A Role for P38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2015 Mar 1

PMID 25724654

Citations 16

Authors

Padmanabhan Mannangatti

Kamalakkannan NarasimhaNaidu

Mohamad Imad Damaj

Sammanda Ramamoorthy

Lankupalle Damodara Jayanthi

Affiliations

Soon will be listed here.

Abstract

The noradrenergic and p38 mitogen-activated protein kinase (p38 MAPK) systems are implicated in cocaine-elicited behaviors. Previously, we demonstrated a role for p38 MAPK-mediated norepinephrine transporter (NET) Thr(30) phosphorylation in cocaine-induced NET up-regulation (Mannangatti, P., Arapulisamy, O., Shippenberg, T. S., Ramamoorthy, S., and Jayanthi, L. D. (2011) J. Biol. Chem. 286, 20239-20250). The present study explored the functional interaction between p38 MAPK-mediated NET regulation and cocaine-induced behaviors. In vitro cocaine treatment of mouse prefrontal cortex synaptosomes resulted in enhanced NET function, surface expression, and phosphorylation. Pretreatment with PD169316, a p38 MAPK inhibitor, completely blocked cocaine-mediated NET up-regulation and phosphorylation. In mice, in vivo administration of p38 MAPK inhibitor SB203580 completely blocked cocaine-induced NET up-regulation and p38 MAPK activation in the prefrontal cortex and nucleus accumbens. When tested for cocaine-induced locomotor sensitization and conditioned place preference (CPP), mice receiving SB203580 on cocaine challenge day or on postconditioning test day exhibited significantly reduced cocaine sensitization and CPP. A transactivator of transcription (TAT) peptide strategy was utilized to test the involvement of the NET-Thr(30) motif. In vitro treatment of synaptosomes with TAT-NET-Thr(30) (wild-type peptide) completely blocked cocaine-mediated NET up-regulation and phosphorylation. In vivo administration of TAT-NET-Thr(30) peptide but not TAT-NET-T30A (mutant peptide) completely blocked cocaine-mediated NET up-regulation and phosphorylation. In the cocaine CPP paradigm, mice receiving TAT-NET-Thr(30) but not TAT-NET-T30A on postconditioning test day exhibited significantly reduced cocaine CPP. Following extinction, TAT-NET-Thr(30) when given prior to cocaine challenge significantly reduced reinstatement of cocaine CPP. These results demonstrate that the direct inhibition of p38 MAPK or the manipulation of NET-Thr(30) motif/phosphorylation via a TAT peptide strategy prevents cocaine-induced NET up-regulation, locomotor sensitization, and CPP, suggesting a role for Thr(30)-linked NET regulation in cocaine-elicited behaviors.

Citing Articles

Individual differences in cocaine-induced conditioned place preference in male rats: Behavioral and transcriptomic evidence.

Atehortua Martinez L, Curis E, Mekdad N, Larrieu C, Courtin C, Jourdren L J Psychopharmacol. 2022; 36(10):1161-1175.

PMID: 36121009 PMC: 9548661. DOI: 10.1177/02698811221123047.

Blunted Amphetamine-induced Reinforcing Behaviors and Transporter Downregulation in Knock-in Mice Carrying Alanine Mutations at Threonine-258 and Serine-259 of Norepinephrine Transporter.

Varman D, Mannangatti P, Subler M, Windle J, Ramamoorthy S, Jayanthi L J Mol Neurosci. 2022; 72(9):1965-1976.

PMID: 35852782 DOI: 10.1007/s12031-022-01988-x.

Neurokinin-1 Antagonism Distinguishes the Role of Norepinephrine Transporter from Dopamine Transporter in Mediating Amphetamine Behaviors.

Mannangatti P, Varman D, Ramamoorthy S, Jayanthi L Pharmacology. 2021; 106(11-12):597-605.

PMID: 34515205 PMC: 8578286. DOI: 10.1159/000518033.

Activation of α7 nicotinic acetylcholine receptor ameliorates HIV-associated neurology and neuropathology.

Zhao X, Wilson K, Uteshev V, He J Brain. 2021; 144(11):3355-3370.

PMID: 34196664 PMC: 8677536. DOI: 10.1093/brain/awab251.

Novelty-induced hyperactivity and suppressed cocaine induced locomotor activation in mice lacking threonine 53 phosphorylation of dopamine transporter.

Varman D, Subler M, Windle J, Jayanthi L, Ramamoorthy S Behav Brain Res. 2021; 408:113267.

PMID: 33794225 PMC: 8117066. DOI: 10.1016/j.bbr.2021.113267.

References

Cao C, Shamoo A, Eldefrawi M . Cocaine-sensitive, ATP-dependent dopamine uptake into striatal synaptosomes. Biochem Pharmacol. 1990; 39(6):R9-14. DOI: 10.1016/0006-2952(90)90275-p. View

Jeannotte A, McCarthy J, Sidhu A . Desipramine induced changes in the norepinephrine transporter, alpha- and gamma-synuclein in the hippocampus, amygdala and striatum. Neurosci Lett. 2009; 467(2):86-9. PMC: 2783378. DOI: 10.1016/j.neulet.2009.10.010. View

Arai A, Tomiyama M, Kannari K, Kimura T, Suzuki C, Watanabe M . Reuptake of L-DOPA-derived extracellular DA in the striatum of a rodent model of Parkinson's disease via norepinephrine transporter. Synapse. 2008; 62(8):632-5. DOI: 10.1002/syn.20535. View

Brebner K, Wong T, Liu L, Liu Y, Campsall P, Gray S . Nucleus accumbens long-term depression and the expression of behavioral sensitization. Science. 2005; 310(5752):1340-3. DOI: 10.1126/science.1116894. View

Bruss M, Wieland A, Bonisch H . Molecular cloning and functional expression of the mouse dopamine transporter. J Neural Transm (Vienna). 2000; 106(7-8):657-62. DOI: 10.1007/s007020050187. View

Smith R, Lobo M, Spencer S, Kalivas P . Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways). Curr Opin Neurobiol. 2013; 23(4):546-52. PMC: 3681928. DOI: 10.1016/j.conb.2013.01.026. View

Murphy S, Frishman W . Protein kinase C in cardiac disease and as a potential therapeutic target. Cardiol Rev. 2004; 13(1):3-12. DOI: 10.1097/01.crd.0000124914.59755.8d. View

Itzhak Y, Anderson K . Changes in the magnitude of drug-unconditioned stimulus during conditioning modulate cocaine-induced place preference in mice. Addict Biol. 2011; 17(4):706-16. PMC: 3142301. DOI: 10.1111/j.1369-1600.2011.00334.x. View

Carboni E, Tanda G, Frau R, Di Chiara G . Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals. J Neurochem. 1990; 55(3):1067-70. DOI: 10.1111/j.1471-4159.1990.tb04599.x. View

10.

Kota D, Martin B, Robinson S, Damaj M . Nicotine dependence and reward differ between adolescent and adult male mice. J Pharmacol Exp Ther. 2007; 322(1):399-407. DOI: 10.1124/jpet.107.121616. View

11.

Volkow N, Wang G, Telang F, Fowler J, Logan J, Childress A . Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci. 2006; 26(24):6583-8. PMC: 6674019. DOI: 10.1523/JNEUROSCI.1544-06.2006. View

12.

Malhotra A, Begley R, Kang B, Rana I, Liu J, Yang G . PKC-{epsilon}-dependent survival signals in diabetic hearts. Am J Physiol Heart Circ Physiol. 2005; 289(4):H1343-50. DOI: 10.1152/ajpheart.01200.2004. View

13.

Valentini V, Frau R, Di Chiara G . Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine. J Neurochem. 2004; 88(4):917-27. DOI: 10.1046/j.1471-4159.2003.02238.x. View

14.

ONeill B, Tilley M, Han D, Thirtamara-Rajamani K, Hill E, Bishop G . Behavior of knock-in mice with a cocaine-insensitive dopamine transporter after virogenetic restoration of cocaine sensitivity in the striatum. Neuropharmacology. 2014; 79:626-33. PMC: 4011184. DOI: 10.1016/j.neuropharm.2013.12.023. View

15.

White F, Kalivas P . Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend. 1998; 51(1-2):141-53. DOI: 10.1016/s0376-8716(98)00072-6. View

16.

Moron J, Brockington A, Wise R, Rocha B, Hope B . Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci. 2002; 22(2):389-95. PMC: 6758674. View

17.

Fujita Y, Kunitachi S, Iyo M, Hashimoto K . The antibiotic minocycline prevents methamphetamine-induced rewarding effects in mice. Pharmacol Biochem Behav. 2012; 101(2):303-6. DOI: 10.1016/j.pbb.2012.01.005. View

18.

Olive M, McGeehan A, Kinder J, McMahon T, Hodge C, Janak P . The mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine decreases ethanol consumption via a protein kinase C epsilon-dependent mechanism. Mol Pharmacol. 2004; 67(2):349-55. DOI: 10.1124/mol.104.003319. View

19.

Cornish J, Kalivas P . Cocaine sensitization and craving: differing roles for dopamine and glutamate in the nucleus accumbens. J Addict Dis. 2001; 20(3):43-54. DOI: 10.1300/J069v20n03_05. View

20.

Tzschentke T, Schmidt W . Discrete quinolinic acid lesions of the rat prelimbic medial prefrontal cortex affect cocaine- and MK-801-, but not morphine- and amphetamine-induced reward and psychomotor activation as measured with the place preference conditioning paradigm. Behav Brain Res. 1998; 97(1-2):115-27. DOI: 10.1016/s0166-4328(98)00034-5. View