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Enhanced tyrosine hydroxylase phosphorylation in the nucleus accumbens and nucleus tractus solitarius-A2 cell group after morphine-conditioned place preference

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Abstract

Although dopamine (DA) has been extensively implicated in the morphine-induced conditioned place preference (CPP; a measure of reward), noradrenaline (NA) and other systems may play a larger role than previously suspected. The mesolimbic DA system, comprised of projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), receives noradrenergic innervations from the nucleus tractus solitaries (NTS)-A2 cell group and is modulated by NA. The purpose of the present study was to evaluate the turnover of DA and NA in the NAc and the site-specific phosphorylation of TH in the NAc, VTA, and NTS on the CPP mice conditioned by morphine. A dose–effect curve for morphine-induced CPP (0.5–8 mg/kg, s.c.) was obtained using 6-day conditioning sessions followed by a CPP test. TH phosphorylation was determined by quantitative blot immunolabeling and immunohistochemistry using phosphorylation state-specific antibodies; NA and DA turnover was evaluated by high-performance liquid chromatography. Morphine-induced CPP phosphorylates TH at serine (Ser)40 but not Ser31 in NAc, which is associated with an enhanced of DA and NA turnover. We also found that morphine-induced CPP increased levels of TH phosphorylated at Ser31 and Ser40 in the NTS. The present study demonstrates that morphine-induced CPP might stimulate TH activity and accelerate DA and NA turnover in the NAc via a mechanism involving phosphorylation of TH.

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References

  • Benoti-Marand M, Jaber M, Gonon F (2000) Release and elimination of dopamine in vivo in mice lacking the dopamine transporter: functional consequences. Eur J Neurosci 12:2985–2992

    Article  Google Scholar 

  • Berhow MT, Russell DS, Terwilliger RZ, Beitner-Johnson D, Self DW, Lindsay RM, Nestler EJ (1995) Influence of neurotrophic factors on morphine- and cocaine-induced biochemical changes in the mesolimbic dopamine system. Neuosci 68:969–979

    Article  CAS  Google Scholar 

  • Bobrovskaya L, Gilligan C, Bolster EK, Flaherty JJ, Dickson PW, Dunkley PR (2007) Sustained phosphorylation of tyrosine hydroxylase at serine 40: a novel mechanism for maintenance of catecholamine synthesis. J Neurochem 100:479–489

    Article  CAS  PubMed  Google Scholar 

  • Budygin EA, Brodie MS, Sotnikova TD, Mateo Y, John CE, Cyr M, Gainetdinov RR, Jones SR (2004) Dissociation of rewarding and dopamine transporter-mediated properties of amphetamine. Proc Natl Acad Sci USA 101:7781–7786

    Article  CAS  PubMed  Google Scholar 

  • Davis WM, Smith SG (1976) Role of conditioned reinforcers in the initiation, maintenance and extinction of drug-seeking behavior. Pavlov J Biol Sci 11:222–236

    CAS  PubMed  Google Scholar 

  • Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278

    Article  PubMed  Google Scholar 

  • Di Chiara G, North AR (1992) Neurobiology of opiate abuse. Trens Pharmacol Sci 13:185–193

    Article  Google Scholar 

  • Drouin C, Darracq L, Trovero F, Blanc G, Glowinski J, Cotecchia S, Tassin J-P (2002) alfa1b-Adrenergic receptors control locomotor and rewarding affects of psychostimulants and opiates. J Neurosci 22:2873–2884

    CAS  PubMed  Google Scholar 

  • Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki EI, Dickson PW (2004) Tyrosine hydroxylase phosphorylation: regulation and consequences. J Neurochem 91:1025–1043

    Article  CAS  PubMed  Google Scholar 

  • Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates, 3rd edn. Academic, San Diego

    Google Scholar 

  • Fuertes G, Laorden ML, Milanés MV (2000) Noradrenergic and dopaminergic activity in the hypothalamic paraventricular nucleus after naloxone-induced morphine withdrawal. Neuroendocrinology 71:60–67

    Article  CAS  PubMed  Google Scholar 

  • Gholami A, Haeri-Rohani A, Sahraie H, Zarrindast MR (2002) Nitric oxide mediation of morphine-induced place preference in the nucleus accumbens of rat. Eur J Pharmacol 449:269–277

    Article  CAS  PubMed  Google Scholar 

  • Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412:141–142

    Article  CAS  PubMed  Google Scholar 

  • Jasmin L, Narasaiah M, Tien D (2006) Noradrenaline is necessary for the hedonic properties of addictive drugs. Vascular Pharmacol 45:243–250

    Article  CAS  Google Scholar 

  • Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13:177–184

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, Sanna PP, Bloom FE (1998) Neuroscience of addiction. Neuron 21:467–476

    Article  CAS  PubMed  Google Scholar 

  • Laorden ML, Castells MT, Martínez MD, Martínez PJ, Milanés MV (2000) Activation of c-fos expression in hypothalamic nuclei by mu- and kappa-receptor agonists: correlation with catecholaminergic activity in the hypothalamic paraventricular nucleus. Endocrinology 141:1366–1376

    Article  CAS  PubMed  Google Scholar 

  • Leri F, Flores J, Rajabi H, Stewart J (2003) Effects of cocaine in rats exposed to heroin. Neuropharmacology 28:2102–2116

    CAS  Google Scholar 

  • Lett BT (1989) Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and cocaine. Psychopharmacology 98:357–362

    Article  CAS  PubMed  Google Scholar 

  • Ma YY, Meng L, Guo CHY, Han JS, lee D, Cui CL (2009) Dose- and time-dependent, context-induced elevation of dopamine and its metabolites in the nucleus accumbens of morphine-induced CPP rats. Behav Brain Res 204:192–199

    Article  CAS  PubMed  Google Scholar 

  • Maldonado R, Saiardi A, Valverde O, Samad TA, Roques BP, Borrelli E (1997) Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 388:586–589

    Article  CAS  PubMed  Google Scholar 

  • Manzanedo C, Aguilar MA, Rodriguez-Arias M, Miñarro J (2001) Effects of dopamine antagonists with different receptor blockade profiles on morphine-induced place preference in male mice. Behav Brain Res 121:189–197

    Article  CAS  PubMed  Google Scholar 

  • Meil WM, Schechter MD (1997) Olanzapine attenuates the reinforcing effects of cocaine. Eur J Pharmacol 340:17–26

    Article  CAS  PubMed  Google Scholar 

  • Milanés MV, Laorden ML, Chapleur-Chateau M, Burlet A (1998) Alterations in corticotrophin-releasing factor and vasopressin content in rat brain during morphine withdrawal: correlation with hypothalamic noradrenergic activity and pituitary–adrenal response. J Pharmacol Exp Ther 285:700–706

    PubMed  Google Scholar 

  • Moaddab M, Haghparast A, Hassanpour-Ezatti M (2009) Effects of reversible inactivation of the ventral tegmental area on the acquisition and expression of morphine-induced conditioned place preference in the rat. Behav Brain Res 198:466–471

    Article  CAS  PubMed  Google Scholar 

  • Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2:119–128

    Article  CAS  PubMed  Google Scholar 

  • Nuñez C, Laorden ML, Milanés MV (2007) Regulation of serine (Ser)-31 and Ser40 tyrosine hydroxylase phosphorylation during morphine withdrawal in the hypothalamic paraventricular nucleus and nucleus tractus solitarius-A2 cell group: Role of ERK1/2. Endocrinology 148:5780–5793

    Article  PubMed  Google Scholar 

  • O’Brien CP, Childress AR, McLellan AT, Ehrman R (1992) Classical conditioning in drug-dependent humans. Ann NY Acad Sci 654:400–415

    Article  PubMed  Google Scholar 

  • Olmstead MC, Franklin KB (1997) The development of a conditioned place preference to morphine: effects of microinjection into various CNS sites. Behav Neurosci 111:1324–1334

    Article  CAS  PubMed  Google Scholar 

  • Olson VG, Heusner CL, Bland RJ (2006) Role of noradrenergic signaling by the nucleus tractus solitarius in mediating opiate reward. Science 311:1017–1020

    Article  CAS  PubMed  Google Scholar 

  • Robinson TE, Berridge KC (2003) Addiction. Ann Rev Psychol 54:25–53

    Article  Google Scholar 

  • Sahraei H, Amiri YA, Haeri-Rohani A, Sepehri H, Salimi SH, Pourmotabbed A (2005) Different effects of GABAergic receptors located in the ventral tegmental area on the expression of morphine-induced conditioned place preference in rat. Eur J Pharmacol 524:95–100

    Article  CAS  PubMed  Google Scholar 

  • Salvatore MF, García-España A, Goldstein M, Deutch AY, Haykock JW (2000) Stoichiometry of tyrosine hydroxylase phosphorylation in the nigrostriatal and mesolimbic systems in vivo: effects of acute haloperidol and related compounds. J Neurochem 75:225–232

    Article  CAS  PubMed  Google Scholar 

  • Sharaei H, Ghazzaghi H, Zarrindast MR, Ghoshooni H, Sepehri H, Haeri-Rohan A (2004) The role of alpha adrenoreceptor mechanisms in morphine-induced conditioned place preference in female mice. Pharmacol Biochem Behav 78:135–141

    Article  Google Scholar 

  • Smith RJ, Aston-Jones G (2008) Noradrenergic transmission in the extended amygdale: role in increased drug-seeking and relapse during protracted drug abstinence. Brain Struct Funct 213:43–61

    Article  PubMed  Google Scholar 

  • Spanagel R, Almeida OF, Shippenberg TS (1993) Long lasting changes in morphine-induced mesolimbic dopamine release after chronic morphine exposure. Synapse 14:243–245

    Article  CAS  PubMed  Google Scholar 

  • Spielewoy C, Gonon F, Roubert C, Fauchey V, Jaber M, Caron MG, Roques BP, Hamon M, Betancur C, Maldonado R, Giros B (2000) Increased rewarding properties of morphine in dopamine-transporter knockout mice. Eur J Neurosci 12:1827–1837

    Article  CAS  PubMed  Google Scholar 

  • Tzschentke TM (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56:613–672

    Article  CAS  PubMed  Google Scholar 

  • Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227–462

    Article  CAS  PubMed  Google Scholar 

  • Tzschentke TM, Schmidt WJ (1995) N-Methyl-D-aspartic acid-receptor antagonists block morphine-induced conditioned place preference in rats. Neurosci Lett 193:37–40

    Article  CAS  PubMed  Google Scholar 

  • Valverde O, Fournie-Zaluski MC, Roques BP, Maldonado R (1996) The CCKB antagonist PD-134, 308 facilitates rewarding effects of endogenous enkephalins but does not induce place preference in rats. Psychopharmacology 123:119–126

    Article  CAS  PubMed  Google Scholar 

  • Ventura R, ALcaro A, Puglisi-Allegra S (2005) Prefrontal cortical norepinephrine release is critical for morphine-induced reward, reinstatement and dopamine release in the nucleus accumbens. Cereb Cortex 15:1877–1886

    Article  PubMed  Google Scholar 

  • Weinshenker D, Schroeder JP (2007) There and back again: a tale of norepinephrine and drug addiction. Neuropsychopharmacology 32:1433–1451

    Article  CAS  PubMed  Google Scholar 

  • Weitemer AZ, Murphy NP (2009) Accumbal dopamine and serotonin activity throughout acquisition and expression of place conditioning: correlative relationships with preference and aversion. Eur J Neurosci 29:1015–1026

    Article  Google Scholar 

  • Zachariou V, Liu R, LaPlant Q, Xiao G, Renthal W, Chan G, Storm DR, Aghajanian G, Nestler E (2008) Distinct roles of adenylyl cyclases 1 and 8 in opiate dependence: behavioral, electrophysiological, and molecular studies. Biol Psychiatry 63:1013–1021

    Article  CAS  PubMed  Google Scholar 

  • Zarrindast MR, Bahreini T, Adl M (2002) Effect of imipramine on the expression and acquisition of morphine-induced conditioned place preference in mice. Pharmacol Biochem Behav 73:941–949

    Article  CAS  PubMed  Google Scholar 

  • Zarrindast MR, Ebrahimi-Ghiri M, Rostami P, Rezayof A (2007) Repeated pre-exposure to morphine into the ventral pallidum enhances morphine-induced place preference: involvement of dopaminergic and opioidergic mechanisms. Behav Brain Res 181:35–41

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Ministerio de Educación y Ciencia (Grants SAF/FEDER 2007-62758, 2009-07178, and 2010-17907) and Red de Trastornos Adictivos (RD06/0001/1006).

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Authors and Affiliations

  1. Department of Nursing, Faculty of Medicine, University of Murcia, Campus de Espinardo, 30100, Murcia, Spain

    A. González-Cuello

  2. Department of Pharmacology, Faculty of Medicine, University of Murcia, Campus de Espinardo, 30100, Murcia, Spain

    L. Mora, J. M. Hidalgo, N. Meca, C. Lasheras, M. V. Milanés & M. L. Laorden

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  1. A. González-Cuello
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  2. L. Mora
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  3. J. M. Hidalgo
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  4. N. Meca
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  5. C. Lasheras
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  6. M. V. Milanés
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  7. M. L. Laorden
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Correspondence to M. L. Laorden.

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González-Cuello, A., Mora, L., Hidalgo, J.M. et al. Enhanced tyrosine hydroxylase phosphorylation in the nucleus accumbens and nucleus tractus solitarius-A2 cell group after morphine-conditioned place preference. Naunyn-Schmied Arch Pharmacol 382, 525–534 (2010). https://doi.org/10.1007/s00210-010-0567-9

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  • DOI: https://doi.org/10.1007/s00210-010-0567-9

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