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Fos expression induced by cocaine-conditioned cues in male and female rats

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Abstract

Previous studies have shown that female rats exhibit different patterns of drug seeking during multiple phases of cocaine addiction when compared with males. However, the underlying mechanisms for these sex differences remain largely unknown. Here, we used a cocaine self-administration/reinstatement model to examine neuronal activation, as determined by Fos expression, following cue-induced reinstatement of cocaine seeking in male and female rats. Fos expression revealed both similarities between sexes in some brain regions, as well as selective sexually dimorphic patterns. As compared to no cue control subjects, conditioned cues induced higher Fos expression in the Cg1 region of the anterior cingulate cortex, but lower expression in the nucleus accumbens in both males and females. Females exhibited higher Fos expression than males in multiple brain regions, including the agranular insular cortex, dorsal medial caudate-putamen, nucleus accumbens shell, ventral tegmental area, dorsal subiculum, and ventral CA1 and CA3 regions of the hippocampus. Notably, only Fos expression in the prelimbic cortex, nucleus accumbens shell, basolateral amygdala, and ventral subiculum correlated positively with lever responding in response to conditioned cues across males and females. These findings indicate that while sexually dimorphic Fos activation does occur, the relationship between cue-induced cocaine seeking and neuronal activation may be similar for males and females in key brain regions of the relapse circuit.

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References

  • Acosta JI, Thiel KJ, Sanabria F, Browning JR, Neisewander JL (2008) Effect of schedule of reinforcement on cue-elicited reinstatement of cocaine-seeking behavior. Behav Pharmacol 19(2):129–136

    Article  CAS  PubMed  Google Scholar 

  • Anderson SM, Bari AA, Pierce RC (2003) Administration of the D1-like dopamine receptor antagonist SCH-23390 into the medial nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug-seeking behavior in rats. Psychopharmacology 168(1–2):132–138

    Article  CAS  PubMed  Google Scholar 

  • Anker JJ, Carroll ME (2011) Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones. Curr Top Behav Neurosci 8:73–96

    Article  CAS  PubMed  Google Scholar 

  • Avants SK, Margolin A, Kosten TR, Cooney NL (1995) Differences between responders and nonresponders to cocaine cues in the laboratory. Addict Behav 20(2):215–224

    Article  CAS  PubMed  Google Scholar 

  • Baeg EH, Jackson ME, Jedema HP, Bradberry CW (2009) Orbitofrontal and anterior cingulate cortex neurons selectively process cocaine-associated environmental cues in the rhesus monkey. J Neurosci 29(37):11619–11627

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bossert JM, Poles GC, Wihbey KA, Koya E, Shaham Y (2007) Differential effects of blockade of dopamine D1-family receptors in nucleus accumbens core or shell on reinstatement of heroin seeking induced by contextual and discrete cues. J Neurosci 27(46):12655–12663

    Article  CAS  PubMed Central  PubMed  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(14):4982–4991

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Boudreau AC, Reimers JM, Milovanovic M, Wolf ME (2007) Cell surface AMPA receptors in the rat nucleus accumbens increase during cocaine withdrawal but internalize after cocaine challenge in association with altered activation of mitogen-activated protein kinases. J Neurosci 27(39):10621–10635

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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(4):1976–1981

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dluzen DE, Anderson LI (1997) Estrogen differentially modulates nicotine-evoked dopamine release from the striatum of male and female rats. Neurosci Lett 230(2):140–142

    Article  CAS  PubMed  Google Scholar 

  • Elman I, Karlsgodt KH, Gastfriend DR (2001) Gender differences in cocaine craving among non-treatment-seeking individuals with cocaine dependence. Am J Drug Alcohol Abuse 27(2):193–202

    Article  CAS  PubMed  Google Scholar 

  • Feltenstein MW, See RE (2008) The neurocircuitry of addiction: an overview. Br J Pharmacol 154(2):261–274

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Feltenstein MW, Henderson AR, See RE (2011) Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cycle. Psychopharmacology 216(1):53–62

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Festa ED, Jenab S, Weiner J, Nazarian A, Niyomchai T, Russo SJ, Kemen LM, Akhavan A, Wu HB, Quinones-Jenab V (2006) Cocaine-induced sex differences in D1 receptor activation and binding levels after acute cocaine administration. Brain Res Bull 68(4):277–284

    Article  CAS  PubMed  Google Scholar 

  • French SJ, Totterdell S (2003) Individual nucleus accumbens-projection neurons receive both basolateral amygdala and ventral subicular afferents in rats. Neuroscience 119(1):19–31

    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 176(3–4):459–465

    Article  CAS  PubMed  Google Scholar 

  • Fuchs RA, Evans KA, Mehta RH, Case JM, See RE (2005) Influence of sex and estrous cyclicity on conditioned cue-induced reinstatement of cocaine-seeking behavior in rats. Psychopharmacology 179(3):662–672

    Article  CAS  PubMed  Google Scholar 

  • Gabbott PL, Warner TA, Jays PR, Salway P, Busby SJ (2005) Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J Comp Neurol 492(2):145–177

    Article  PubMed  Google Scholar 

  • Griffin ML, Weiss RD, Mirin SM, Lange U (1989) A comparison of male and female cocaine abusers. Arch Gen Psychiatry 46(2):122–126

    Article  CAS  PubMed  Google Scholar 

  • Groenewegen HJ, Berendse HW, Wolters JG, Lohman AH (1990) The anatomical relationship of the prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization. Prog Brain Res 85:95–116 (discussion 116–118)

    Article  CAS  PubMed  Google Scholar 

  • Hoover WB, Vertes RP (2007) Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct Funct 212(2):149–179

    Article  PubMed  Google Scholar 

  • Isgor C, Sengelaub DR (1998) Prenatal gonadal steroids affect adult spatial behavior, CA1 and CA3 pyramidal cell morphology in rats. Horm Behav 34(2):183–198

    Article  CAS  PubMed  Google Scholar 

  • Isgor C, Sengelaub DR (2003) Effects of neonatal gonadal steroids on adult CA3 pyramidal neuron dendritic morphology and spatial memory in rats. J Neurobiol 55(2):179–190

    Article  CAS  PubMed  Google Scholar 

  • Jackson LR, Robinson TE, Becker JB (2006) Sex differences and hormonal influences on acquisition of cocaine self-administration in rats. Neuropsychopharmacology 31(1):129–138

    CAS  PubMed  Google Scholar 

  • Jay TM, Witter MP (1991) Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris-leucoagglutinin. J Comp Neurol 313(4):574–586

    Article  CAS  PubMed  Google Scholar 

  • Juraska JM (1991) Sex differences in “cognitive” regions of the rat brain. Psychoneuroendocrinology 16(1–3):105–109

    Article  CAS  PubMed  Google Scholar 

  • Kilts CD, Gross RE, Ely TD, Drexler KP (2004) The neural correlates of cue-induced craving in cocaine-dependent women. Am J Psychiatry 161(2):233–241

    Article  PubMed  Google Scholar 

  • Kippin TE, Fuchs RA, Mehta RH, Case JM, Parker MP, Bimonte-Nelson HA, See RE (2005) Potentiation of cocaine-primed reinstatement of drug seeking in female rats during estrus. Psychopharmacology 182(2):245–252

    Article  CAS  PubMed  Google Scholar 

  • 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(10):823–835

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • LaLumiere RT, Smith KC, Kalivas PW (2012) Neural circuit competition in cocaine-seeking: roles of the infralimbic cortex and nucleus accumbens shell. Eur J Neurosci 35(4):614–622

    Article  PubMed Central  PubMed  Google Scholar 

  • Lynch WJ, Carroll ME (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology 144(1):77–82

    Article  CAS  PubMed  Google Scholar 

  • Lynch WJ, Taylor JR (2004) Sex differences in the behavioral effects of 24-h/day access to cocaine under a discrete trial procedure. Neuropsychopharmacology 29(5):943–951

    Article  CAS  PubMed  Google Scholar 

  • McCance-Katz EF, Carroll KM, Rounsaville BJ (1999) Gender differences in treatment-seeking cocaine abusers–implications for treatment and prognosis. Am J Addict 8(4):300–311

    Article  CAS  PubMed  Google Scholar 

  • McKay JR, Rutherford MJ, Cacciola JS, Kabasakalian-McKay R, Alterman AI (1996) Gender differences in the relapse experiences of cocaine patients. J Nerv Ment Dis 184(10):616–622

    Article  CAS  PubMed  Google Scholar 

  • 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 168(1–2):57–65

    Article  CAS  PubMed  Google Scholar 

  • Mello NK, Knudson IM, Mendelson JH (2007) Sex and menstrual cycle effects on progressive ratio measures of cocaine self-administration in cynomolgus monkeys. Neuropsychopharmacology 32(9):1956–1966

    Article  CAS  PubMed  Google Scholar 

  • Miller CA, Marshall JF (2004) Altered prelimbic cortex output during cue-elicited drug seeking. J Neurosci 24(31):6889–6897

    Article  CAS  PubMed  Google Scholar 

  • Miller CA, Marshall JF (2005) Altered Fos expression in neural pathways underlying cue-elicited drug seeking in the rat. Eur J Neurosci 21(5):1385–1393

    Article  PubMed  Google Scholar 

  • Nazarian A, Sun WL, Zhou L, Kemen LM, Jenab S, Quinones-Jenab V (2009) Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens. Psychopharmacology 203(3):641–650

    Article  CAS  PubMed  Google Scholar 

  • Parducz A, Garcia-Segura LM (1993) Sexual differences in the synaptic connectivity in the rat dentate gyrus. Neurosci Lett 161(1):53–56

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, San Diego

    Google Scholar 

  • Pennartz CM, Groenewegen HJ, Lopes da Silva FH (1994) The nucleus accumbens as a complex of functionally distinct neuronal ensembles: an integration of behavioural, electrophysiological and anatomical data. Prog Neurobiol 42(6):719–761

    Article  CAS  PubMed  Google Scholar 

  • Potenza MN, Hong KI, Lacadie CM, Fulbright RK, Tuit KL, Sinha R (2012) Neural correlates of stress-induced and cue-induced drug craving: influences of sex and cocaine dependence. Am J Psychiatry 169(4):406–414

    Article  PubMed Central  PubMed  Google Scholar 

  • Robbins SJ, Ehrman RN, Childress AR, O’Brien CP (1999) Comparing levels of cocaine cue reactivity in male and female outpatients. Drug Alcohol Depend 53(3):223–230

    Article  CAS  PubMed  Google Scholar 

  • Roberts DC, Bennett SA, Vickers GJ (1989) The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology 98(3):408–411

    Article  CAS  PubMed  Google Scholar 

  • Roth ME, Carroll ME (2004) Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration. Pharmacol Biochem Behav 78(2):199–207

    Article  CAS  PubMed  Google Scholar 

  • Schindler CW, Carmona GN (2002) Effects of dopamine agonists and antagonists on locomotor activity in male and female rats. Pharmacol Biochem Behav 72(4):857–863

    Article  CAS  PubMed  Google Scholar 

  • See RE, Elliott JC, Feltenstein MW (2007) The role of dorsal vs ventral striatal pathways in cocaine-seeking behavior after prolonged abstinence in rats. Psychopharmacology 194(3):321–331

    Article  CAS  PubMed  Google Scholar 

  • Sterling RC, Dean J, Weinstein SP, Murphy J, Gottheil E (2004) Gender differences in cue exposure reactivity and 9-month outcome. J Subst Abuse Treat 27(1):39–44

    Article  PubMed  Google Scholar 

  • Sun W, Rebec GV (2003) Lidocaine inactivation of ventral subiculum attenuates cocaine-seeking behavior in rats. J Neurosci 23(32):10258–10264

    CAS  PubMed  Google Scholar 

  • Waldrop AE, Back SE, Verduin ML, Brady KT (2007) Triggers for cocaine and alcohol use in the presence and absence of posttraumatic stress disorder. Addict Behav 32(3):634–639

    Article  PubMed  Google Scholar 

  • Waldrop AE, Price KL, Desantis SM, Simpson AN, Back SE, McRae AL, Spratt EG, Kreek MJ, Brady KT (2010) Community-dwelling cocaine-dependent men and women respond differently to social stressors versus cocaine cues. Psychoneuroendocrinology 35(6):798–806

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Walker QD, Rooney MB, Wightman RM, Kuhn CM (2000) Dopamine release and uptake are greater in female than male rat striatum as measured by fast cyclic voltammetry. Neuroscience 95(4):1061–1070

    Article  CAS  PubMed  Google Scholar 

  • Walker QD, Ray R, Kuhn CM (2006) Sex differences in neurochemical effects of dopaminergic drugs in rat striatum. Neuropsychopharmacology 31(6):1193–1202

    CAS  PubMed  Google Scholar 

  • Walker QD, Johnson ML, Van Swearingen AE, Arrant AE, Caster JM, Kuhn CM (2012) Individual differences in psychostimulant responses of female rats are associated with ovarian hormones and dopamine neuroanatomy. Neuropharmacology 62(7):2267–2277

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Westermeyer J, Boedicker AE (2000) Course, severity, and treatment of substance abuse among women versus men. Am J Drug Alcohol Abuse 26(4):523–535

    Article  CAS  PubMed  Google Scholar 

  • Witter MP, Groenewegen HJ (1990) The subiculum: cytoarchitectonically a simple structure, but hodologically complex. Prog Brain Res 83:47–58

    Article  CAS  PubMed  Google Scholar 

  • Zavala AR, Biswas S, Harlan RE, Neisewander JL (2007) Fos and glutamate AMPA receptor subunit coexpression associated with cue-elicited cocaine-seeking behavior in abstinent rats. Neuroscience 145(2):438–452

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang D, Yang S, Yang C, Jin G, Zhen X (2008) Estrogen regulates responses of dopamine neurons in the ventral tegmental area to cocaine. Psychopharmacology 199(4):625–635

    Article  CAS  PubMed  Google Scholar 

  • Zhou L, Nazarian A, Sun WL, Jenab S, Quinones-Jenab V (2009) Basal and cocaine-induced sex differences in the DARPP-32-mediated signaling pathway. Psychopharmacology 203(1):175–183

    Article  CAS  PubMed  Google Scholar 

  • Zhou L, Ghee SM, Chan C, Lin L, Cameron MD, Kenny PJ, See RE (2012) Orexin-1 receptor mediation of cocaine seeking in male and female rats. J Pharmacol Exp Ther 340(3):801–809

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This research was supported by NIH Grant P50 DA016511, NCMHD Grant P20 MD003942, and NIH grant C06 RR015455. We thank Dr. Wei-Lun Sun for his comments on this manuscript. We also thank Shannon Ghee and Clifford Chan for technical assistance.

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The authors declare no conflict of interest.

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Correspondence to Luyi Zhou.

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Zhou, L., Pruitt, C., Shin, C.B. et al. Fos expression induced by cocaine-conditioned cues in male and female rats. Brain Struct Funct 219, 1831–1840 (2014). https://doi.org/10.1007/s00429-013-0605-8

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  • DOI: https://doi.org/10.1007/s00429-013-0605-8

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