Abstract
Rationale
Stress exposure has a lasting impact on motivated behavior and can exacerbate existing vulnerabilities for developing a substance use disorder. Several models have been developed to examine how stressful experiences shape drug reward. These range from locomotor sensitization and conditioned place preference to the propensity for drug self-administration or responding to drug-predictive cues. While self-administration studies are considered to have more translational relevance, most of the studies to date have been conducted in rats. Further, many self-administration studies are conducted in single-housed animals, adding the additional stressor of social isolation.
Objectives
We sought to establish how chronic social defeat stress (CSDS) and social housing conditions impact cocaine self-administration and cocaine-seeking behaviors in C57BL/6 mice.
Methods
We assessed self-administration behavior (cocaine or saline, 0.5 mg/kg/infusion) in C57BL/6 mice subjected to 10-day CSDS or in unstressed controls. Mice were housed either in pairs or in isolation during self-administration. We compared the effect of housing on acquisition of self-administration, seeking, extinction, drug-induced reinstatement, and after re-exposure to the social stressor.
Results
Pair-housing during self-administration revealed increased social avoidance after CSDS is associated with decreased cocaine intake. In contrast, single-housing revealed stress-sensitive cocaine intake, with increased social avoidance after CSDS associated with increased early cocaine intake. Pair-, but not single-housed mice are susceptible to drug-induced reinstatement independent of CSDS history. Stress re-exposure sensitized cocaine-seeking in stressed single-housed mice.
Conclusions
The social context surrounding cocaine intake can bidirectionally influence cocaine-related behaviors after psychosocial stress and should be considered when studying stress and drug cross-sensitization.
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References
Ahmed SH, Badiani A, Miczek KA, Muller CP (2020) Non-pharmacological factors that determine drug use and addiction. Neurosci Biobehav Rev 110:3–27. https://doi.org/10.1016/j.neubiorev.2018.08.015
Arena DT, Covington HE 3rd, DeBold JF, Miczek KA (2019) Persistent increase of I.V. cocaine self-administration in a subgroup of C57BL/6J male mice after social defeat stress. Psychopharmacology 236:2027–2037. https://doi.org/10.1007/s00213-019-05191-6
Baron A, Kish GB (1962) Low-intensity auditory and visual stimuli as reinforcers for the mouse. J Comp Physiol Psychol 55:1011–1013. https://doi.org/10.1037/h0044286
Berton O et al (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868. https://doi.org/10.1126/science.1120972
Bogdan R, Pizzagalli DA (2006) Acute stress reduces reward responsiveness: implications for depression. Biol Psychiatry 60:1147–1154. https://doi.org/10.1016/j.biopsych.2006.03.037
Burke AR, Miczek KA (2015) Escalation of cocaine self-administration in adulthood after social defeat of adolescent rats: role of social experience and adaptive coping behavior. Psychopharmacology 232:3067–3079. https://doi.org/10.1007/s00213-015-3947-5
Chandra R et al (2017a) Drp1 mitochondrial fission in D1 neurons mediates behavioral and cellular plasticity during early cocaine abstinence. Neuron 96:1327–1341 e1326. https://doi.org/10.1016/j.neuron.2017.11.037
Chandra R et al (2017b) Reduced Slc6a15 in nucleus accumbens D2-neurons underlies stress susceptibility, J Neurosci. 37:6527–6538. https://doi.org/10.1523/JNEUROSCI.3250-16.2017
Covington HE 3rd, Miczek KA (2001) Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration “binges”. Psychopharmacology 158:388–398. https://doi.org/10.1007/s002130100858
Der-Avakian A, Mazei-Robison MS, Kesby JP, Nestler EJ, Markou A (2014) Enduring deficits in brain reward function after chronic social defeat in rats: susceptibility, resilience, and antidepressant response. Biol Psychiatry 76:542–549. https://doi.org/10.1016/j.biopsych.2014.01.013
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 U S A 85:5274–5278
Engeln M, Mitra S, Chandra R, Gyawali U, Fox ME, Dietz DM, Lobo MK (2020) Sex-specific role for Egr3 in nucleus accumbens D2-medium spiny neurons following long-term abstinence from cocaine self-administration. Biol Psychiatry 87:992–1000. https://doi.org/10.1016/j.biopsych.2019.10.019
Fox ME, Lobo MK (2019) The molecular and cellular mechanisms of depression: a focus on reward circuitry. Mol Psychiatry 24:1798–1815. https://doi.org/10.1038/s41380-019-0415-3
Fox ME et al (2020) Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior. Mol Psychiatry 25:1022–1034. https://doi.org/10.1038/s41380-018-0211-5
Francis TC et al (2017) Molecular basis of dendritic atrophy and activity in stress susceptibility. Mol Psychiatry 22:1512–1519. https://doi.org/10.1038/mp.2017.178
Francis TC, Gaynor A, Chandra R, Fox ME, Lobo MK (2019) The selective RhoA inhibitor Rhosin promotes stress resiliency through enhancing D1-medium spiny neuron plasticity and reducing hyperexcitability. Biol Psychiatry 85:1001–1010. https://doi.org/10.1016/j.biopsych.2019.02.007
Funk D, Harding S, Juzytsch W, Le AD (2005) Effects of unconditioned and conditioned social defeat on alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology 183:341–349. https://doi.org/10.1007/s00213-005-0194-1
Funk D, Li Z, Le AD (2006) Effects of environmental and pharmacological stressors on c-fos and corticotropin-releasing factor mRNA in rat brain: relationship to the reinstatement of alcohol seeking. Neuroscience 138:235–243. https://doi.org/10.1016/j.neuroscience.2005.10.062
Gipson CD, Beckmann JS, El-Maraghi S, Marusich JA, Bardo MT (2011) Effect of environmental enrichment on escalation of cocaine self-administration in rats. Psychopharmacology 214:557–566. https://doi.org/10.1007/s00213-010-2060-z
Golden SA, Covington HE 3rd, Berton O, Russo SJ (2011) A standardized protocol for repeated social defeat stress in mice. Nat Protoc 6:1183–1191. https://doi.org/10.1038/nprot.2011.361
Gong S, Doughty M, Harbaugh CR, Cummins A, Hatten ME, Heintz N, Gerfen CR (2007) Targeting Cre recombinase to specific neuron populations with bacterial artificial chromosome constructs. J Neurosci 27:9817–9823. https://doi.org/10.1523/JNEUROSCI.2707-07.2007
Green TA et al (2010) Environmental enrichment produces a behavioral phenotype mediated by low cyclic adenosine monophosphate response element binding (CREB) activity in the nucleus accumbens. Biol Psychiatry 67:28–35. https://doi.org/10.1016/j.biopsych.2009.06.022
Greenfield SF, Back SE, Lawson K, Brady KT (2010) Substance abuse in women. Psychiatr Clin North Am 33:339–355. https://doi.org/10.1016/j.psc.2010.01.004
Griffin WC 3rd, Randall PK, Middaugh LD (2007) Intravenous cocaine self-administration: individual differences in male and female C57BL/6J mice. Pharmacol Biochem Behav 87:267–279. https://doi.org/10.1016/j.pbb.2007.04.023
Han X, Albrechet-Souza L, Doyle MR, Shimamoto A, DeBold JF, Miczek KA (2015) Social stress and escalated drug self-administration in mice II. Cocaine and dopamine in the nucleus accumbens. Psychopharmacology 232:1003–1010. https://doi.org/10.1007/s00213-014-3734-8
Han X, DeBold JF, Miczek KA (2017) Prevention and reversal of social stress-escalated cocaine self-administration in mice by intra-VTA CRFR1 antagonism. Psychopharmacology 234:2813–2821. https://doi.org/10.1007/s00213-017-4676-8
Haney M, Maccari S, Le Moal M, Simon H, Piazza PV (1995) Social stress increases the acquisition of cocaine self-administration in male and female rats. Brain Res 698:46–52. https://doi.org/10.1016/0006-8993(95)00788-r
Harris AZ et al (2018) A novel method for chronic social defeat stress in female mice. Neuropsychopharmacology 43:1276–1283. https://doi.org/10.1038/npp.2017.259
Hatzigiakoumis DS, Martinotti G, Giannantonio MD, Janiri L (2011) Anhedonia and substance dependence: clinical correlates and treatment options. Front Psych 2:10. https://doi.org/10.3389/fpsyt.2011.00010
Heshmati M, Russo SJ (2015) Anhedonia and the brain reward circuitry in depression. Curr Behav Neurosci Rep 2:146–153. https://doi.org/10.1007/s40473-015-0044-3
Highland JN, Zanos P, Georgiou P, Gould TD (2019) Group II metabotropic glutamate receptor blockade promotes stress resilience in mice. Neuropsychopharmacology 44:1788–1796. https://doi.org/10.1038/s41386-019-0380-1
Hofford RS, Prendergast MA, Bardo MT (2015) Pharmacological manipulation of glucocorticoid receptors differentially affects cocaine self-administration in environmentally enriched and isolated rats. Behav Brain Res 283:196–202. https://doi.org/10.1016/j.bbr.2015.01.049
Hollon NG, Burgeno LM, Phillips PE (2015) Stress effects on the neural substrates of motivated behavior. Nat Neurosci 18:1405–1412. https://doi.org/10.1038/nn.4114
Holly EN, Boyson CO, Montagud-Romero S, Stein DJ, Gobrogge KL, DeBold JF, Miczek KA (2016) Episodic social stress-escalated cocaine self-administration: role of phasic and tonic corticotropin releasing factor in the anterior and posterior ventral tegmental area. J Neurosci 36:4093–4105. https://doi.org/10.1523/JNEUROSCI.2232-15.2016
Iniguez SD et al (2018) Vicarious social defeat stress induces depression-related outcomes in female mice. Biol Psychiatry 83:9–17. https://doi.org/10.1016/j.biopsych.2017.07.014
Kabbaj M, Norton CS, Kollack-Walker S, Watson SJ, Robinson TE, Akil H (2001) Social defeat alters the acquisition of cocaine self-administration in rats: role of individual differences in cocaine-taking behavior. Psychopharmacology 158:382–387. https://doi.org/10.1007/s002130100918
Kalivas PW, Duffy P (1995) Selective activation of dopamine transmission in the shell of the nucleus accumbens by stress. Brain Res 675:325–328. https://doi.org/10.1016/0006-8993(95)00013-g
Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev 16:223–244. https://doi.org/10.1016/0165-0173(91)90007-u
Khibnik LA, Beaumont M, Doyle M, Heshmati M, Slesinger PA, Nestler EJ, Russo SJ (2016) Stress and cocaine trigger divergent and cell type-specific regulation of synaptic transmission at single spines in nucleus accumbens. Biol Psychiatry 79:898–905. https://doi.org/10.1016/j.biopsych.2015.05.022
Krishnan V et al (2007) Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131:391–404. https://doi.org/10.1016/j.cell.2007.09.018
Le AD, Harding S, Juzytsch W, Funk D, Shaham Y (2005) Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology 179:366–373. https://doi.org/10.1007/s00213-004-2036-y
Lloyd DA, Turner RJ (2008) Cumulative lifetime adversities and alcohol dependence in adolescence and young adulthood. Drug Alcohol Depend 93:217–226. https://doi.org/10.1016/j.drugalcdep.2007.09.012
Manvich DF, Stowe TA, Godfrey JR, Weinshenker D (2016) A method for psychosocial stress-induced reinstatement of cocaine seeking in rats. Biol Psychiatry 79:940–946. https://doi.org/10.1016/j.biopsych.2015.07.002
McGrath AG, Lenz JD, Briand LA (2018) PKMzeta in the nucleus accumbens acts to dampen cocaine seeking. Neuropsychopharmacology 43:2390–2398. https://doi.org/10.1038/s41386-018-0170-1
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. https://doi.org/10.1523/JNEUROSCI.0637-11.2011
Nam H, Chandra R, Francis TC, Dias C, Cheer JF, Lobo MK (2019) Reduced nucleus accumbens enkephalins underlie vulnerability to social defeat stress. Neuropsychopharmacology 44:1876–1885. https://doi.org/10.1038/s41386-019-0422-8
Nasca C et al (2019) Multidimensional predictors of susceptibility and resilience to social defeat stress. Biol Psychiatry 86:483–491. https://doi.org/10.1016/j.biopsych.2019.06.030
Neisewander JL, Peartree NA, Pentkowski NS (2012) Emotional valence and context of social influences on drug abuse-related behavior in animal models of social stress and prosocial interaction. Psychopharmacology 224:33–56. https://doi.org/10.1007/s00213-012-2853-3
Newman EL, Leonard MZ, Arena DT, de Almeida RMM, Miczek KA (2018) Social defeat stress and escalation of cocaine and alcohol consumption: Focus on CRF. Neurobiol Stress 9:151–165. https://doi.org/10.1016/j.ynstr.2018.09.007
Newman EL, Covington HE 3rd, Suh J, Bicakci MB, Ressler KJ, DeBold JF, Miczek KA (2019) Fighting females: neural and behavioral consequences of social defeat stress in female mice. Biol Psychiatry 86:657–668. https://doi.org/10.1016/j.biopsych.2019.05.005
Olsen CM, Winder DG (2009) Operant sensation seeking engages similar neural substrates to operant drug seeking in C57 mice. Neuropsychopharmacology 34:1685–1694. https://doi.org/10.1038/npp.2008.226
Pagliusi M Jr, Bonet IJM, Brandao AF, Magalhaes SF, Tambeli CH, Parada CA, Sartori CR (2020) Therapeutic and preventive effect of voluntary running wheel exercise on social defeat stress (SDS)-induced depressive-like behavior and chronic pain in mice. Neuroscience 428:165–177. https://doi.org/10.1016/j.neuroscience.2019.12.037
Paine TA, Jackman SL, Olmstead MC (2002) Cocaine-induced anxiety: alleviation by diazepam, but not buspirone, dimenhydrinate or diphenhydramine. Behav Pharmacol 13:511–523. https://doi.org/10.1097/00008877-200211000-00001
Ribeiro Do Couto B, Aguilar MA, Manzanedo C, Rodriguez-Arias M, Armario A, Minarro J (2006) Social stress is as effective as physical stress in reinstating morphine-induced place preference in mice. Psychopharmacology 185:459–470. https://doi.org/10.1007/s00213-006-0345-z
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 207:485–498. https://doi.org/10.1007/s00213-009-1678-1
Roberts DC, Gabriele A, Zimmer BA (2013) Conflation of cocaine seeking and cocaine taking responses in IV self-administration experiments in rats: methodological and interpretational considerations. Neurosci Biobehav Rev 37:2026–2036. https://doi.org/10.1016/j.neubiorev.2013.04.017
Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37:577–582. https://doi.org/10.1016/s0896-6273(03)00021-7
Sapolsky RM (2015) Stress and the brain: individual variability and the inverted-U. Nat Neurosci 18:1344–1346. https://doi.org/10.1038/nn.4109
Shaham Y, Funk D, Erb S, Brown TJ, Walker CD, Stewart J (1997) Corticotropin-releasing factor, but not corticosterone, is involved in stress-induced relapse to heroin-seeking in rats. J Neurosci 17:2605–2614
Sinha R (2008) Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci 1141:105–130. https://doi.org/10.1196/annals.1441.030
Smith MA (2012) Peer influences on drug self-administration: social facilitation and social inhibition of cocaine intake in male rats. Psychopharmacology 224:81–90. https://doi.org/10.1007/s00213-012-2737-6
Takahashi A, Chung JR, Zhang S, Zhang H, Grossman Y, Aleyasin H, Flanigan ME, Pfau ML, Menard C, Dumitriu D, Hodes GE, McEwen BS, Nestler EJ, Han MH, Russo SJ (2017) Establishment of a repeated social defeat stress model in female mice. Sci Rep 7:12838. https://doi.org/10.1038/s41598-017-12811-8
Tidey JW, Miczek KA (1997) Acquisition of cocaine self-administration after social stress: role of accumbens dopamine. Psychopharmacology 130:203–212. https://doi.org/10.1007/s002130050230
van Erp AM, Miczek KA (2001) Persistent suppression of ethanol self-administration by brief social stress in rats and increased startle response as index of withdrawal. Physiol Behav 73:301–311. https://doi.org/10.1016/s0031-9384(01)00458-9
Wang T, Han W, Wang B, Jiang Q, Solberg-Woods LC, Palmer AA, Chen H (2014) Propensity for social interaction predicts nicotine-reinforced behaviors in outbred rats. Genes Brain Behav 13:202–212. https://doi.org/10.1111/gbb.12112
Ward SJ, Walker EA (2009) Sex and cannabinoid CB1 genotype differentiate palatable food and cocaine self-administration behaviors in mice. Behav Pharmacol 20:605–613. https://doi.org/10.1097/FBP.0b013e328331ba30
Wemm SE, Sinha R (2019) Drug-induced stress responses and addiction risk and relapse. Neurobiology of stress 10:100148. https://doi.org/10.1016/j.ynstr.2019.100148
Westenbroek C, Perry AN, Becker JB (2013) Pair housing differentially affects motivation to self-administer cocaine in male and female rats. Behav Brain Res 252:68–71. https://doi.org/10.1016/j.bbr.2013.05.040
Yap JJ, Miczek KA (2007) Social defeat stress, sensitization, and intravenous cocaine self-administration in mice. Psychopharmacology 192:261–273. https://doi.org/10.1007/s00213-007-0712-4
Yap JJ, Miczek KA (2008) Stress and rodent models of drug addiction: role of VTA-accumbens-PFC-amygdala circuit. Drug Discov Today Dis Model 5:259–270. https://doi.org/10.1016/j.ddmod.2009.03.010
Funding
This work was funded by NIH grants R01MH106500, R01DA038613, R01DA047843 (to MKL), and K99DA050575 (to MEF).
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Engeln, M., Fox, M.E. & Lobo, M.K. Housing conditions during self-administration determine motivation for cocaine in mice following chronic social defeat stress. Psychopharmacology 238, 41–54 (2021). https://doi.org/10.1007/s00213-020-05657-y
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DOI: https://doi.org/10.1007/s00213-020-05657-y