The GSK3 signaling pathway is activated by cocaine and is critical for cocaine conditioned reward in mice.

The Akt - GSK3 signaling pathway has been recently implicated in psychostimulant-induced behavioral and cellular effects. Here, the ability of cocaine to regulate the activity of Akt and GSK3 was investigated by measuring the phosphorylation states of the two kinases. The anatomical specificity of t...

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Autores principales:	Jonathan S Miller, Jeffrey L Barr, Lauren J Harper, Rachel L Poole, Thomas J Gould, Ellen M Unterwald
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d4b567fb87404a50bc2ad13d8c19f62b
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spelling	oai:doaj.org-article:d4b567fb87404a50bc2ad13d8c19f62b2021-11-18T08:33:53ZThe GSK3 signaling pathway is activated by cocaine and is critical for cocaine conditioned reward in mice.1932-620310.1371/journal.pone.0088026https://doaj.org/article/d4b567fb87404a50bc2ad13d8c19f62b2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24505362/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The Akt - GSK3 signaling pathway has been recently implicated in psychostimulant-induced behavioral and cellular effects. Here, the ability of cocaine to regulate the activity of Akt and GSK3 was investigated by measuring the phosphorylation states of the two kinases. The anatomical specificity of the response was determined, as was the contributions of dopamine and NMDA receptors to the actions of cocaine. As GSK3 activity was found to be increased by cocaine, subsequent experiments investigated the importance of GSK3 activation in cocaine conditioned reward. Adult male CD-1 mice were injected with cocaine or saline, and levels of phosphorylated Akt and GSK3α/β were measured 30 minutes later. Acute administration of cocaine significantly decreased the phosphorylation of Akt-Thr308 (pAkt-Thr308) and GSK3β in the caudate putamen and nucleus accumbens core, without altering pAkt-Ser473 and pGSK3α. To investigate the role of dopamine and NMDA receptors in the regulation of Akt and GSK3 by cocaine, specific receptor antagonists were administered prior to cocaine. Blockade of dopamine D2 receptors with eticlopride prevented the reduction of pAkt-Thr308 produced by cocaine, whereas antagonists at dopamine D1, dopamine D2 or glutamatergic NMDA receptors each blocked cocaine-induced reductions in pGSK3β. The potential importance of GSK3 activity in the rewarding actions of cocaine was determined using a cocaine conditioned place preference procedure. Administration of the selective GSK3 inhibitor, SB 216763, prior to cocaine conditioning sessions blocked the development of cocaine place preference. In contrast, SB 216763 did not alter the acquisition of a contextual fear conditioning response, demonstrating that SB 216763 did not globally inhibit contextual learning processes. The results of this study indicate that phosphorylation of GSK3β is reduced, hence GSK3β activity is increased following acute cocaine, an effect that is contingent upon both dopaminergic and glutamatergic receptors. Further, GSK3 activity is required for the development of cocaine conditioned reward.Jonathan S MillerJeffrey L BarrLauren J HarperRachel L PooleThomas J GouldEllen M UnterwaldPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 2, p e88026 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jonathan S Miller Jeffrey L Barr Lauren J Harper Rachel L Poole Thomas J Gould Ellen M Unterwald The GSK3 signaling pathway is activated by cocaine and is critical for cocaine conditioned reward in mice.
description	The Akt - GSK3 signaling pathway has been recently implicated in psychostimulant-induced behavioral and cellular effects. Here, the ability of cocaine to regulate the activity of Akt and GSK3 was investigated by measuring the phosphorylation states of the two kinases. The anatomical specificity of the response was determined, as was the contributions of dopamine and NMDA receptors to the actions of cocaine. As GSK3 activity was found to be increased by cocaine, subsequent experiments investigated the importance of GSK3 activation in cocaine conditioned reward. Adult male CD-1 mice were injected with cocaine or saline, and levels of phosphorylated Akt and GSK3α/β were measured 30 minutes later. Acute administration of cocaine significantly decreased the phosphorylation of Akt-Thr308 (pAkt-Thr308) and GSK3β in the caudate putamen and nucleus accumbens core, without altering pAkt-Ser473 and pGSK3α. To investigate the role of dopamine and NMDA receptors in the regulation of Akt and GSK3 by cocaine, specific receptor antagonists were administered prior to cocaine. Blockade of dopamine D2 receptors with eticlopride prevented the reduction of pAkt-Thr308 produced by cocaine, whereas antagonists at dopamine D1, dopamine D2 or glutamatergic NMDA receptors each blocked cocaine-induced reductions in pGSK3β. The potential importance of GSK3 activity in the rewarding actions of cocaine was determined using a cocaine conditioned place preference procedure. Administration of the selective GSK3 inhibitor, SB 216763, prior to cocaine conditioning sessions blocked the development of cocaine place preference. In contrast, SB 216763 did not alter the acquisition of a contextual fear conditioning response, demonstrating that SB 216763 did not globally inhibit contextual learning processes. The results of this study indicate that phosphorylation of GSK3β is reduced, hence GSK3β activity is increased following acute cocaine, an effect that is contingent upon both dopaminergic and glutamatergic receptors. Further, GSK3 activity is required for the development of cocaine conditioned reward.
format	article
author	Jonathan S Miller Jeffrey L Barr Lauren J Harper Rachel L Poole Thomas J Gould Ellen M Unterwald
author_facet	Jonathan S Miller Jeffrey L Barr Lauren J Harper Rachel L Poole Thomas J Gould Ellen M Unterwald
author_sort	Jonathan S Miller
title	The GSK3 signaling pathway is activated by cocaine and is critical for cocaine conditioned reward in mice.
title_short	The GSK3 signaling pathway is activated by cocaine and is critical for cocaine conditioned reward in mice.
title_full	The GSK3 signaling pathway is activated by cocaine and is critical for cocaine conditioned reward in mice.
title_fullStr	The GSK3 signaling pathway is activated by cocaine and is critical for cocaine conditioned reward in mice.
title_full_unstemmed	The GSK3 signaling pathway is activated by cocaine and is critical for cocaine conditioned reward in mice.
title_sort	gsk3 signaling pathway is activated by cocaine and is critical for cocaine conditioned reward in mice.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/d4b567fb87404a50bc2ad13d8c19f62b
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The GSK3 signaling pathway is activated by cocaine and is critical for cocaine conditioned reward in mice.

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