Abstract
Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to drug abuse. Due to the difficulty of implementing in mice the procedure of instrumental intravenous self-administration, mechanisms of reinstatement have so far been studied almost exclusively in rats. A mouse model of reinstatement of cocaine seeking has recently been characterized (Soria et al. 2008). The aim of the present study was to assess regional brain activation, as measured by induction of the immediate early genes (IEG) arc and zif268, during priming- or cue-elicited reinstatement of cocaine seeking using this new mouse model and the in situ hybridization technique. We have demonstrated that cue-elicited reinstatement of cocaine seeking was associated with induction of the IEG in the medial prefrontal cortex (prelimbic and infralimbic) and basolateral amygdala. Priming-induced reinstatement produced a more widespread up-regulation of those genes in forebrain regions including medial prefrontal, orbitofrontal and motor cortex, dorsal striatum and basolateral amygdala. These patterns of IEG expression are in agreement with previous results obtained in rats and thus indicate that the new mouse model of reinstatement is functionally equivalent to rat models. That comparability adds to the usefulness of the mouse model as a tool for addressing neurobiological mechanisms of addiction.
Similar content being viewed by others
References
Alleweireldt AT, Kirschner KF, Blake CB, Neisewander JL (2003) D1-receptor drugs and cocaine-seeking behavior: investigation of receptor mediation and behavioral disruption in rats. Psychopharmacology (Berl) 168:109–117
Ammon S, Mayer P, Riechert U, Tischmeyer H, Höllt V (2003) Microarray analysis of genes expressed in the frontal cortex of rats chronically treated with morphine and after naloxone precipitated withdrawal. Mol Brain Res 112:113–125
Anton RF (1999) What is craving? Models and implications for treatment. Alcohol Res Health 23:165–173
Berke JD, Paletzki RF, Aronson GJ, Hyman SE, Gerfen CR (1998) A complex program of striatal gene expression induced by dopaminergic stimulation. J Neurosci 8:5301–5310
Berretta S, Robertson HA, Graybiel AM (1992) Dopamine and glutamate agonists stimulate neuron-specific expression of Fos-like protein in the striatum. J Neurophysiol 68:767–777
Bonson KR, Grant SJ, Contoreggi CS, Links JM, Metcalfe J, Weyl HL et al (2002) Neural systems and cue-induced cocaine craving. Neuropsychopharmacology 26:376–386
Capriles N, Rodaros D, Sorge RE, Stewart J (2003) A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 168:66–74
Changeux JP (2010) Nicotine addiction and nicotinic receptors: lessons from genetically modified mice. Nat Rev Neurosci 11:389–401
Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O’Brien CP (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:11–18
Ciccocioppo R, Sanna PP, Weiss F (2001) Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: reversal by D(1) antagonists. Proc Natl Acad Sci USA 98:1976–1981
Fosnaugh JS, Bhat RV, Yamagata K, Worley PF, Baraban JM (1995) Activation of arc, a putative ‘‘effector’’ immediate early gene, by cocaine in rat brain. J Neurochem 64:2377–2380
Franken IH (2003) Drug craving and addiction: integrating psychological and neuropsychopharmacological approaches. Prog Neuropsychopharmacol Biol Psychiatry 27:563–579
Fuchs RA, Evans KA, Parker MP, See RE (2004) Differential involvement of orbitofrontal cortex subregions in conditioned cue-induced and cocaine-primed reinstatement of cocaine seeking in rats. J Neurosci 24:6600–6610
Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C et al (1996) Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci USA 93:12040–12045
Graybiel AM, Moratalla R, Robertson HA (1990) Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum. Proc Natl Acad Sci USA 87:6912–6916
Harlan RE, Garcia MM (1998) Drugs of abuse and immediate-early genes in the forebrain. Mol Neurobiol 16:221–267
Hearing MC, Miller SW, See RE, McGinty JF (2008a) Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats. Psychopharmacology (Berl) 198:77–91
Hearing MC, See RE, McGinty JF (2008b) Relapse to cocaine-seeking increases activity-regulated gene expression differentially in the striatum and cerebral cortex of rats following short or long periods of abstinence. Brain Struct Funct 213:215–227
Herdegen T, Leah JD (1998) Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. Brain Res Rev 28:370–490
Kaczmarek L, Chaudhuri A (1997) Sensory regulation of immediate-early gene expression in mammalian visual cortex: implications for functional mapping and neural plasticity. Brain Res Rev 23:237–256
Kantak KM, Black Y, Valencia E, Green-Jordan K, Eichenbaum HB (2002) Dissociable effects of lidocaine inactivation of the rostral and caudal basolateral amygdala on the maintenance and reinstatement of cocaine-seeking behavior in rats. J Neurosci 22:1126–1136
Kelly MP, Deadwyler SA (2003) Experience-dependent regulation of the immediate-early gene arc differs across brain regions. J Neurosci 23:6443–6451
Kieffer BL, Gavériaux-Ruff C (2002) Exploring the opioid system by gene knockout. Prog Neurobiol 66:285–306
Kilts CD, Schweitzer JB, Quinn CK, Gross RE, Faber TL, Muhammad F et al (2001) Neural activity related to drug craving in cocaine addiction. Arch Gen Psychiatry 58:334–341
Kufahl PR, Zavala AR, Singh A, Thiel KJ, Dickey ED, Joyce JN, Neisewander JL (2009) c-Fos expression associated with reinstatement of cocaine-seeking behavior by response-contingent conditioned cues. Synapse 63:823–835
Lemberger T, Parkitna JR, Chai M, Schütz G, Engblom D (2008) CREB has a context-dependent role in activity-regulated transcription and maintains neuronal cholesterol homeostasis. FASEB J 22:2872–2879
McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663
McLaughlin J, See RE (2003) Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology (Berl) 168:57–65
Meil WM, See RE (1997) Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine. Behav Brain Res 87:139–148
Moratalla R, Robertson HA, Graybiel AM (1992) Dynamic regulation of NGFI-A (zif268, egr1) gene expression in the striatum. J Neurosci 12:2609–2622
Morgan JI, Cohen DR, Hempstead JL, Curran T (1987) Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237:192–197
Nair SG, Adams-Deutsch T, Epstein DH, Shaham Y (2009) The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking. Prog Neurobiol 89:18–45
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
O’Brien CP, Childress AR, Ehrman R, Robbins SJ (1998) Conditioning factors in drug abuse: can they explain compulsion? J Psychopharmacol 12:15–22
Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, CD-ROM version
Rodriguez Parkitna J, Bilbao A, Rieker C, Engblom D, Piechota M, Nordheim A, Spanagel R, Schutz G (2010) Loss of the serum response factor in the dopamine system leads to hyperactivity. FASEB J 24(7):2427–2435
Sagar SM, Sharp FR, Curran T (1988) Expression of c-fos protein in brain: metabolic mapping at the cellular level. Science 240:1328–1331
Schmidt HD, Anderson SM, Famous KR, Kumaresan V, Pierce RC (2005) Anatomy and pharmacology of cocaine priming-induced reinstatement of drug seeking. Eur J Pharmacol 526:65–76
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
Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42
Sora I, Li B, Igari M, Hall FS, Ikeda K (2010) Transgenic mice in the study of drug addiction and the effects of psychostimulant drugs. Ann N Y Acad Sci 1187:218–246
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
Stephens DN, Mead AN, Ripley TL (2002) Studying the neurobiology of stimulant and alcohol abuse and dependence in genetically manipulated mice. Behav Pharmacol 13:327–345
Thomas KL, Arroyo M, Everitt BJ (2003) Induction of the learning and plasticity-associated gene Zif268 following exposure to a discrete cocaine-associated stimulus. Eur J Neurosci 17:1964–1972
Thomsen M, Caine SB (2007) Intravenous drug self-administration in mice: practical considerations. Behav Genet 37:101–118
Wisden W, Errington ML, Williams S, Dunnett SB, Waters C, Hitchcock D et al (1990) Differential expression of immediate early genes in the hippocampus and spinal cord. Neuron 4:603–614
Worley PF, Bhat RV, Baraban JM, Erickson CA, McNaughton BL, Barnes CA (1993) Thresholds for synaptic activation of transcription factors in hippocampus: correlation with long-term enhancement. J Neurosci 13:4776–4786
Young WS 3rd, Bonner TI, Brann MR (1986) Mesencephalic dopamine neurons regulate the expression of neuropeptide mRNAs in the rat forebrain. Proc Natl Acad Sci USA 83:9827–9831
Yun IA, Fields HL (2003) Basolateral amygdala lesions impair both cue- and cocaine-induced reinstatement in animals trained on a discriminative stimulus task. Neuroscience 121:747–757
Zavala AR, Osredkar T, Joyce JN, Neisewander JL (2008) Upregulation of Arc mRNA expression in the prefrontal cortex following cue-induced reinstatement of extinguished cocaine-seeking behavior. Synapse 62:421–431
Ziółkowska B, Przewłocki R (2002) Methods used in inducible transcription factor studies: focus on mRNA. In: Kaczmarek L, Robertson HA (eds) Handbook of Chemical Neuroanatomy, vol 19. Immediate early genes and inducible transcription factors in mapping of the central nervous system function and dysfunction. Elsevier, Amsterdam, pp 1–38
Acknowledgments
This work was supported by the EU grant LSHM-CT-2007-037669 (PHECOMP), the Polish Ministry of Science and Higher Education subsidiary grant No. 478/6. PR UE/2007/7, statutory funds from the Institute of Pharmacology, Polish Academy of Sciences, the Spanish Ministerio de Ciencia e Innovación (#SAF 2007-64062), the Catalan Government (S6R 2009-00131) and the ICREA Foundation (ICREA-Academia 2008).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ziółkowska, B., Kiełbiński, M., Gieryk, A. et al. Regulation of the immediate-early genes arc and zif268 in a mouse operant model of cocaine seeking reinstatement. J Neural Transm 118, 877–887 (2011). https://doi.org/10.1007/s00702-011-0583-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-011-0583-z