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Decreased prefrontal cortex dopamine activity following adolescent social defeat in male rats: role of dopamine D2 receptors

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Abstract

Rationale

Adverse social experience in adolescence causes reduced medial prefrontal cortex (mPFC) dopamine (DA) and associated behavioral deficits in early adulthood.

Objective

This study aims to determine whether mPFC DA hypofunction following social stress is specific to adolescent experience and if this results from stress-induced DA D2 receptor activation.

Materials and methods

Male rats exposed to repeated social defeat during adolescence or adulthood had mPFC DA activity sampled 17 days later. Separate experiments used freely moving microdialysis to measure mPFC DA release in response to adolescent defeat exposure. At P40, 49 and 56 mPFC DA turnover was assessed to identify when DA activity decreased in relation to the adolescent defeat experience. Finally, nondefeated adolescent rats received repeated intra-mPFC infusions of the D2 receptor agonist quinpirole, while another adolescent group received intra-mPFC infusions of the D2 antagonist amisulpride before defeat exposure.

Results

Long-term decreases or increases in mPFC DA turnover were observed following adolescent or adult defeat, respectively. Adolescent defeat exposure elicits sustained increases in mPFC DA release, and DA turnover remains elevated beyond the stress experience before declining to levels below normal at P56. Activation of mPFC D2 receptors in nondefeated adolescents decreases DA activity in a similar manner to that caused by adolescent defeat, while defeat-induced reductions in mPFC DA activity are prevented by D2 receptor blockade.

Conclusions

Both the developing and mature PFC DA systems are vulnerable to social stress, but only adolescent defeat causes DA hypofunction. This appears to result in part from stress-induced activation of mPFC D2 autoreceptors.

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References

  • Andersen SL (2003) Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev 27:3–18

    Article  PubMed  Google Scholar 

  • Andersen SL, Teicher MH (2008) Stress, sensitive periods and maturational events in adolescent depression. Trends Neurosci 31:183–191

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

  • Andersen SL, Dumont NL, Teicher MH (1997) Developmental differences in dopamine synthesis inhibition by (+/−)-7-OH-DPAT. Naunyn Schmiedebergs Arch Pharmacol 356:173–181

    Article  PubMed  CAS  Google Scholar 

  • Andersen SL, Thompson AT, Rutstein M, Hostetter JC, Teicher MH (2000) Dopamine receptor pruning in prefrontal cortex during the periadolescent period in rats. Synapse 37:167–169

    Article  PubMed  CAS  Google Scholar 

  • Barik S, de Beaurepaire R (1996) Evidence for a functional role of the dopamine D3 receptors in the cerebellum. Brain Res 737:347–350

    Article  PubMed  CAS  Google Scholar 

  • Barr JL, Forster GL (2011) Serotonergic neurotransmission in the ventral hippocampus is enhanced by corticosterone and altered by chronic amphetamine treatment. Neuroscience 182:105–114

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B et al (2006) Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry 60:1111–1120

    Article  PubMed  CAS  Google Scholar 

  • Beyer CE, Steketee JD (1999) Dopamine depletion in the medial prefrontal cortex induces sensitized-like behavioral and neurochemical responses to cocaine. Brain Res 833:133–141

    Article  PubMed  CAS  Google Scholar 

  • Brenhouse HC, Sonntag KC, Andersen SL (2008) Transient D1 dopamine receptor expression on prefrontal cortex projection neurons: relationship to enhanced motivational salience of drug cues in adolescence. J Neurosci 28:2375–2382

    Article  PubMed  CAS  Google Scholar 

  • Brown TE (2008) ADD/ADHD and impaired executive function in clinical practice. Curr Psychiatry Rep 10:407–411

    Article  PubMed  Google Scholar 

  • Brunstein Klomek A, Marrocco F, Kleinman M, Schonfeld IS, Gould MS (2007) Bullying, depression, and suicidality in adolescents. J Am Acad Child Adolesc Psychiatry 46:40–49

    Article  PubMed  Google Scholar 

  • Burke AR, Renner KJ, Forster GL, Watt MJ (2010) Adolescent social defeat alters neural, endocrine and behavioral responses to amphetamine in adult male rats. Brain Res 1352:147–156

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Burke AR, Forster GL, Novick AM, Roberts CL, Watt MJ (2013) Effects of adolescent social defeat on adult amphetamine-induced locomotion and corticoaccumbal dopamine release in male rats. Neuropharmacology 67:357–369

    Article  CAS  Google Scholar 

  • Cenci MA, Kalen P, Mandel RJ, Bjorklund A (1992) Regional differences in the regulation of dopamine and noradrenaline release in medial frontal cortex, nucleus accumbens and caudate-putamen: a microdialysis study in the rat. Brain Res 581:217–228

    Article  PubMed  CAS  Google Scholar 

  • Coppens CM, Siripornmongcolchai T, Wibrand K, Alme MN, Buwalda B, de Boer SF, Koolhaas JM, Bramham CR (2011) Social defeat during adolescence and adulthood differentially induce BDNF-regulated immediate early genes. Front Behav Neurosci 5:72

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Covington HE 3rd, Miczek KA (2005) Intense cocaine self-administration after episodic social defeat stress, but not after aggressive behavior: dissociation from corticosterone activation. Psychopharmacology 183:331–340

    Article  PubMed  CAS  Google Scholar 

  • Crone EA, Dahl RE (2012) Understanding adolescence as a period of social-affective engagement and goal flexibility. Nat Rev Neurosci 13:636–650

    Article  PubMed  CAS  Google Scholar 

  • Doherty MD, Gratton A (1999) Effects of medial prefrontal cortical injections of GABA receptor agonists and antagonists on the local and nucleus accumbens dopamine responses to stress. Synapse 32:288–300

    Article  PubMed  CAS  Google Scholar 

  • Douglas LA, Varlinskaya EI, Spear LP (2004) Rewarding properties of social interactions in adolescent and adult male and female rats: impact of social versus isolate housing of subjects and partners. Dev Psychobiol 45:153–162

    Article  PubMed  Google Scholar 

  • Everitt BJ, Wolf ME (2002) Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22:3312–3320

    PubMed  CAS  Google Scholar 

  • Fernandez Espejo E (2003) Prefrontocortical dopamine loss in rats delays long-term extinction of contextual conditioned fear, and reduces social interaction without affecting short-term social interaction memory. Neuropsychopharmacology 28:490–498

    Article  PubMed  CAS  Google Scholar 

  • Floresco SB, Magyar O (2006) Mesocortical dopamine modulation of executive functions: beyond working memory. Psychopharmacology 188:567–585

    Article  PubMed  CAS  Google Scholar 

  • Galloway MP, Wolf ME, Roth RH (1986) Regulation of dopamine synthesis in the medial prefrontal cortex is mediated by release modulating autoreceptors: studies in vivo. J Pharmacol Exp Ther 236:689–698

    PubMed  CAS  Google Scholar 

  • Hawker DS, Boulton MJ (2000) Twenty years’ research on peer victimization and psychosocial maladjustment: a meta-analytic review of cross-sectional studies. J Child Psychol Psychiatry 41:441–455

    Article  PubMed  CAS  Google Scholar 

  • Holmberg K, Hjern A (2008) Bullying and attention-deficit-hyperactivity disorder in 10-year-olds in a Swedish community. Dev Med Child Neurol 50:134–138

    Article  PubMed  Google Scholar 

  • Kalivas PW, Volkow N, Seamans J (2005) Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45:647–650

    Article  PubMed  CAS  Google Scholar 

  • Kalsbeek A, Voorn P, Buijs RM, Pool CW, Uylings HB (1988) Development of the dopaminergic innervation in the prefrontal cortex of the rat. J Comp Neurol 269:58–72

    Article  PubMed  CAS  Google Scholar 

  • Kaltiala-Heino R, Rimpela M, Rantanen P, Rimpela A (2000) Bullying at school—an indicator of adolescents at risk for mental disorders. J Adolesc 23:661–674

    Article  PubMed  CAS  Google Scholar 

  • Kim SY, Choi KC, Chang MS, Kim MH, Kim SY, Na YS, Lee JE, Jin BK, Lee BH, Baik JH (2006) The dopamine D2 receptor regulates the development of dopaminergic neurons via extracellular signal-regulated kinase and Nurr1 activation. J Neurosci 26:4567–4576

    Article  PubMed  CAS  Google Scholar 

  • Leussis MP, Lawson K, Stone K, Andersen SL (2008) 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 62:185–192

    Article  PubMed  CAS  Google Scholar 

  • Lewis DA (1997) Development of the prefrontal cortex during adolescence: insights into vulnerable neural circuits in schizophrenia. Neuropsychopharmacology 16:385–398

    Article  PubMed  CAS  Google Scholar 

  • Lucas LR, Celen Z, Tamashiro KL, Blanchard RJ, Blanchard DC, Markham C, Sakai RR, McEwen BS (2004) Repeated exposure to social stress has long-term effects on indirect markers of dopaminergic activity in brain regions associated with motivated behavior. Neuroscience 124:449–457

    Article  PubMed  CAS  Google Scholar 

  • Lyss PJ, Andersen SL, LeBlanc CJ, Teicher MH (1999) Degree of neuronal activation following FG-7142 changes across regions during development. Brain Res 116:201–203

    Article  CAS  Google Scholar 

  • MacLennan AJ, Pelleymounter MA, Atmadja S, Jakubovic A, Maier SF, Fibiger HC (1989) D2 dopamine receptors in the rat prefrontal cortex: characterization and alteration by stress. Brain Res 477:300–307

    Article  PubMed  CAS  Google Scholar 

  • Majer M, Nater UM, Lin JM, Capuron L, Reeves WC (2010) Association of childhood trauma with cognitive function in healthy adults: a pilot study. BMC Neurol 10:61

    Article  PubMed Central  PubMed  Google Scholar 

  • Mathews IZ, McCormick CM (2012) Role of medial prefrontal cortex dopamine in age differences in response to amphetamine in rats: locomotor activity after intra-mPFC injections of dopaminergic ligands. Dev Neurobiol 72:1415–1421

    Article  PubMed  CAS  Google Scholar 

  • McCormick CM, Robarts D, Kopeikina K, Kelsey JE (2005) 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 48:64–74

    Article  PubMed  CAS  Google Scholar 

  • McCormick CM, Thomas CM, Sheridan CS, Nixon F, Flynn JA, Mathews IZ (2012) Social instability stress in adolescent male rats alters hippocampal neurogenesis and produces deficits in spatial location memory in adulthood. Hippocampus 22:1300–1312

    Article  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Miczek KA, Nikulina EM, Shimamoto A, Covington HE 3rd (2011) Escalated or suppressed cocaine reward, tegmental BDNF, and accumbal dopamine caused by episodic versus continuous social stress in rats. J Neurosci 31:9848–9857

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Morrissey MD, Mathews IZ, McCormick CM (2011) Enduring deficits in contextual and auditory fear conditioning after adolescent, not adult, social instability stress in male rats. Neurobiol Learn Mem 95:46–56

    Article  PubMed  Google Scholar 

  • Morrow BA, Elsworth JD, Rasmusson AM, Roth RH (1999) The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat. Neuroscience 92:553–564

    Article  PubMed  CAS  Google Scholar 

  • Nikulina EM, Covington HE 3rd, Ganschow L, Hammer RP Jr, Miczek KA (2004) Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala. Neuroscience 123:857–865

    Article  PubMed  CAS  Google Scholar 

  • Novick AM, Forster GL, Tejani-Butt SM, Watt MJ (2011) Adolescent social defeat alters markers of adult dopaminergic function. Brain Res Bull 86:123–128

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Novick AM, Scholl JL, Roberts CL, Hassell J, Tejani-Butt SM, Forster GL, Watt MJ (2012) Altered prefrontal cortex dopamine transporter expression and function following adolescent social defeat. SFN Abstr 693:03

    Google Scholar 

  • Novick AM, Miiller LC, Forster GL, Watt MJ (2013) Adolescent social defeat decreases spatial working memory performance in adulthood. Behav Brain Funct 9:39

    Article  PubMed Central  PubMed  Google Scholar 

  • O’Donnell P (2010) Adolescent maturation of cortical dopamine. Neurotox Res 18:306–312

    Article  PubMed  CAS  Google Scholar 

  • Ozaki N, Nakahara D, Miura H, Kasahara Y, Nagatsu T (1989) Effects of apomorphine on in vivo release of dopamine and its metabolites in the prefrontal cortex and the striatum, studied by a microdialysis method. J Neurochem 53:1861–1864

    Article  PubMed  CAS  Google Scholar 

  • Pani L, Porcella A, Gessa GL (2000) The role of stress in the pathophysiology of the dopaminergic system. Mol Psychiatry 5:14–21

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic, New York

    Google Scholar 

  • Pezze MA, Feldon J (2004) Mesolimbic dopaminergic pathways in fear conditioning. Prog Neurobiol 74:301–320

    Article  PubMed  CAS  Google Scholar 

  • Robbins TW, Arnsten AF (2009) The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Annu Rev Neurosci 32:267–287

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Sacchetti P, Mitchell TR, Granneman JG, Bannon MJ (2001) Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism. J Neurochem 76:1565–1572

    Article  PubMed  CAS  Google Scholar 

  • Sandstrom NJ, Hart SR (2005) Isolation stress during the third postnatal week alters radial arm maze performance and corticosterone levels in adulthood. Behav Brain Res 156:289–296

    Article  PubMed  CAS  Google Scholar 

  • Scholl JL, Renner KJ, Forster GL, Tejani-Butt S (2010) Central monoamine levels differ between rat strains used in studies of depressive behavior. Brain Res 1355:41–51

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463

    Article  PubMed  CAS  Google Scholar 

  • Sterlemann V, Rammes G, Wolf M, Liebl C, Ganea K, Muller MB, Schmidt MV (2010) Chronic social stress during adolescence induces cognitive impairment in aged mice. Hippocampus 20:540–549

    PubMed  Google Scholar 

  • Talmaciu RK, Hoffmann IS, Cubeddu LX (1986) Dopamine autoreceptors modulate dopamine release from the prefrontal cortex. J Neurochem 47:865–870

    Article  PubMed  CAS  Google Scholar 

  • Tidey JW, Miczek KA (1996) Social defeat stress selectively alters mesocorticolimbic dopamine release: an in vivo microdialysis study. Brain Res 721:140–149

    Article  PubMed  CAS  Google Scholar 

  • Varlinskaya EI, Spear LP (2008) Social interactions in adolescent and adult Sprague–Dawley rats: impact of social deprivation and test context familiarity. Behav Brain Res 188:398–405

    Article  PubMed Central  PubMed  Google Scholar 

  • Ventura R, Alcaro A, Cabib S, Conversi D, Mandolesi L, Puglisi-Allegra S (2004) Dopamine in the medial prefrontal cortex controls genotype-dependent effects of amphetamine on mesoaccumbens dopamine release and locomotion. Neuropsychopharmacology 29:72–80

    Article  PubMed  CAS  Google Scholar 

  • Vidal J, Bie J, Granneman RA, Wallinga AE, Koolhaas JM, Buwalda B (2007) Social stress during adolescence in Wistar rats induces social anxiety in adulthood without affecting brain monoaminergic content and activity. Physiol Behav 92:824–830

    Article  PubMed  CAS  Google Scholar 

  • Watt MJ, Burke AR, Renner KJ, Forster GL (2009) Adolescent male rats exposed to social defeat exhibit altered anxiety behavior and limbic monoamines as adults. Behav Neurosci 123:564–576

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Wolf ME, Roth RH (1987) Dopamine neurons projecting to the medial prefrontal cortex possess release-modulating autoreceptors. Neuropharmacology 26:1053–1059

    Article  PubMed  CAS  Google Scholar 

  • Wolf ME, Galloway MP, Roth RH (1986) Regulation of dopamine synthesis in the medial prefrontal cortex: studies in brain slices. J Pharmacol Exp Ther 236:699–707

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by NSF IOS 1257679 (MJW), NIDA RO1 DA019921 (GLF), Joseph F. and Martha P. Nelson grants (AMN, KJR, and MJW), and NIH P20 RR015567, which is designated a Center of Biomedical Research Excellence (COBRE). The authors thank Kathryn Oliver, Eric Haaland, Mark Mingo, James Hassell, and Shaydie Engel for valuable technical assistance.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E Clark St, Vermillion, SD, 57069, USA

    Michael J. Watt, Christina L. Roberts, Jamie L. Scholl, Danielle L. Meyer, Leah C. Miiller, Jeffrey L. Barr, Andrew M. Novick, Kenneth J. Renner & Gina L. Forster

  2. Department of Pharmacology, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA

    Jeffrey L. Barr

  3. Department of Biology, University of South Dakota, Vermillion, SD, USA

    Kenneth J. Renner

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  1. Michael J. Watt
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  2. Christina L. Roberts
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  3. Jamie L. Scholl
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  4. Danielle L. Meyer
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  5. Leah C. Miiller
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  6. Jeffrey L. Barr
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  9. Gina L. Forster
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Correspondence to Michael J. Watt.

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Watt, M.J., Roberts, C.L., Scholl, J.L. et al. Decreased prefrontal cortex dopamine activity following adolescent social defeat in male rats: role of dopamine D2 receptors. Psychopharmacology 231, 1627–1636 (2014). https://doi.org/10.1007/s00213-013-3353-9

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