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Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens

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Abstract

Introduction

Alterations in protein kinase (PKA) protein levels have been implicated in the regulation of responses to and development of cocaine addiction. However, the contribution of differences in PKA intracellular cascade to the known sex differences in responses to cocaine is not well understood. This study examined whether there are intrinsic or cocaine-induced alterations in PKA-mediated responses, such as phosphorylation of cyclic AMP response element binding protein, in male and female rats.

Materials and methods

To this end, protein levels of PKA and phosphorylated CREB (pCREB) in the caudate putamen (CPu) and nucleus accumbens (NAc) of male and female rats were measured basally or after acute (one 30-mg/kg intraperitoneal injection) or chronic (twice-daily 15-mg/kg injections for 14 days) cocaine administration. Behavioral responses to both cocaine administration paradigms were also studied.

Results

Similar to previous findings, ambulatory, rearing, and stereotypic activities were higher in female rats after acute cocaine administration. Sex differences in cocaine-induced responses were also observed after chronic cocaine administration: While males developed a robust sensitization in ambulatory activities to cocaine, females developed tolerance in cocaine-induced rearing and stereotypic activities. In the basal group, females had significantly higher PKA protein levels in the NAc. Regardless of the cocaine administration paradigm, PKA protein levels in the NAc were higher overall in females than in males. Furthermore, after cocaine administration, while pCREB protein levels in male rats were induced for a longer amount of time than in female rats, the magnitude of change on pCREB levels were higher in female than male rats. However, in the CPu, no sex differences in PKA or pCREB protein levels were observed either in the basal group or after acute or chronic cocaine administration.

Discussion

Taken together, these findings suggest that sex differences in basal and cocaine-induced alterations in the PKA signaling regulation in the NAc may contribute to sex differences in the psychomotor responses to cocaine.

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References

  • Andersen SL, Teicher MH (2000) Sex differences in dopamine receptors and their relevance to ADHD. Neurosci Biobehav Rev 24:137–141

    Article  CAS  PubMed  Google Scholar 

  • Anderson SM Pierce RC (2005) Cocaine-induced alterations in dopamine receptor signaling: Implications for reinforcement and reinstatement. Pharmacol Ther 106:389–403

    Article  Google Scholar 

  • Becker JB (1999) Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharmacol Biochem Behav 64:803–812

    Article  CAS  PubMed  Google Scholar 

  • Borgkvist A, Fisone G (2007a) Psychoactive drugs and regulation of the cAMP/PKA/DARPP-32 cascade in striatal medium spiny neurons. Neurosci Biobehav Rev 31:79–88

    Article  CAS  PubMed  Google Scholar 

  • Borgkvist A, Fisone G (2007b) Psychoactive drugs and regulation of the cAMP/PKA/DARPP-32 cascade in striatal medium spiny neurons. Neurosci Biobehav Rev 31:79–88

    Article  CAS  PubMed  Google Scholar 

  • Campbell UC, Morgan AD, Carroll ME (2002) Sex differences in the effects of baclofen on the acquisition of intravenous cocaine self-administration in rats. Drug Alcohol Depend 66:61–69

    Article  CAS  PubMed  Google Scholar 

  • Carlezon WA Jr, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, Duman RS, Neve RL, Nestler EJ (1998) Regulation of cocaine reward by CREB. Science 282:2272–2275

    Article  CAS  PubMed  Google Scholar 

  • Carlezon WA Jr, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28:436–445

    Article  CAS  PubMed  Google Scholar 

  • Cervo L, Mukherjee S, Bertaglia A, Samanin R (1997) Protein kinases A and C are involved in the mechanisms underlying consolidation of cocaine place conditioning. Brain Res 775:30–36

    Article  CAS  PubMed  Google Scholar 

  • Chen RH, Juo PC, Curran T, Blenis J (1996) Phosphorylation of c-Fos at the C-terminus enhances its transforming activity. Oncogene 12:1493–1502

    CAS  PubMed  Google Scholar 

  • Chin J, Sternin O, Wu HBK Fletcher H, Perrotti LI, Jenab S, Quiñones-Jenab V (2001) Sex differences in cocaine-induced behavioral sensitization. Cell Mol Biol 47:1089–1095

    CAS  PubMed  Google Scholar 

  • Chin J, Sternin O, Wu HBK, Burrell S, Lu D, Jenab S, Perrotti LI, Quinones-Jenab V (2002) Endogenous gonadal hormones modulate behavioral and neurochemical responses to acute and chronic cocaine administration. Brain Res 945:123–130

    Article  CAS  PubMed  Google Scholar 

  • Crawford CA, Choi FY, Kohutek JL, Yoshida ST, McDougall SA (2004) Changes in PKA activity and Gs alpha and Golf alpha levels after amphetamine- and cocaine-induced behavioral sensitization. Synapse 51:241–248

    Article  CAS  PubMed  Google Scholar 

  • Creese I, Iversen D (1974) The role of forebrain dopamine systems in amphetamine induced stereotypic behaviors in the rat. Psychopharmacology 39:345–257

    Article  CAS  Google Scholar 

  • Ellinwood EH, King GR, Davidson C, Lee TH (2000) The dopamine D2/D3 antagonist DS121 potentiates the effect of cocaine on locomotion and reduces tolerance in cocaine tolerant rats. Behav Brain Res 116:169–175

    Article  CAS  PubMed  Google Scholar 

  • Festa ED, Jenab S, Chin J, Gazi FM, Wu HBK, Russo SJ, Quinones-Jenab V (2003) Frequency of cocaine administration affects behavioral and endocrine responses in male and female Fischer rats. Cell Mol Biol 49:1275–1280

    CAS  PubMed  Google Scholar 

  • Festa ED, Russo SJ, Gazi FM, Niyomchai T, Kemen LM, Lin S-N, Foltz R, Jenab S, Quinones-Jenab V (2004) Sex differences in cocaine-induced behavioral responses, pharmacokinetics, and monoamine levels. Neuropharmacology 46:672–687

    Article  CAS  PubMed  Google Scholar 

  • Festa ED, Jenab S, Weiner J, Nazarian A, Niyomachai 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 68:277–284

    Article  CAS  PubMed  Google Scholar 

  • Glick SD, Hinds PA, Shapiro RM (1983) Cocaine-induced rotation: sex-dependent differences between left- and right-sided rats. Science 221:775–776

    Article  CAS  PubMed  Google Scholar 

  • Harrod S, Booze RM, Welch MA, Browning CE, Mactutus CF (2005) Acute and repeated intravenous cocaine-induced locomotor activity is altered as a function of sex and gonadectomy. Pharmacol Biochem Behav 82:170–181

    Article  CAS  PubMed  Google Scholar 

  • Hope BT, Crombag HS, Jedynak JP, Wise RA (2005) Neuroadaptations of total levels of adenylate cyclase, protein kinase A, tyrosine hydroxylase, cdk5 and neurofilaments in the nucleus accumbens and ventral tegmental area do not correlate with expression of sensitized or tolerant locomotor responses to cocaine. J Neurochem 92:536–545

    Article  CAS  PubMed  Google Scholar 

  • Hope BT, Nagarkar D, Leonard S, Wise RA (2007) Long-term upregulation of protein kinase A and adenylate cyclase levels in human smokers. J Neurosci 27:1964–1972

    Article  CAS  PubMed  Google Scholar 

  • Hu M, Crombag HS, Robinson TE, Becker JB (2003) Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology 29:81–85

    Article  Google Scholar 

  • Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29:565–598

    Article  CAS  PubMed  Google Scholar 

  • Inada T, Polk K, Purser C, Hume A, Hoskins B, Ho IK, Rockhold RW (1992) Behavioral and neurochemical effects of continuous infusion of cocaine in rats. Neuropharmacology 31:701–708

    Article  CAS  PubMed  Google Scholar 

  • Izenwasser S, French D, Carroll FI, Kunko PM (1999) Continuous infusion of selective dopamine uptake inhibitors or cocaine produces time-dependent changes in rat locomotor activity. Behav Brain Res 99:201–208

    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 31:129–138

    CAS  PubMed  Google Scholar 

  • Jones S, Bonci A (2005) Synaptic plasticity and drug addiction. Curr Opin Pharmacol 5:20–25

    Article  CAS  PubMed  Google Scholar 

  • Kalivas PW, Duffy P, DuMars LA, Skinner C (1988) Behavioral and neurochemical effects of acute and daily cocaine administration in rats. Pharmacol Exp Ther 245:485–492

    CAS  Google Scholar 

  • King GR, Joyner C, Lee TH, Kuhn C, Ellinwood EH (1992) Intermittent and continuous cocaine administration: residual behavioral states during withdrawal. Pharmacol Biochem Behav 43:243–248

    Article  CAS  PubMed  Google Scholar 

  • Kosten TA, Gawin FH, Kosten TR, Rounsaville BJ (1993) Gender differences in cocaine use and treatment response. J Subst Abuse Treat 10:63–66

    Article  CAS  PubMed  Google Scholar 

  • Kosten TR, Kosten TA, McDougle CJ, Hameedi FA, McCance EF, Rosen MI, Oliveto AH, Price LH (1996) Gender differences in response to intranasal cocaine administration to humans. Biol Psychiatry 39:147–148

    Article  CAS  PubMed  Google Scholar 

  • Kunko PM, French D, Izenwasser S (1998) Alterations in the locomotor activity during chronic cocaine administration: effect on dopamine receptors and interaction with opioids. J Pharm Exp Ther 285:277–285

    CAS  Google Scholar 

  • Lu L, Grimm JW, Shaham Y, Hope BT (2003) Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self-administration in rats. J Neurochem 85:1604–1613

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lynch WJ, Taylor JR (2005) Persistent changes in motivation to self-administer cocaine following modulation of cyclic AMP-dependent protein kinase A (PKA) activity in the nucleus accumbens. Eur J Neurosci 22:1214–1220

    Article  CAS  PubMed  Google Scholar 

  • Lynch WJ, Roth ME, Carroll ME (2002) Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology 164:121–137

    Article  CAS  PubMed  Google Scholar 

  • Lynch WJ, Kiraly DD, Caldarone BJ, Picciotto MR, Taylor JR (2007) Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats. Psychopharmacology 191:263–271

    Article  CAS  PubMed  Google Scholar 

  • Machado BH, Brody MJ (1990) Mechanisms of pressor response produced by stimulation of nucleus ambiguous. Am J Physiol 259:R955–R962

    CAS  PubMed  Google Scholar 

  • Mattson BJ, Bossert JM, Simmons DE, Nozaki N, Nagarkar D, Kreuter JD, Hope BT (2005) Cocaine-induced CREB phosphorylation in nucleus accumbens of cocaine-sensitized rats is enabled by enhanced activation of extracellular signal-related kinase, but not protein kinase A. J Neurochem 95:1481–1494

    Article  CAS  PubMed  Google Scholar 

  • McClung CA, Sidiropoulou K, Vitaterna M, Takahashi JS, White FJ, Cooper DC, Nestler EJ (2005) Regulation of dopaminergic transmission and cocaine reward by the Clock gene. Proc Natl Acad Sci 102:9377–9381

    Article  CAS  PubMed  Google Scholar 

  • Mello NK, Mendelson JH, Negus S, Kelly M (2004) Ovarian steroid hormone modulation of the acute effects of cocaine on luteinizing hormone and prolactin levels in ovariectomized rhesus monkeys. J Pharm Exp Ther 66:156–167

    Google Scholar 

  • Miserendino MJ, Nestler EJ (1995) Behavioral sensitization to cocaine: modulation by the cyclic AMP system in the nucleus accumbens. Brain Res 674:299–306

    Article  CAS  PubMed  Google Scholar 

  • Nestler EJ (2004) Molecular mechanisms of drug addiction. Neuropharmacology 47:24–32

    Article  CAS  PubMed  Google Scholar 

  • Pliakas AM, Carlson RR, Neve RL, Konradi C, Nestler EJ, Carlezon WA Jr (2001) Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. J Neurosci 21:7397–7403

    CAS  PubMed  Google Scholar 

  • Reith MEA, Benuck M, Lajtha A (1987) Cocaine disposition in the brain after continuous or intermittent treatment and locomotor stimulation in mice. J Pharmacol Exp Ther 243:281–287

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Roth ME, Cosgrove KP, Carroll ME (2004) Sex differences in the vulnerability to drug abuse: a review of preclinical studies. Neurosci Biobehav Rev 28:533–546

    Article  CAS  PubMed  Google Scholar 

  • Russo SJ, Jenab S, Fabian SJ, Festa ED, Kemen LM, Quinones-Jenab V (2003) Sex differences in the conditioned rewarding effects of cocaine. Brain Res 970:214–220

    Article  CAS  PubMed  Google Scholar 

  • Sakai N, Thome J, Newton SS, Chen J, Kelz MB, Steffen C, Nestler EJ, Duman RS (2002) Inducible and brain regionspecific CREB transgenic mice. Mol Pharmacol 61:1453–64

    Article  CAS  PubMed  Google Scholar 

  • Schroeder JA, Hummel M, Unterwald EM (2004) Repeated intracerebroventricular forskolin administration enhances behavioral sensitization to cocaine. Behav Brain Res 153:255–260

    Article  CAS  PubMed  Google Scholar 

  • Self DW, Genova LM, Hope BT, Barnhart WJ, Spencer JJ, Nestler EJ (1998) Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior. J Neurosci 18:1848–1859

    CAS  PubMed  Google Scholar 

  • Sell SL, Scalzitti JM, Thomas ML, Cunningham KA (2000) Influence of ovarian hormones and estrous cycle on the behavioral response to cocaine in female rats. J Pharmacol Exp Ther 293:879–886

    CAS  PubMed  Google Scholar 

  • Svenningsson P, Nairn AC, Greengard P (2005) DARPP-32 mediates the actions of multiple drugs of abuse. AAPS J 7:353–360

    Article  Google Scholar 

  • Van Etten ML, Anthony JC (2001) Male–female differences in transitions from first drug opportunity to first use: searching for subgroup variation by age, race, region, and urban status. J Womens Health Gend-Based Med 8:797–804

    Article  Google Scholar 

  • Van Haaren F, Meyer ME (1991) Sex differences in locomotor activity after acute and chronic cocaine administration. Pharmacol Biochem Behav 39:923–927

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Walker QD, Cabassa J, Hilmar AS, Uhn CM (2001) Sex differences in cocaine-stimulated motor behavior: disparate effects of gonadectomy. Neuropsychopharmacology 25:118–130

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Walters CL, Blendy JA (2001) Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse. J Neurosci 21:9438–9444

    CAS  PubMed  Google Scholar 

  • Willingale HL, Gardiner NJ, McLymont N, Grubb G, Grubb BD (1997) Prostanoids synthesized by cyclooxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability. Br J Pharmacol 122:1593–1604

    Article  CAS  PubMed  Google Scholar 

  • Wolf ME, Mangiavacchi S, Sun X (2003) Mechanisms by which dopamine receptors may influence synaptic plasticity. Ann N Y Acad Sci 1003:241–249

    Article  CAS  PubMed  Google Scholar 

  • Zhou L, Nazarian A, Sun WL, Jenab S, Quinones-Jenab V (2008) Basal and cocaine-induced sex differences in the DARPP-32-mediated signaling pathway. Psychopharmacology (Berl) (in press)

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Acknowledgments

We are grateful to Dr. Patricia Stephens for her editorial comments. This work is supported by SCORE 506-GM60654 and MIDARP DA-12136.

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Authors and Affiliations

  1. Department of Psychology, Hunter College, 695 Park Avenue, New York, NY, 10021, USA

    Arbi Nazarian, Wei-Lun Sun, Luyi Zhou, Lynne M. Kemen, Shirzad Jenab & Vanya Quinones-Jenab

  2. Doctoral Subprogram in Biopsychology and Behavioral Neuroscience, Graduate School, City University of New York, New York, NY, USA

    Arbi Nazarian, Wei-Lun Sun, Luyi Zhou, Lynne M. Kemen, Shirzad Jenab & Vanya Quinones-Jenab

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  1. Arbi Nazarian
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  2. Wei-Lun Sun
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Correspondence to Vanya Quinones-Jenab.

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Nazarian, A., Sun, WL., Zhou, L. et al. Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens. Psychopharmacology 203, 641–650 (2009). https://doi.org/10.1007/s00213-008-1411-5

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