Abstract
Rational
In this study, we sought to examine individual differences in stress-induced behavioral sensitization to d-amphetamine after repeated social defeat stress. In an effort to understand what mechanisms underlie stress-induced sensitization to d-amphetamine, we examined striatal gene expression of the dopamine receptor D2. Additionally, we investigated if repeated social defeat was associated with changes in dendritic spine density in the hippocampus, prefrontal cortex, and nucleus accumbens of rats that exhibit stress-induced sensitization.
Methods
Male rats were classified into high responders (HR) and low responders (LR) based on their locomotor response to a novel environment. Then, rats were either handled as a control or defeated on four occasions by aggressive rats. Two weeks after the last defeat, animals were challenged with one of three doses of d-amphetamine and their locomotor activity was recorded.
Results
Non-defeated HR rats exhibited higher locomotor activity in response to d-amphetamine when compared to LR non-defeated rats. Fourteen days from the last repeated social defeat, LR rats and HR rats were behaviorally identical in response to acute injections of amphetamine. Furthermore, HR non-defeated rats had less D2 mRNA expression in the nucleus accumbens core and dorsal striatum than do LR non-defeated rats. However, after repeated social defeat, HR and LR rats had identical D2 mRNA expression in both the core and dorsal striatum. Finally, there were no changes in dendritic spine density in any of the brain areas examined in LR rats.
Conclusion
Repeated social defeat abolishes individual differences in behavioral responses to d-amphetamine which may be due to a down-regulation of striatal dopamine D2 receptors in LR rats.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ahmed SH, Stinus L, Le Moal M, Cador M (1995) Social deprivation enhances the vulnerability of male Wistar rats to stressor—and amphetamine—induced behavioral sensitization. Psychopharmacology (Berl) 117:116–24
Badiani A, Oates MM, Robinson TE (2000) Modulation of morphine sensitization in the rat by contextual stimuli. Psychopharmacology (Berl) 151:273–282
Cabib S, Giardino L, Calza L, Zanni M, Mele A, Puglisi-Allegra S (1998) Stress promotes major changes in dopamine receptor densities within the mesoaccumbens and nigrostriatal systems. Neuroscience 84:193–200
Carlson JN, Glick SD, Hinds PA (1987) Changes in d-amphetamine elicited rotational behavior in rats exposed to uncontrollable footshock stress. Pharmacol Biochem Behav 26:17–21
Chefer VI, Zakharova I, Shippenberg TS (2003) Enhanced responsiveness to novelty and cocaine is associated with decreased basal dopamine uptake and release in the nucleus accumbens: quantitative microdialysis in rats under transient conditions. J Neurosci 23:3076–84
Covington H, Miczek K (2001) Repeated social-defeat stress, cocaine or morphine. Psychopharmacology (Berl) 158:388–398
Covington H, Miczek K (2005) Intense cocaine self-administration after episodic social defeat stress, but not after aggressive behavior: dissociation from corticosterone activation. Psychopharmacology (Berl) 183:331–340
Dansky BS, Byrne CA, Brady KT (1999) Intimate violence and post-traumatic stress disorder among individuals with cocaine dependence. Am J Drug Alcohol Abuse 25:257–268
de Jong JG, van der Vegt BJ, Buwalda B, Koolhaas JM (2005) Social environment determines the long-term effects of social defeat. Physiol Behav 84:87–95
Deroche V, Marinelli M, Maccari S, Le Moal M, Simon H, Piazza PV (1995) Stress-induced sensitization and glucocorticoids I. Sensitization of dopamine-dependent locomotor effects of amphetamine and morphine depends on stress-induced corticosterone secretion. J Neurosci 15:7181–7188
Dietz DM, Tapocik J, Gaval-Cruz M, Kabbaj M (2005) Dopamine transporter, but not tyrosine hydroxylase, may be implicated in determining individual differences in behavioral sensitization to amphetamine. Physiol Behav 86:347–355
Fuchs E, Flugge G, Czeh B (2006) Remodeling of neuronal networks by stress. Front Biosci 11:2746–58
Garrett BE, Holtzman SG (1996) Comparison of the effects of prototypical behavioral stimulants on locomotor activity and rotational behavior in rats. PharmacolBiochem Behav 54:469–477
Hooks MS, Jones GH, Smith AD, Neill DB, Justice JB (1991) Individual differences in locomotor activity and sensitization. Pharmacol Biochem Behav 38:467–470
Hooks MS, Colvin AC, Juncos JL, Justice JB Jr (1992a) Individual differences in basal and cocaine-stimulated extracellular dopamine in the nucleus accumbens using quantitative microdialysis. Brain Res 587:306–312
Hooks MS, Jones GH, Neill DB, Justice JB (1992b) Individual differences in amphetamine sensitization: dose-dependent effects. Pharmacol Biochem Behav 41:203–210
Hooks MS, Juncos JL, Justice JB Jr, Meiergerd SM, Povlock SL, Schenk JO, Kalivas PW (1994) Individual locomotor response to novelty predicts selective alterations in D1 and D2 receptors and mRNAs. J Neurosci 14:6144–6152
Isgor C, Kabbaj M, Akil H, Watson S (2004) Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats. Hippocampus 14:636–648
Kabbaj M (2004) Neurobiological bases of individual differences in emotional and stress responsiveness: high responders-low responders model. Arch Neurol 61:1009–1012
Kabbaj M (2006) Individual Differences in Vulnerability to Drug Abuse: The High Responders/Low Responders Model. CNS Neurol Disord Drug Targets 5:513–520
Kabbaj M, Devine DP, Savage VR, Akil H (2000) Neurobiological correlates of individual differences in novelty-seeking behavior in the rat: differential expression of stress-related molecules. J Neurosci 20:6983–6988
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 (Berl) 158:382–387
Kabbaj M, Morley-Fletcher S, Le Moal M, Maccari S (2007) Individual differences in the effects of chronic prazosin hydrochloride treatment on hippocampal mineralocorticoid and glucocorticoid receptors. Eur J Neurosci 25:3312–3318
Lammers C-H, D’Souza UM, Qin Z-H, Lee S-H, Yajima S, Mouradian MM (1999) Regulation of striatal dopamine receptors by corticosterone: an in vivo and in vitro study. Brain Res Mol Brain Res 69:281–285
Lucas LR, Celen Z, Tamashiro KLK, 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
Mallo T, Alttoa A, Koiv K, Tonissaar M, Eller M, Harro J (2007) Rats with persistently low or high exploratory activity: Behaviour in tests of anxiety and depression, and extracellular levels of dopamine. Behav Brain Res 177:269–281
Marinelli M, Le Moal M, Piazza PV (1996) Acute pharmacological blockade of corticosterone secretion reverses food restriction-induced sensitization of the locomotor response to cocaine. Brain Res 724:251–255
Miczek KA, Covington HE, Nikulina EM, Hammer RP (2004) Aggression and defeat: persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits. Neurosci Biobehav Rev 27:787–802
Morgan D, Grant KA, Gage HD, Mach RH, Kaplan JR, Prioleau O, Nader SH, Buchheimer N, Ehrenkaufer RL, Nader MA (2002) Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat Neurosci 5:169–174
Nestler EJ (2002) Common Molecular and Cellular Substrates of Addiction and Memory. Neurobiol Learn Mem 78:637–647
Nikulina EM, Covington HE, Ganschow L, Hammer RP, 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
Norrholm SD, Ouimet CC (2000) Chronic fluoxetine administration to juvenile rats prevents age-associated dendritic spine proliferation in hippocampus. Brain Res 883:205–215
Norrholm SD, Bibb JA, Nestler EJ, Ouimet CC, Taylor JR, Greengard P (2003) Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5. Neuroscience 116:19–22
Pacchioni AM, Gioino G, Assis A, Cancela LM (2002) A single exposure to restraint stress induces behavioral and neurochemical sensitization to stimulating effects of amphetamine: involvement of NMDA receptors. Ann N Y Acad Sci 965:233–246
Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates. Elsevier, Amsterdam
Piazza PV, Deminiere JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511–1513
Piazza PV, Deminiere JM, le Moal M, Simon H (1990) Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration. Brain Res 514:22–26
Pierre PJ, Vezina P (1997) Predisposition to self-administer amphetamine: the contribution of response to novelty and prior exposure to the drug. Psychopharmacology (Berl) 129:277–284
Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, McEwen BS, Morrison JH (2006) Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex 16:313–20
Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 396:157–198
Robinson TE, Berridge KC (2001) Incentive-sensitization and addiction. Addiction 96:103–114
Robinson TE, Kolb B (2004) Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 47:33–46
Rouge-Pont F, Marinelli M, Le Moal M, Simon H, Piazza PV (1995) Stress-induced sensitization and glucocorticoids. II. Sensitization of the increase in extracellular dopamine induced by cocaine depends on stress-induced corticosterone secretion. J Neurosci 15:7189–7195
Shaham Y, Hope BT (2005) The role of neuroadaptations in relapse to drug seeking. Nat Neurosci 8:1437–1439
Shors TJ, Chua C, Falduto J (2001) Sex Differences and Opposite Effects of Stress on Dendritic Spine Density in the Male Versus Female Hippocampus. J Neurosci 21:6292–6297
Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berl) 158:343–359
Thanos PK, Taintor NB, Rivera SN, Umegaki H, Ikari H, Roth G, Ingram DK, Hitzemann R, Fowler JS, Gatley SJ, Wang GJ, Volkow ND (2004) DRD2 gene transfer into the nucleus accumbens core of the alcohol-preferring and nonpreferring rats attenuates alcohol drinking. Alcohol Clin Exp Res 28:720–728
Tidey JW, Miczek KA (1997) Acquisition of cocaine self-administration after social stress: role of accumbens dopamine. Psychopharmacology (Berl) 130:203–212
Tornatzky W, Miczek KA (1993) Long-term impairment of autonomic circadian rhythms after brief intermittent social stress. Physiol Behav 53:983–993
Volkow ND, Wang GJ, Fowler JS, Thanos PP, Logan J, Gatley SJ, Gifford A, Ding YS, Wong C, Pappas N (2002) Brain DA D2 receptors predict reinforcing effects of stimulants in humans: replication study. Synapse 46:79–82
Volkow ND, Fowler JS, Wang GJ, Swanson JM (2004) Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry 9:557–569
Volkow ND, Wang G-J, Begleiter H, Porjesz B, Fowler JS, Telang F, Wong C, Ma Y, Logan J, Goldstein R, Alexoff D, Thanos PK (2006) High Levels of Dopamine D2 Receptors in Unaffected Members of Alcoholic Families: Possible Protective Factors. Arch Gen Psychiatry 63:999–1008
Young EA, Abelson J, Lightman SL (2004) Cortisol pulsatility and its role in stress regulation and health. Front Neuroendocrinol 25:69–76
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dietz, D.M., Dietz, K.C., Moore, S. et al. Repeated social defeat stress-induced sensitization to the locomotor activating effects of d-amphetamine: role of individual differences. Psychopharmacology 198, 51–62 (2008). https://doi.org/10.1007/s00213-008-1078-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-008-1078-y