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Early social isolation stress increases addiction vulnerability to heroin and alters c-Fos expression in the mesocorticolimbic system

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Abstract

Rationale

Adverse psychosocial factors during early childhood or adolescence compromise neural structure and brain function, inducing susceptibility for many psychiatric disorders such as substance use disorder. Nevertheless, the mechanisms underlying early life stress-induced addiction vulnerability is still unclear, especially for opioids.

Objectives

To address this, we used a mouse heroin self-administration model to examine how chronic early social isolation (ESI) stress (5 weeks, beginning at weaning) affects the behavioral and neural responses to heroin during adulthood.

Results

We found that ESI stress did not alter the acquisition for sucrose or heroin self-administration, nor change the motivation for sucrose on a progressive ratio schedule. However, ESI stress induced an upward shift of heroin dose-response curve in female mice and increased motivation and seeking for heroin in both sexes. Furthermore, we examined the neuronal activity (measured by c-Fos expression) within the key brain regions of the mesocorticolimbic system, including the prelimbic cortex (PrL), infralimbic cortex (IL), nucleus accumbens (NAc) core and shell, caudate putamen, and ventral tegmental area (VTA). We found that ESI stress dampened c-Fos expression in the PrL, IL, and VTA after 14-day forced abstinence, while augmented the neuronal responses to heroin-predictive context and cue in the IL and NAc core. Moreover, ESI stress disrupted the association between c-Fos expression and attempted infusions during heroin-seeking test in the PrL.

Conclusions

These data indicate that ESI stress leads to increased seeking and motivation for heroin, and this may be associated with distinct changes in neuronal activities in different subregions of the mesocorticolimbic system.

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References

  • Anderson EM, Engelhardt A, D’emis S, Porath E, Hearing MC (2020) Sex-specific prefrontal cortex dysfunction underlying opioid-induced cognitive impairment. Bio-rxiv

  • Anglin MD, Hser YI, McGlothlin WH (1987) Sex differences in addict careers. 2. Becoming addicted. Am J Drug Alcohol Abuse 13:59–71

    Article  CAS  PubMed  Google Scholar 

  • Barrett AE, Turner RJ (2006) Family structure and substance use problems in adolescence and early adulthood: examining explanations for the relationship. Addiction 101:109–120

    Article  PubMed  Google Scholar 

  • Bossert JM, Adhikary S, St Laurent R, Marchant NJ, Wang HL, Morales M, Shaham Y (2016) Role of projections from ventral subiculum to nucleus accumbens shell in context-induced reinstatement of heroin seeking in rats. Psychopharmacology (Berl) 233:1991–2004

    Article  CAS  Google Scholar 

  • Bossert JM, Liu SY, Lu L, Shaham Y (2004) A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking. J Neurosci 24:10726–10730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bossert JM, Stern AL, Theberge FR, Cifani C, Koya E, Hope BT, Shaham Y (2011) Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin. Nat Neurosci 14:420–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bossert JM, Stern AL, Theberge FR, Marchant NJ, Wang HL, Morales M, Shaham Y (2012) Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking. J Neurosci 32:4982–4991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boyle AE, Gill K, Smith BR, Amit Z (1991) Differential effects of an early housing manipulation on cocaine-induced activity and self-administration in laboratory rats. Pharmacol Biochem Behav 39:269–274

    Article  CAS  PubMed  Google Scholar 

  • Bozarth MA, Murray A, Wise RA (1989) Influence of housing conditions on the acquisition of intravenous heroin and cocaine self-administration in rats. Pharmacol Biochem Behav 33:903–907

    Article  CAS  PubMed  Google Scholar 

  • Bullitt E (1990) Expression of c-fos-like protein as a marker for neuronal activity following noxious stimulation in the rat. J Comp Neurol 296:517–530

    Article  CAS  PubMed  Google Scholar 

  • Caruso MJ, Crowley NA, Reiss DE, Caulfield JI, Luscher B, Cavigelli SA, Kamens HM (2018) Adolescent social stress increases anxiety-like behavior and alters synaptic transmission, without influencing nicotine responses, in a sex-dependent manner. Neuroscience 373:182–198

    Article  CAS  PubMed  Google Scholar 

  • Chang L, Kigar SL, Ho JH, Cuarenta A, Gunderson HC, Baldo BA, Bakshi VP, Auger AP (2019) Early life stress alters opioid receptor mRNA levels within the nucleus accumbens in a sex-dependent manner. Brain Res 1710:102–108

    Article  CAS  PubMed  Google Scholar 

  • Chassin L, Mann LM, Sher KJ (1988) Self-awareness theory, family history of alcoholism, and adolescent alcohol involvement. J Abnorm Psychol 97:206–217

    Article  CAS  PubMed  Google Scholar 

  • Cortes-Patino DM, Serrano C, Garcia-Mijares M (2016) Early social isolation increases persistence of alcohol-seeking behavior in alcohol-related contexts. Behav Pharmacol 27:185–191

    Article  CAS  PubMed  Google Scholar 

  • Costa FM, Jessor R, Turbin MS (1999) Transition into adolescent problem drinking: the role of psychosocial risk and protective factors. J Stud Alcohol 60:480–490

    Article  CAS  PubMed  Google Scholar 

  • Cruz FC, Javier Rubio F, Hope BT (2015) Using c-fos to study neuronal ensembles in corticostriatal circuitry of addiction. Brain Res 1628:157–173

    Article  CAS  PubMed  Google Scholar 

  • Engeln M, Fox ME, Lobo MK (2021) Housing conditions during self-administration determine motivation for cocaine in mice following chronic social defeat stress. Psychopharmacology (Berl) 238:41–54

    Article  CAS  Google Scholar 

  • Fanous S, Goldart EM, Theberge FR, Bossert JM, Shaham Y, Hope BT (2012) Role of orbitofrontal cortex neuronal ensembles in the expression of incubation of heroin craving. J Neurosci 32:11600–11609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Fuchs RA, Evans KA, Parker MC, See RE (2004) Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 176:459–465

    Article  CAS  Google Scholar 

  • Fuchs RA, Lasseter HC, Ramirez DR, Xie X (2008) Relapse to drug seeking following prolonged abstinence: the role of environmental stimuli. Drug Discov Today Dis Models 5:251–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gancarz AM, Kausch MA, Lloyd DR, Richards JB (2012) Between-session progressive ratio performance in rats responding for cocaine and water reinforcers. Psychopharmacology (Berl) 222:215–223

    Article  CAS  Google Scholar 

  • Gancarz AM, Wang ZJ, Schroeder GL, Damez-Werno D, Braunscheidel KM, Mueller LE, Humby MS, Caccamise A, Martin JA, Dietz KC, Neve RL, Dietz DM (2015) Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity. Nat Neurosci 18:959–961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldstein RZ, Volkow ND (2011) Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nature Review Neuroscience 12(11):652–669. https://doi.org/10.1038/nrn3119

  • Gratton A, Sullivan RM (2005) Role of prefrontal cortex in stress responsivity. In Handbook of stress and the Brian, Elsevier Dusseldorf, p 1

    Google Scholar 

  • Gregg L, Barrowclough C, Haddock G (2007) Reasons for increased substance use in psychosis. Clin Psychol Rev 27:494–510

    Article  PubMed  Google Scholar 

  • Harvey BK, Hope BT, Shaham Y (2007) Tolerance to opiate reward: role of midbrain IRS2-Akt pathway. Nat Neurosci 10:9–10

    Article  CAS  PubMed  Google Scholar 

  • Hermes G, Li N, Duman C, Duman R (2011) Post-weaning chronic social isolation produces profound behavioral dysregulation with decreases in prefrontal cortex synaptic-associated protein expression in female rats. Physiol Behav 104:354–359

    Article  CAS  PubMed  Google Scholar 

  • Hodes GE, Pfau ML, Purushothaman I, Ahn HF, Golden SA, Christoffel DJ, Magida J, Brancato A, Takahashi A, Flanigan ME, Menard C, Aleyasin H, Koo JW, Lorsch ZS, Feng J, Heshmati M, Wang M, Turecki G, Neve R et al (2015) Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J Neurosci 35:16362–16376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944

    Article  CAS  PubMed  Google Scholar 

  • Howes SR, Dalley JW, Morrison CH, Robbins TW, Everitt BJ (2000) Leftward shift in the acquisition of cocaine self-administration in isolation-reared rats: relationship to extracellular levels of dopamine, serotonin and glutamate in the nucleus accumbens and amygdala-striatal FOS expression. Psychopharmacology (Berl) 151:55–63

    Article  CAS  Google Scholar 

  • Hser YI, Anglin MD, Booth MW (1987) Sex differences in addict careers. 3. Addiction. Am J Drug Alcohol Abuse 13:231–251

    Article  CAS  PubMed  Google Scholar 

  • Ito R, Robbins TW, Everitt BJ (2004) Differential control over cocaine-seeking behavior by nucleus accumbens core and shell. Nat Neurosci 7:389–397

    Article  CAS  PubMed  Google Scholar 

  • Krystal JH, D'Souza DC, Gallinat J, Driesen N, Abi-Dargham A, Petrakis I, Heinz A, Pearlson G (2006) The vulnerability to alcohol and substance abuse in individuals diagnosed with schizophrenia. Neurotox Res 10:235–252

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Dietz K, DeLoyht JM, Pedre X, Kelkar D, Kaur J, Vialou V, Lobo MK, Dietz DM, Nestler EJ, Dupree J, Casaccia P (2012) Impaired adult myelination in the prefrontal cortex of socially isolated mice. Nat Neurosci 15:1621–1623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu L, Shepard JD, Hall FS, Shaham Y (2003) Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review. Neurosci Biobehav Rev 27:457–491

    Article  CAS  PubMed  Google Scholar 

  • Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434–445

    Article  CAS  PubMed  Google Scholar 

  • Luscher C, Malenka RC (2011) Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69:650–663

    Article  PubMed  PubMed Central  Google Scholar 

  • Marks-Kaufman R, Lewis MJ (1984) Early housing experience modifies morphine self-administration and physical dependence in adult rats. Addict Behav 9:235–243

    Article  CAS  PubMed  Google Scholar 

  • Martin-Garcia E, Burokas A, Kostrzewa E, Gieryk A, Korostynski M, Ziolkowska B, Przewlocka B, Przewlocki R, Maldonado R (2011) New operant model of reinstatement of food-seeking behavior in mice. Psychopharmacology (Berl) 215:49–70

    Article  CAS  Google Scholar 

  • Martin JA, Caccamise A, Werner CT, Viswanathan R, Polanco JJ, Stewart AF, Thomas SA, Sim FJ, Dietz DM (2018) A novel role for oligodendrocyte precursor cells (OPCs) and Sox10 in mediating cellular and behavioral responses to heroin. Neuropsychopharmacology 43:1385–1394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin TJ, Walker LE, Sizemore GM, Smith JE, Dworkin SI (1996) Within-session determination of dose-response curves for heroin self-administration in rats: comparison with between-session determination and effects of naltrexone. Drug Alcohol Depend 41:93–100

    Article  CAS  PubMed  Google Scholar 

  • Melendez RI, Gregory ML, Bardo MT, Kalivas PW (2004) Impoverished rearing environment alters metabotropic glutamate receptor expression and function in the prefrontal cortex. Neuropsychopharmacology 29:1980–1987

    Article  CAS  PubMed  Google Scholar 

  • Mikics E, Guirado R, Umemori J, Toth M, Biro L, Miskolczi C, Balazsfi D, Zelena D, Castren E, Haller J, Karpova NN (2018) Social learning requires plasticity enhanced by fluoxetine through prefrontal Bdnf-TrkB signaling to limit aggression induced by post-weaning social isolation. Neuropsychopharmacology 43:235–245

    Article  CAS  PubMed  Google Scholar 

  • Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LT, Palmer A, Marshall JF (2000) Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 20:798–805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nestler EJ, Luscher C (2019) The molecular basis of drug addiction: linking epigenetic to synaptic and circuit mechanisms. Neuron 102:48–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Newcomb MD, Bentler PM (1988) Impact of adolescent drug use and social support on problems of young adults: a longitudinal study. J Abnorm Psychol 97:64–75

    Article  CAS  PubMed  Google Scholar 

  • Newcomb MD, Harlow LL (1986) Life events and substance use among adolescents: mediating effects of perceived loss of control and meaninglessness in life. J Pers Soc Psychol 51:564–577

    Article  CAS  PubMed  Google Scholar 

  • Ordones Sanchez E, Bavley CC, Deutschmann AU, Carpenter R, Peterson DR, Karbalaei R, Flowers J 2nd, Rogers CM, Langrehr MG, Ardekani CS, Famularo ST, Bongiovanni AR, Knouse MC, Floresco SB, Briand LA, Wimmer ME, Bangasser DA (2021) Early life adversity promotes resilience to opioid addiction-related phenotypes in male rats and sex-specific transcriptional changes. Proc Natl Acad Sci U S A:118

  • Paus T, Keshavan M, Giedd JN (2008) Why do many psychiatric disorders emerge during adolescence? Nat Rev Neurosci 9:947–957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paxinos G, Watson CR, Emson PC (1980) AChE-stained horizontal sections of the rat brain in stereotaxic coordinates. J Neurosci Methods 3:129–149

    Article  CAS  PubMed  Google Scholar 

  • Pena CJ, Smith M, Ramakrishnan A, Cates HM, Bagot RC, Kronman HG, Patel B, Chang AB, Purushothaman I, Dudley J, Morishita H, Shen L, Nestler EJ (2019) Early life stress alters transcriptomic patterning across reward circuitry in male and female mice. Nat Commun 10:5098

    Article  PubMed  PubMed Central  Google Scholar 

  • Phillips GD, Howes SR, Whitelaw RB, Wilkinson LS, Robbins TW, Everitt BJ (1994) Isolation rearing enhances the locomotor response to cocaine and a novel environment, but impairs the intravenous self-administration of cocaine. Psychopharmacology (Berl) 115:407–418

    Article  CAS  Google Scholar 

  • Piazza PV, Deroche-Gamonent V, Rouge-Pont F, Le Moal M (2000) Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction. J Neurosci 20:4226–4232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pickens CL, Airavaara M, Theberge F, Fanous S, Hope BT, Shaham Y (2011) Neurobiology of the incubation of drug craving. Trends Neurosci 34:411–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reiner DJ, Fredriksson I, Lofaro OM, Bossert JM, Shaham Y (2019) Relapse to opioid seeking in rat models: behavior, pharmacology and circuits. Neuropsychopharmacology 44:465–477

    Article  PubMed  Google Scholar 

  • Ren Y, Whittard J, Higuera-Matas A, Morris CV, Hurd YL (2009) Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J Neurosci 29:14764–14769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ribeiro Do Couto B, Aguilar MA, Lluch J, Rodriguez-Arias M, Minarro J (2009) Social experiences affect reinstatement of cocaine-induced place preference in mice. Psychopharmacology (Berl) 207:485–498

    Article  CAS  Google Scholar 

  • Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11

    Article  CAS  PubMed  Google Scholar 

  • Rogers JL, Ghee S, See RE (2008) The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse. Neuroscience 151:579–588

    Article  CAS  PubMed  Google Scholar 

  • Russo SJ, Bolanos CA, Theobald DE, DeCarolis NA, Renthal W, Kumar A, Winstanley CA, Renthal NE, Wiley MD, Self DW, Russell DS, Neve RL, Eisch AJ, Nestler EJ (2007) IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates. Nat Neurosci 10:93–99

    Article  CAS  PubMed  Google Scholar 

  • Schenk S, Robinson B, Amit Z (1988) Housing conditions fail to affect the intravenous self-administration of amphetamine. Pharmacol Biochem Behav 31:59–62

    Article  CAS  PubMed  Google Scholar 

  • Schmidt ED, Voorn P, Binnekade R, Schoffelmeer AN, De Vries TJ (2005) Differential involvement of the prelimbic cortex and striatum in conditioned heroin and sucrose seeking following long-term extinction. Eur J Neurosci 22:2347–2356

    Article  PubMed  Google Scholar 

  • Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168:3–20

    Article  CAS  Google Scholar 

  • Shalev U, Morales M, Hope B, Yap J, Shaham Y (2001) Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats. Psychopharmacology (Berl) 156:98–107

    Article  CAS  Google Scholar 

  • Shepard RD, Nugent FS (2020) Early life stress- and drug-induced histone modifications within the ventral tegmental area. Front Cell Dev Biol 8:588476

    Article  PubMed  PubMed Central  Google Scholar 

  • Sher KJ, Gershuny BS, Peterson L, Raskin G (1997) The role of childhood stressors in the intergenerational transmission of alcohol use disorders. J Stud Alcohol 58:414–427

    Article  CAS  PubMed  Google Scholar 

  • Sinha R (2008) Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci 1141:105–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith JP, Book SW (2008) Anxiety and substance use disorders: a review. Psychiatr Times 25:19–23

    PubMed  PubMed Central  Google Scholar 

  • Soria G, Barbano MF, Maldonado R, Valverde O (2008) A reliable method to study cue-, priming-, and stress-induced reinstatement of cocaine self-administration in mice. Psychopharmacology (Berl) 199:593–603

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Theberge FR, Li X, Kambhampati S, Pickens CL, St Laurent R, Bossert JM, Baumann MH, Hutchinson MR, Rice KC, Watkins LR, Shaham Y (2013) Effect of chronic delivery of the Toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving. Biol Psychiatry 73:729–737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Theberge FR, Pickens CL, Goldart E, Fanous S, Hope BT, Liu QR, Shaham Y (2012) Association of time-dependent changes in mu opioid receptor mRNA, but not BDNF, TrkB, or MeCP2 mRNA and protein expression in the rat nucleus accumbens with incubation of heroin craving. Psychopharmacology (Berl) 224:559–571

    Article  CAS  Google Scholar 

  • Towers EB, Tunstall BJ, McCracken ML, Vendruscolo LF, Koob GF (2019) Male and female mice develop escalation of heroin intake and dependence following extended access. Neuropharmacology 151:189–194

    Article  CAS  PubMed  Google Scholar 

  • Walker DM, Cunningham AM, Gregory JK, Nestler EJ (2019) Long-term behavioral effects of post-weaning social isolation in males and females. Front Behav Neurosci 13:66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker DM, Zhou X, Cunningham AM, Lipschultz AP, Ramakrishnan A, Cates HM, Bagot RC, Shen L, Zhang B, Nestler EJ (2021) Sex-specific transcriptional changes in response to adolescent social stress in the brain’s reward circuitry. Biol Psychiatry.

  • Wang ZJ, Martin JA, Gancarz AM, Adank DN, Sim FJ, Dietz DM (2017) Activin A is increased in the nucleus accumbens following a cocaine binge. Sci Rep 7:43658

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang ZJ, Martin JA, Mueller LE, Caccamise A, Werner CT, Neve RL, Gancarz AM, Li JX, Dietz DM (2016) BRG1 in the nucleus accumbens regulates cocaine-seeking behavior. Biol Psychiatry 80:652–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang ZJ, Zhang XQ, Cui XY, Cui SY, Yu B, Sheng ZF, Li SJ, Cao Q, Huang YL, Xu YP, Zhang YH (2015) Glucocorticoid receptors in the locus coeruleus mediate sleep disorders caused by repeated corticosterone treatment. Sci Rep 5:9442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Whitaker LR, Degoulet M, Morikawa H (2013) Social deprivation enhances VTA synaptic plasticity and drug-induced contextual learning. Neuron 77:335–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wikler A (1973) Dynamics of drug dependence. Implications of a conditioning theory for research and treatment. Arch Gen Psychiatry 28:611–616

    Article  CAS  PubMed  Google Scholar 

  • Wilkerson JL, Ghosh S, Mustafa M, Abdullah RA, Niphakis MJ, Cabrera R, Maldonado RL, Cravatt BF, Lichtman AH (2017) The endocannabinoid hydrolysis inhibitor SA-57: intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice. Neuropharmacology 114:156–167

    Article  CAS  PubMed  Google Scholar 

  • Wills TA, Cleary SD (1996) How are social support effects mediated? A test with parental support and adolescent substance use. J Pers Soc Psychol 71:937–952

    Article  CAS  PubMed  Google Scholar 

  • Wills TA, Vaccaro D, McNamara G (1992) The role of life events, family support, and competence in adolescent substance use: a test of vulnerability and protective factors. Am J Community Psychol 20:349–374

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  • Yamamuro K, Yoshino H, Ogawa Y, Makinodan M, Toritsuka M, Yamashita M, Corfas G, Kishimoto T (2018) Social isolation during the critical period reduces synaptic and intrinsic excitability of a subtype of pyramidal cell in mouse prefrontal cortex. Cereb Cortex 28:998–1010

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. David Dietz (State University of New York at Buffalo) for his feedback on experimental design. We also thank Dr. Adam Smith and Dr. Jai Subramanian (University of Kansas) for technical support.

Funding

This study was supported by University of Kansas start-up funding and the National Institutes of Health National Institute on Drug Abuse (Grant Number K01DA050908 to Z.-J. W.).

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  1. Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS, 66045, USA

    Archana Singh, Yang Xie, Ashton Davis & Zi-Jun Wang

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  1. Archana Singh
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Contributions

A.S. performed experiments, analyzed data, and wrote part of the Methods; Y. X. performed experiments and analyzed data; A. D. performed experiments; and Z.-J. W. designed experiments, performed experiments, supervised the project, and wrote the manuscript.

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Correspondence to Zi-Jun Wang.

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Singh, A., Xie, Y., Davis, A. et al. Early social isolation stress increases addiction vulnerability to heroin and alters c-Fos expression in the mesocorticolimbic system. Psychopharmacology 239, 1081–1095 (2022). https://doi.org/10.1007/s00213-021-06024-1

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