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Social Isolation in Male Rats During Adolescence Inhibits the Wnt/β-Catenin Pathway in the Prefrontal Cortex and Enhances Anxiety and Cocaine-Induced Plasticity in Adulthood

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Abstract

In adult animals, it is well established that stress has a proactive effect on psychostimulant responses. However, whether only a short period of stress during adolescence can also affect cocaine responses later in life and what mechanisms are involved are unknown. Here, we showed that 5 days of social isolation during rat adolescence had a long-term impact on anxiety-like behaviors, cocaine-induced conditioned place preference, and the expression of sensitization during adulthood. At the molecular level, social isolation decreased the activity of the Wnt/β-catenin pathway in the prefrontal cortex (PFC). Furthermore, after the expression of cocaine sensitization, isolated rats showed an increase in this pathway in the nucleus accumbens. Together, these findings suggest that, adolescent social isolation by altering the Wnt/β-catenin pathway in the developing PFC might increase the cocaine responses during adulthood, introducing this pathway as a novel neuroadaptation in the cortical-accumbens connection that may mediate a stress-induced increase in vulnerability to drugs.

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References

  1. van Duijvenvoorde ACK, Peters S, Braams BR, Crone EA. What motivates adolescents? Neural responses to rewards and their influence on adolescents’ risk taking, learning, and cognitive control. Neurosci Biobehav Rev 2016, 70: 135–147.

    Article  PubMed  Google Scholar 

  2. Caballero A, Granberg R, Tseng KY. Mechanisms contributing to prefrontal cortex maturation during adolescence. Neurosci Biobehav Rev 2016, 70: 4–12.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lin Y, Li M, Zhou Y, Deng W, Ma X, Wang Q, et al. Age-related reduction in cortical thickness in first-episode treatment-naive patients with schizophrenia. Neurosci Bull 2019, 35: 688–696.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Fuhrmann D, Knoll LJ, Blakemore SJ. Adolescence as a sensitive period of brain development. Trends Cogn Sci 2015, 19: 558–566.

    Article  PubMed  Google Scholar 

  5. Braun K, Bock J. The experience-dependent maturation of prefronto-limbic circuits and the origin of developmental psychopathology: implications for the pathogenesis and therapy of behavioural disorders. Dev Med Child Neurol 2011, 53 Suppl 4: 14–18.

    Article  PubMed  Google Scholar 

  6. Cacioppo JT, Hawkley LC. Perceived social isolation and cognition. Trends Cogn Sci 2009, 13: 447–454.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Baarendse PJ, Counotte DS, O’Donnell P, Vanderschuren LJ. Early social experience is critical for the development of cognitive control and dopamine modulation of prefrontal cortex function. Neuropsychopharmacology 2013, 38: 1485–1494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Burke AR, McCormick CM, Pellis SM, Lukkes JL. Impact of adolescent social experiences on behavior and neural circuits implicated in mental illnesses. Neurosci Biobehav Rev 2017, 76: 280–300.

    Article  PubMed  Google Scholar 

  9. Burke AR, Miczek KA. Stress in adolescence and drugs of abuse in rodent models: role of dopamine, CRF, and HPA axis. Psychopharmacology (Berl) 2014, 231: 1557–1580.

    Article  CAS  Google Scholar 

  10. Fosnocht AQ, Lucerne KE, Ellis AS, Olimpo NA, Briand LA. Adolescent social isolation increases cocaine seeking in male and female mice. Behav Brain Res 2019, 359: 589–596.

    Article  CAS  PubMed  Google Scholar 

  11. Baarendse PJ, Limpens JH, Vanderschuren LJ. Disrupted social development enhances the motivation for cocaine in rats. Psychopharmacology (Berl) 2014, 231: 1695–1704.

    Article  CAS  Google Scholar 

  12. Karkhanis AN, Leach AC, Yorgason JT, Uneri A, Barth S, Niere F, et al. Chronic social isolation stress during peri-adolescence alters presynaptic dopamine terminal dynamics via augmentation in accumbal dopamine availability. ACS Chem Neurosci 2019, 10: 2033–2044.

    Article  CAS  PubMed  Google Scholar 

  13. Yajie D, Lin K, Baoming L, Lan M. Enhanced cocaine self-administration in adult rats with adolescent isolation experience. Pharmacol Biochem Behav 2005, 82: 673–677.

    Article  CAS  Google Scholar 

  14. Phillips GD, Howes SR, Whitelaw RB, Robbins TW, Everitt BJ. Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbens d-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists. Psychopharmacology (Berl) 1994, 115: 419–429.

    Article  CAS  Google Scholar 

  15. Leussis MP, Andersen SL. Is adolescence a sensitive period for depression? Behavioral and neuroanatomical findings from a social stress model. Synapse 2008, 62: 22–30.

    Article  CAS  PubMed  Google Scholar 

  16. Leussis MP, Lawson K, Stone K, Andersen SL. The enduring effects of an adolescent social stressor on synaptic density, part II: poststress reversal of synaptic loss in the cortex by adinazolam and MK-801. Synapse 2008, 62: 185–192.

    Article  CAS  PubMed  Google Scholar 

  17. McCormick CM, Robarts D, Kopeikina K, Kelsey JE. Long-lasting, sex- and age-specific effects of social stressors on corticosterone responses to restraint and on locomotor responses to psychostimulants in rats. Horm Behav 2005, 48: 64–74.

    Article  CAS  PubMed  Google Scholar 

  18. McCormick CM, Smith C, Mathews IZ. Effects of chronic social stress in adolescence on anxiety and neuroendocrine response to mild stress in male and female rats. Behav Brain Res 2008, 187: 228–238.

    Article  CAS  PubMed  Google Scholar 

  19. Dias C, Feng J, Sun H, Shao NY, Mazei-Robison MS, Damez-Werno D, et al. beta-catenin mediates stress resilience through Dicer1/microRNA regulation. Nature 2014, 516: 51–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wilkinson MB, Dias C, Magida J, Mazei-Robison M, Lobo M, Kennedy P, et al. A novel role of the WNT-dishevelled-GSK3beta signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. J Neurosci 2011, 31: 9084–9092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 2013, 13: 11–26.

    Article  CAS  PubMed  Google Scholar 

  22. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell 2012, 149: 1192–1205.

    Article  CAS  PubMed  Google Scholar 

  23. Oliva CA, Vargas JY, Inestrosa NC. Wnts in adult brain: from synaptic plasticity to cognitive deficiencies. Front Cell Neurosci 2013, 7: 224.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Nusse R, Clevers H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell 2017, 169: 985–999.

    Article  CAS  PubMed  Google Scholar 

  25. Metcalfe C, Bienz M. Inhibition of GSK3 by Wnt signalling–two contrasting models. J Cell Sci 2011, 124: 3537–3544.

    Article  CAS  PubMed  Google Scholar 

  26. Maguschak KA, Ressler KJ. The dynamic role of beta-catenin in synaptic plasticity. Neuropharmacology 2012, 62: 78–88.

    Article  CAS  PubMed  Google Scholar 

  27. Alimohamad H, Rajakumar N, Seah YH, Rushlow W. Antipsychotics alter the protein expression levels of beta-catenin and GSK-3 in the rat medial prefrontal cortex and striatum. Biol Psychiatry 2005, 57: 533–542.

    Article  CAS  PubMed  Google Scholar 

  28. Alimohamad H, Sutton L, Mouyal J, Rajakumar N, Rushlow WJ. The effects of antipsychotics on beta-catenin, glycogen synthase kinase-3 and dishevelled in the ventral midbrain of rats. J Neurochem 2005, 95: 513–525.

    Article  CAS  PubMed  Google Scholar 

  29. Sutton LP, Rushlow WJ. Regulation of Akt and Wnt signaling by the group II metabotropic glutamate receptor antagonist LY341495 and agonist LY379268. J Neurochem 2011, 117: 973–983.

    Article  CAS  PubMed  Google Scholar 

  30. Cuesta S, Batuecas J, Severin MJ, Funes A, Rosso SB, Pacchioni AM. Role of Wnt/beta-catenin pathway in the nucleus accumbens in long-term cocaine-induced neuroplasticity: a possible novel target for addiction treatment. J Neurochem 2017, 140: 114–125.

    Article  CAS  PubMed  Google Scholar 

  31. Cuesta S, Severin MJ, Batuecas J, Rosso SB, Pacchioni AM. Wnt/beta-catenin pathway in the prefrontal cortex is required for cocaine-induced neuroadaptations. Addict Biol 2017, 22: 933–945.

    Article  CAS  PubMed  Google Scholar 

  32. Hiroi R, Neumaier JF. Differential effects of ovarian steroids on anxiety versus fear as measured by open field test and fear-potentiated startle. Behav Brain Res 2006, 166: 93–100.

    Article  CAS  PubMed  Google Scholar 

  33. Steketee JD, Kalivas PW. Drug wanting: behavioral sensitization and relapse to drug-seeking behavior. Pharmacol Rev 2011, 63: 348–365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pierce RC, Kalivas PW. A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Brain Res Rev 1997, 25: 192–216.

    Article  CAS  PubMed  Google Scholar 

  35. Pierce RC, Bell K, Duffy P, Kalivas PW. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J Neurosci 1996, 16: 1550–1560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pacchioni AM, Vallone J, Worley PF, Kalivas PW. Neuronal pentraxins modulate cocaine-induced neuroadaptations. J Pharmacol Exp Ther 2009, 328: 183–192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bardo M, Bevins R. Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology 2000, 153: 31–43.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  39. Cui X, Li J, Li T, Ji F, Bu X, Zhang N, et al. Propofol and ketamine-induced anesthetic depth-dependent decrease of CaMKII phosphorylation levels in rat hippocampus and cortex. J Neurosurg Anesthesiol 2009, 21: 145–154.

    Article  PubMed  Google Scholar 

  40. Tedesco V, Ravagnani C, Bertoglio D, Chiamulera C. Acute ketamine-induced neuroplasticity: ribosomal protein S6 phosphorylation expression in drug addiction-related rat brain areas. Neuroreport 2013, 24: 388–393.

    Article  CAS  PubMed  Google Scholar 

  41. Silva Pereira V, Elfving B, Joca SRL, Wegener G. Ketamine and aminoguanidine differentially affect Bdnf and Mtor gene expression in the prefrontal cortex of adult male rats. Eur J Pharmacol 2017, 815: 304–311.

    Article  PubMed  CAS  Google Scholar 

  42. Li Y, Xu J, Xu Y, Zhao XY, Liu Y, Wang J, et al. Regulatory effect of general anesthetics on activity of potassium channels. Neurosci Bull 2018, 34: 887–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Heffner TG, Hartman JA, Seiden LS. A rapid method for the regional dissection of the rat brain. Pharmacol Biochem Behav 1980, 13: 453–456.

    Article  CAS  PubMed  Google Scholar 

  44. Naneix F, Marchand AR, Di Scala G, Pape JR, Coutureau E. Parallel maturation of goal-directed behavior and dopaminergic systems during adolescence. J Neurosci 2012, 32: 16223–16232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pelloux Y, Costentin J, Duterte-Boucher D. Anxiety increases the place conditioning induced by cocaine in rats. Behav Brain Res 2009, 197: 311–316.

    Article  CAS  PubMed  Google Scholar 

  46. Andersen SL, Teicher MH. Desperately driven and no brakes: Developmental stress exposure and subsequent risk for substance abuse. Neurosci Biobehav Rev 2009, 33: 516–524.

    Article  PubMed  Google Scholar 

  47. Spear LP. Adolescent brain development and animal models. Ann N Y Acad Sci 2004, 1021: 23–26.

    Article  PubMed  Google Scholar 

  48. Ren X, Rizavi HS, Khan MA, Dwivedi Y, Pandey GN. Altered Wnt signalling in the teenage suicide brain: focus on glycogen synthase kinase-3beta and beta-catenin. Int J Neuropsychopharmacol 2013, 16: 945–955.

    Article  CAS  PubMed  Google Scholar 

  49. Dickins EM, Salinas PC. Wnts in action: from synapse formation to synaptic maintenance. Front Cell Neurosci 2013, 7: 162.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Abercrombie ED, Keefe KA, DiFrischia DS, Zigmond MJ. Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex. J Neurochem 1989, 52: 1655–1658.

    Article  CAS  PubMed  Google Scholar 

  51. Cabib S, Puglishi-Allegra S. Different effects of repeated stressful experiences on mesocortical and mesolimbic dopamine metabolism. Neuroscience 1996, 73: 375–380.

    Article  CAS  PubMed  Google Scholar 

  52. Ball TM, Ramsawh HJ, Campbell-Sills L, Paulus MP, Stein MB. Prefrontal dysfunction during emotion regulation in generalized anxiety and panic disorders. Psychol Med 2013, 43: 1475–1486.

    Article  PubMed  Google Scholar 

  53. Page CE, Coutellier L. Adolescent stress disrupts the maturation of anxiety-related behaviors and alters the developmental trajectory of the prefrontal cortex in a sex- and age-specific manner. Neuroscience 2018, 390: 265–277.

    Article  CAS  PubMed  Google Scholar 

  54. Ladron de Guevara-Miranda D, Pavon FJ, Serrano A, Rivera P, Estivill-Torrus G, Suarez J, et al. Cocaine-conditioned place preference is predicted by previous anxiety-like behavior and is related to an increased number of neurons in the basolateral amygdala. Behav Brain Res 2016, 298: 35–43.

  55. Prast JM, Schardl A, Sartori SB, Singewald N, Saria A, Zernig G. Increased conditioned place preference for cocaine in high anxiety related behavior (HAB) mice is associated with an increased activation in the accumbens corridor. Front Behav Neurosci 2014, 8: 441.

    PubMed  PubMed Central  Google Scholar 

  56. Dias C, Dietz D, Mazei-Robison M, Sun H, Damez-Werno D, Ferguson D, et al. Dishevelled-2 regulates cocaine-induced structural plasticity and Rac1 activity in the nucleus accumbens. Neurosci Lett 2015, 598: 23–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mathews IZ, Mills RG, McCormick CM. Chronic social stress in adolescence influenced both amphetamine conditioned place preference and locomotor sensitization. Dev Psychobiol 2008, 50: 451–459.

    Article  CAS  PubMed  Google Scholar 

  58. Burke AR, Watt MJ, Forster GL. Adolescent social defeat increases adult amphetamine conditioned place preference and alters D2 dopamine receptor expression. Neuroscience 2011, 197: 269–279.

    Article  CAS  PubMed  Google Scholar 

  59. Cunningham CL, Ferree NK, Howard MA. Apparatus bias and place conditioning with ethanol in mice. Psychopharmacology (Berl) 2003, 170: 409–422.

    Article  CAS  Google Scholar 

  60. DeVries AC, Pert A. Conditioned increases in anxiogenic-like behavior following exposure to contextual stimuli associated with cocaine are mediated by corticotropin-releasing factor. Psychopharmacology (Berl) 1998, 137: 333–340.

    Article  CAS  Google Scholar 

  61. Miczek KA, Yap JJ, Covington HE, 3rd. Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake. Pharmacol Ther 2008, 120: 102–128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Florencia Cerchiara and Patricia Rivera Podesta for their assistance with technical English. This work was supported by Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, PIP 112-201001-00243), Secretaría de Ciencia, Tecnología e Innovación Productiva de la Prov. Santa Fe (SeCTeI, 2010-058-12), and Universidad Nacional de Rosario (UNR, BIO 295).

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  1. Santiago Cuesta

    Present address: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

Authors and Affiliations

  1. Área Toxicología, Departamento de Ciencias de los Alimentos y del Medioambiente, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000, Rosario, Santa Fe, Argentina

    Santiago Cuesta, Alejandrina Funes & Alejandra M. Pacchioni

  2. Consejo Nacional de Investigaciones Científicas y Técnicas, Rosario, Argentina

    Santiago Cuesta, Alejandrina Funes & Alejandra M. Pacchioni

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  1. Santiago Cuesta
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  2. Alejandrina Funes
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Correspondence to Alejandra M. Pacchioni.

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Cuesta, S., Funes, A. & Pacchioni, A.M. Social Isolation in Male Rats During Adolescence Inhibits the Wnt/β-Catenin Pathway in the Prefrontal Cortex and Enhances Anxiety and Cocaine-Induced Plasticity in Adulthood. Neurosci. Bull. 36, 611–624 (2020). https://doi.org/10.1007/s12264-020-00466-x

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