j.toxicon.2007.03.014This item comprises data from the following sources: Web of Science