Archival Report| Volume 78, ISSUE 12, P871-879, December 15, 2015

Anhedonia, Reduced Cocaine Reward, and Dopamine Dysfunction in a Rat Model of Posttraumatic Stress Disorder

  • Nicole M. Enman
    Address correspondence to Nicole M. Enman, Ph.D., Temple University School of Medicine Center for Substance Abuse Research, Medical Education and Research Building Room 883A, 3500 N Broad St, Philadelphia, PA 19140
    Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania

    Center for Substance Abuse Research (NME, EMU), Temple University School of Medicine, Philadelphia, Pennsylvania
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  • Kayti Arthur
    Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania
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  • Sara J. Ward
    Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania
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  • Shane A. Perrine
    Department of Psychiatry and Behavioral Neurosciences (SAP), Wayne State University School of Medicine, Detroit, Michigan
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  • Ellen M. Unterwald
    Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania

    Center for Substance Abuse Research (NME, EMU), Temple University School of Medicine, Philadelphia, Pennsylvania
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      Posttraumatic stress disorder (PTSD) co-occurs with substance use disorders at high rates, but the neurobiological basis of this relationship is largely unknown. PTSD and drug addiction each involve dysregulation of brain reward circuitry; therefore, the identification of pathology of the mesolimbic dopamine system may aid in understanding their functional relationship. Dopamine reward dysfunction also may be relevant to the mechanisms underlying the PTSD symptoms of anhedonia and emotional numbing.


      Single-prolonged stress (SPS) was used as a rat model of PTSD, and a series of behavioral and neuropharmacologic assays were applied to assess the impact of SPS on reward, cocaine intake, and components of the striatal dopamine system.


      Exposure to SPS increased anhedonia-like behaviors and decreased the rewarding properties of cocaine compared with control handling. Altered cocaine intake during extended access self-administration sessions was observed in rats exposed to SPS, further suggesting a difference in the reinforcing properties of cocaine following severe stress. SPS reduced tissue content of dopamine and its metabolites in the striatum, as well as altered striatal dopamine transporter and D2, but not D1, receptor densities.


      These results support a role for altered dopaminergic transmission in reduced reward function in PTSD. Pathology of the dopamine system and the degradation of reward processes may contribute to PTSD symptomology and have implications for co-occurring psychiatric disorders such as substance abuse or depression.


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        • Bremner J.D.
        • Southwick S.M.
        • Darnell A.
        • Charney D.S.
        Chronic PTSD in Vietnam combat veterans: Course of illness and substance abuse.
        Am J Psychiatry. 1996; 153: 369-375
        • Chilcoat H.D.
        • Menard C.
        Epidemiological investigations: Comorbidity of posttraumatic stress disorder and substance use disorder.
        in: Ouimette P. Brown P.J. Trauma and Substance Abuse. American Psychological Association, Washington DC2003
        • Back S.E.
        • Brady K.T.
        • Jaanimägi U.
        • Jackson J.L.
        Cocaine dependence and PTSD: A pilot study of symptom interplay and treatment preferences.
        Addict Behav. 2006; 31: 351-354
        • Hien D.A.
        • Jiang H.
        • Campbell A.N.C.
        • Hu M.-C.
        • Miele G.M.
        • Cohen L.R.
        • et al.
        Do treatment improvements in PTSD severity affect substance use outcomes? A secondary analysis from a randomized clinical trial in NIDA׳s clinical trials network.
        Am J Psychiatry. 2010; 167: 95-101
        • Brown P.J.
        • Stout R.L.
        • Gannon-Rowley J.
        Substance use disorder-PTSD comorbidity: Patients׳ perceptions of symptom interplay and treatment issues.
        J Subst Abuse Treat. 1998; 15: 445-448
        • Leeies M.
        • Pagura J.
        • Sareen J.
        • Bolton J.M.
        The use of alcohol and drugs to self-medicate symptoms of posttraumatic stress disorder.
        Depress Anxiety. 2010; 27: 731-736
        • Back S.E.
        • Brady K.T.
        • Sonne S.C.
        • Verduin M.L.
        Symptom improvement in co-occurring PTSD and alcohol dependence.
        J Nerv Ment Dis. 2006; 194: 690-696
        • Burns M.N.
        • Lehman K.A.
        • Milby J.B.
        • Wallace D.
        • Schumacher J.E.
        Do PTSD symptoms and course predict continued substance use for homeless individuals in contingency management for cocaine dependence?.
        Behav Res Ther. 2010; 48: 588-598
        • Schultz W.
        Reward signaling by dopamine neurons.
        Neuroscientist. 2001; 7: 293-302
        • Pierce R.C.
        • Kumaresan V.
        The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse?.
        Neurosci Biobehav Rev. 2006; 30: 215-238
        • Elman I.
        • Ariely D.
        • Mazar N.
        • Aharon I.
        • Lasko N.B.
        • Macklin M.L.
        • et al.
        Probing reward function in post-traumatic stress disorder with beautiful facial images.
        Psychiatry Res. 2005; 135: 179-183
        • Hopper J.W.
        • Pitman R.K.
        • Su Z.
        • Heyman G.M.
        • Lasko N.B.
        • Macklin M.L.
        • et al.
        Probing reward function in posttraumatic stress disorder: Expectancy and satisfaction with monetary gains and losses.
        J Psychiatr Res. 2008; 42: 802-807
        • Elman I.
        • Lowen S.
        • Frederick B.B.
        • Chi W.
        • Becerra L.
        • Pitman R.K.
        Functional neuroimaging of reward circuitry responsivity to monetary gains and losses in posttraumatic stress disorder.
        Biol Psychiatry. 2009; 66: 1083-1090
        • Jatzko A.
        • Schmitt A.
        • Demirakca T.
        • Weimer E.
        • Braus D.
        Disturbance in the neural circuitry underlying positive emotional processing in post-traumatic stress disorder (PTSD).
        Eur Arch Psychiatry Clin Neurosci. 2006; 256: 112-114
        • Sailer U.
        • Robinson S.
        • Fischmeister F.P.
        • Konig D.
        • Oppenauer C.
        • Lueger-Schuster B.
        • et al.
        Altered reward processing in the nucleus accumbens and mesial prefrontal cortex of patients with posttraumatic stress disorder.
        Neuropsychologia. 2008; 46: 2836-2844
        • Felmingham K.L.
        • Falconer E.M.
        • Williams L.
        • Kemp A.H.
        • Allen A.
        • Peduto A.
        • Bryant R.A.
        Reduced amygdala and ventral striatal activity to happy faces in PTSD is associated with emotional numbing.
        PLoS One. 2014; 9: e103653
        • Admon R.
        • Lubin G.
        • Rosenblatt J.D.
        • Stern O.
        • Kahn I.
        • Assaf M.
        • Hendler T.
        Imbalanced neural responsivity to risk and reward indicates stress vulnerability in humans.
        Cereb Cortex. 2013; 23: 28-35
        • Hoexter M.Q.
        • Fadel G.
        • Felicio A.C.
        • Calzavara M.B.
        • Batista I.R.
        • Reis M.A.
        • et al.
        Higher striatal dopamine transporter density in PTSD: An in vivo SPECT study with [99mTc]TRODAT-1.
        Psychopharmacology (Berl). 2012; 224: 337-345
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders (4th ed, Text Revision).
        American Psychiatric Association, Washington DC2000
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders, 5th ed..
        American Psychiatric Association, Arlington, VA2013
        • Carmassi C.
        • Akiskal H.S.
        • Bessonov D.
        • Massimetti G.
        • Calderani E.
        • Stratta P.
        • et al.
        Gender differences in DSM-5 versus DSM-IV-TR PTSD prevalence and criteria comparison among 512 survivors to the L׳Aquila earthquake.
        J Affect Disord. 2014; 160: 55-61
        • Franklin C.L.
        • Zimmerman M.
        Posttraumatic stress disorder and major depressive disorder: Investigating the role of overlapping symptoms in diagnostic comorbidity.
        J Nerv Ment Dis. 2001; 189: 548-551
        • Nawijn L.
        • van Zuiden M.
        • Frijling J.L.
        • Koch S.B.
        • Veltman D.J.
        • Olff M.
        Reward functioning in PTSD: A systematic review exploring the mechanisms underlying anhedonia.
        Neurosci Biobehav Rev. 2015; 51: 189-204
        • Koob G.F.
        • Volkow N.D.
        Neurocircuitry of addiction.
        Neuropsychopharmacology. 2010; 35: 217-238
        • Martinez D.
        • Narendran R.
        • Foltin R.W.
        • Slifstein M.
        • Hwang D.-R.
        • Broft A.
        • et al.
        Amphetamine-induced dopamine release: Markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine.
        Am J Psychiatry. 2007; 164: 622-629
        • Koob G.
        • Kreek M.J.
        Stress, dysregulation of drug reward pathways, and the transition to drug dependence.
        Am J Psychiatry. 2007; 164: 1149-1159
        • Morgan D.
        • Grant K.A.
        • Gage H.D.
        • Mach R.H.
        • Kaplan J.R.
        • Prioleau O.
        • et al.
        Social dominance in monkeys: Dopamine D2 receptors and cocaine self-administration.
        Nat Neurosci. 2002; 5: 169-174
        • Khan S.
        • Liberzon I.
        Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD.
        Psychopharmacology (Berl). 2004; 172: 225-229
        • Ganon-Elazar E.
        • Akirav I.
        Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress.
        Neuropsychopharmacology. 2012; 37: 456-466
        • Iwamoto Y.
        • Morinobu S.
        • Takahashi T.
        • Yamawaki S.
        Single prolonged stress increases contextual freezing and the expression of glycine transporter 1 and vesicle-associated membrane protein 2 mRNA in the hippocampus of rats.
        Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31: 642-651
        • Knox D.
        • George S.A.
        • Fitzpatrick C.J.
        • Rabinak C.A.
        • Maren S.
        • Liberzon I.
        Single prolonged stress disrupts retention of extinguished fear in rats.
        Learn Mem. 2012; 19: 43-49
        • Knox D.
        • Nault T.
        • Henderson C.
        • Liberzon I.
        Glucocorticoid receptors and extinction retention deficits in the single prolonged stress model.
        Neuroscience. 2012; 223: 163-173
        • Yamamoto S.
        • Morinobu S.
        • Fuchikami M.
        • Kurata A.
        • Kozuru T.
        • Yamawaki S.
        Effects of single prolonged stress and D-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD.
        Neuropsychopharmacology. 2008; 33: 2108-2116
        • Ganon-Elazar E.
        • Akirav I.
        Cannabinoids and traumatic stress modulation of contextual fear extinction and GR expression in the amygdala-hippocampal-prefrontal circuit.
        Psychoneuroendocrinology. 2013; 38: 1675-1687
        • Eagle A.L.
        • Fitzpatrick C.J.
        • Perrine S.A.
        Single prolonged stress impairs social and object novelty recognition in rats.
        Behav Brain Res. 2013; 256: 591-597
        • Peng Y.
        • Feng S.-F.
        • Wang Q.
        • Wang H.-N.
        • Hou W.-G.
        • Xiong L.
        • et al.
        Hyperbaric oxygen preconditioning ameliorates anxiety-like behavior and cognitive impairments via upregulation of thioredoxin reductases in stressed rats.
        Prog Neuropsychopharmacol Biol Psychiatry. 2010; 34: 1018-1025
        • Liberzon I.
        • Krstov M.
        • Young E.A.
        Stress-restress: Effects on ACTH and fast feedback.
        Psychoneuroendocrinology. 1997; 22: 443-453
      1. National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals (2011): Guide for the Care and Use of Laboratory Animals, 8th ed. Washington, DC: The National Academies Press

        • Unterwald E.M.
        • Ho A.
        • Rubenfeld J.M.
        • Kreek M.J.
        Time course of the development of behavioral sensitization and dopamine receptor up-regulation during binge cocaine administration.
        J Pharmacol Exp Ther. 1994; 270: 1387-1396
        • Ben-Shahar O.
        • Moscarello J.M.
        • Ettenberg A.
        One hour, but not six hours, of daily access to self-administered cocaine results in elevated levels of the dopamine transporter.
        Brain Res. 2006; 1095: 148-153
        • Madras B.K.
        • Spealman R.D.
        • Fahey M.A.
        • Neumeyer J.L.
        • Saha J.K.
        • Milius R.A.
        Cocaine receptors labeled by [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane.
        Mol Pharmacol. 1989; 36: 518-524
        • Canfield D.R.
        • Spealman R.D.
        • Kaufman M.J.
        • Madras B.K.
        Autoradiographic localization of cocaine binding sites by [3H]CFT ([3H]WIN 35,428) in the monkey brain.
        Synapse. 1990; 6: 189-195
        • Saunders E.C.
        • Lambert-Harris C.
        • McGovern M.P.
        • Meier A.
        • Xie H.
        The prevalence of posttraumatic stress disorder symptoms among addiction treatment patients with cocaine use disorders.
        J Psychoactive Drugs. 2015; 47: 42-50
        • Najavits L.M.
        • Gastfriend D.R.
        • Barber J.P.
        • Reif S.
        • Muenz L.R.
        • Blaine J.
        • et al.
        Cocaine dependence with and without PTSD among subjects in the National Institute on Drug Abuse Collaborative Cocaine Treatment Study.
        Am J Psychiatry. 1998; 155: 214-219
        • Najavits L.M.
        • Runkel R.
        • Neuner C.
        • Frank A.F.
        • Thase M.E.
        • Crits-Christoph P.
        • Blaine J.
        Rates and symptoms of PTSD among cocaine-dependent patients.
        J Stud Alcohol. 2003; 65: 601-606
        • Yamamoto S.
        • Morinobu S.
        • Takei S.
        • Fuchikami M.
        • Matsuki A.
        • Yamawaki S.
        • Liberzon I.
        Single prolonged stress: Toward an animal model of posttraumatic stress disorder.
        Depress Anxiety. 2009; 26: 1110-1117
        • Pitman R.K.
        • Rasmusson A.M.
        • Koenen K.C.
        • Shin L.M.
        • Orr S.P.
        • Gilbertson M.W.
        • et al.
        Biological studies of post-traumatic stress disorder.
        Nat Rev Neurosci. 2012; 13: 769-787
        • Willner P.
        • Towell A.
        • Sampson D.
        • Sophokleous S.
        • Muscat R.
        Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant.
        Psychopharmacology (Berl). 1987; 93: 358-364
        • Chiba S.
        • Numakawa T.
        • Ninomiya M.
        • Richards M.C.
        • Wakabayashi C.
        • Kunugi H.
        Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex.
        Prog Neuropsychopharmacol Biol Psychiatry. 2012; 39: 112-119
        • Miczek K.A.
        • Nikulina E.M.
        • Shimamoto A.
        • Covington H.E.
        Escalated or suppressed cocaine reward, tegmental BDNF, and accumbal dopamine caused by episodic versus continuous social stress in rats.
        J Neurosci. 2011; 31: 9848-9857
        • Rygula R.
        • Abumaria N.
        • Flugge G.
        • Fuchs E.
        • Ruther E.
        • Havemann-Reinecke U.
        Anhedonia and motivational deficits in rats: Impact of chronic social stress.
        Behav Brain Res. 2005; 162: 127-134
        • Leventhal A.M.
        Relations between anhedonia and physical activity.
        Am J Health Behav. 2012; 36: 860-872
        • Roshanaei-Moghaddam B.
        • Katon W.J.
        • Russo J.
        The longitudinal effects of depression on physical activity.
        Gen Hosp Psychiatry. 2009; 31: 306-315
        • Litz B.T.
        • Orsillo S.M.
        • Kaloupek D.
        • Weathers F.
        Emotional processing in posttraumatic stress disorder.
        J Abnorm Psychol. 2000; 109: 26-39
        • Ritz M.C.
        • Lamb R.J.
        • Goldberg S.R.
        • Kuhar M.J.
        Cocaine receptors on dopamine transporters are related to self-administration of cocaine.
        Science. 1987; 238: 1219-1223
        • Ritz M.C.
        • Lamb R.J.
        • Goldberg S.R.
        • Kuhar M.J.
        Cocaine self-administration appears to be mediated by dopamine uptake inhibition.
        Progr Neuropsychopharmacol Biol Psychiatry. 1988; 12: 233-239
        • Eagle A.L.
        • Perrine S.A.
        Methamphetamine-induced behavioral sensitization in a rodent model of posttraumatic stress disorder.
        Drug Alcohol Depend. 2013; 131: 36-43
        • Eagle A.L.
        • Singh R.
        • Kohler R.J.
        • Friedman A.L.
        • Liebowitz C.P.
        • Galloway M.P.
        • et al.
        Single prolonged stress effects on sensitization to cocaine and cocaine self-administration in rats.
        Behav Brain Res. 2015; 284 (281-224)
        • Toledano D.
        • Tassin J.P.
        • Gisquet-Verrier P.
        Traumatic stress in rats induces noradrenergic-dependent long-term behavioral sensitization: Role of individual differences and similarities with dependence on drugs of abuse.
        Psychopharmacology (Berl). 2013; 230: 465-476
        • Toledano D.
        • Gisquet-Verrier P.
        Only susceptible rats exposed to a model of PTSD exhibit reactivity to trauma-related cues and other symptoms: An effect abolished by a single amphetamine injection.
        Behav Brain Res. 2014; 272: 165-174
        • Litz B.T.
        • Gray M.J.
        Emotional numbing in posttraumatic stress disorder: Current and future research directions.
        Aust N Z J Psychiatry. 2002; 36: 198-204
        • Wenzel J.M.
        • Rauscher N.A.
        • Cheer J.F.
        • Oleson E.B.
        A role for phasic dopamine release within the nucleus accumbens in encoding aversion: A review of the neurochemical literature.
        ACS Chem Neurosci. 2015; 6: 16-26
        • Volkow N.D.
        • Fowler J.S.
        • Wang G.-J.
        • Swanson J.M.
        • Telang F.
        Dopamine in drug abuse and addiction: Results of imaging studies and treatment implications.
        Arch Neurol. 2007; 64: 1575-1579
        • Bailey A.
        • Metaxas A.
        • Yoo J.H.
        • McGee T.
        • Kitchen I.
        Decrease of D2 receptor binding but increase in D2-stimulated G-protein activation, dopamine transporter binding and behavioural sensitization in brains of mice treated with a chronic escalating dose ‘binge’ cocaine administration paradigm.
        Eur J Neurosci. 2008; 28: 759-770
        • Letchworth S.R.
        • Nader M.A.
        • Smith H.R.
        • Friedman D.P.
        • Porrino L.J.
        Progression of changes in dopamine transporter binding site density as a result of cocaine self-administration in rhesus monkeys.
        J Neurosci. 2001; 21: 2799-2807
        • Little K.Y.
        • Zhang L.
        • Desmond T.
        • Frey K.A.
        • Dalack G.W.
        • Cassin B.J.
        Striatal dopaminergic abnormalities in human cocaine users.
        Am J Psychiatry. 1999; 156: 238-245
        • Malison R.T.
        • Best S.E.
        • van Dyck C.H.
        • McCance E.F.
        • Wallace E.A.
        • Laruelle M.
        • et al.
        Elevated striatal dopamine transporters during acute cocaine abstinence as measured by [123I] beta-CIT SPECT.
        Am J Psychiatry. 1998; 155: 832-834
        • Mash D.C.
        • Pablo J.
        • Ouyang Q.
        • Hearn W.L.
        • Izenwasser S.
        Dopamine transport function is elevated in cocaine users.
        J Neurochem. 2002; 81: 292-300
        • Staley J.K.
        • Hearn W.L.
        • Ruttenber A.J.
        • Wetli C.V.
        • Mash D.C.
        High affinity cocaine recognition sites on the dopamine transporter are elevated in fatal cocaine overdose victims.
        J Pharmacol Exp Ther. 1994; 271: 1678-1685
        • Zhang W.N.
        • Chang S.H.
        • Guo L.Y.
        • Zhang K.L.
        • Wang J.
        The neural correlates of reward-related processing in major depressive disorder: A meta-analysis of functional magnetic resonance imaging studies.
        J Affect Disord. 2013; 151: 531-539
        • Brady K.T.
        • Killeen T.K.
        • Brewerton T.
        • Lucerini S.
        Comorbidity of psychiatric disorders and posttraumatic stress disorder.
        J Clin Psychiatry. 2000; 61: 22-32
        • Serova L.I.
        • Tillinger A.
        • Alaluf L.G.
        • Laukova M.
        • Keegan K.
        • Sabban E.L.
        Single intranasal neuropeptide Y infusion attenuates development of PTSD-like symptoms to traumatic stress in rats.
        Neuroscience. 2013; 236: 298-312

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      • Capturing Individual Differences: Challenges in Animal Models of Posttraumatic Stress Disorder and Drug Abuse
        Biological PsychiatryVol. 78Issue 12
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          Many psychiatric disorders are comorbid with substance use disorder (SUD). Individuals with any mood or anxiety disorder are twice as likely to develop SUD compared with healthy individuals (1). Patients with posttraumatic stress disorder (PTSD) are no exception, with PTSD patients four times more likely to develop SUD than individuals without PTSD (2). However, despite numerous clinical reports of increased drug use in patients with PTSD and other mood disorders, preclinical studies have had difficulty replicating these effects in rodents.
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