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Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats

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Abstract

Rationale

Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction.

Objective

Given sex differences in the progression to cocaine addiction, we examined the possibility that the PKA pathway is differentially activated by cocaine in male and female rats.

Materials and methods

Rats were given 24-h access to cocaine (1.5 mg/kg) or saline for 7 days under a discrete trial procedure (four trials per hour). Rats were then retested on responding for cocaine under a progressive-ratio schedule after either 0 (no-delay retest) or 10 (10-day-delay retest) days of abstinence. Markers of PKA-regulated signaling in the striatum and nucleus accumbens were evaluated by Western blotting, including phosphorylation of DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 and glutamate receptor 1 (GluR1) at Ser 845.

Results

Compared to males, females had higher levels of DARPP-32 phosphorylated at the PKA site in the striatum. Increased phosphorylation of DARPP-32 at the PKA site was also seen in the nucleus accumbens of females compared to males, particularly among controls and rats tested after a 10-day abstinence period. DARPP-32 phosphorylation was also increased as a consequence of cocaine when tested after a 0-day abstinence period in male rats but not female rats.

Conclusion

These findings indicate sex differences in PKA-regulated signaling in drug-naïve controls. Furthermore, these data suggest that regulation of PKA signaling by cocaine is differentially influenced in male and female rats as a consequence of cocaine exposure and cocaine abstinence period.

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References

  • Andersen SL, Teicher MH (2000) Sex differences in dopamine receptors and their relevance to ADHD. Neurosci Biobehav Rev 24(1):137–141

    Article  PubMed  CAS  Google Scholar 

  • Arnold JM, Roberts DC (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57(3):441–447

    Article  PubMed  CAS  Google Scholar 

  • Becker JB (1999) Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharmacol Biochem Behav 64(4):803–812

    Article  PubMed  CAS  Google Scholar 

  • Benavides DR, Bibb JA (2004) Role of Cdk5 in drug abuse and plasticity. Ann NY Acad Sci 1025:335–344

    Article  PubMed  CAS  Google Scholar 

  • Beninger RJ, Nakonechny PL, Savina I (2003) cAMP-dependent protein kinase and reward-related learning: intra-accumbens Rp-cAMPS blocks amphetamine-produced place conditioning in rats. Psychopharmacology 170:23–32

    Article  PubMed  CAS  Google Scholar 

  • Berhow MT, Russell DS, Terwilliger RZ, Beitner-Johnson D, Self DW, Lindsay RM, Nestler EJ (1995) Influence of neurotrophic factors on morphine- and cocaine-induced biochemical changes in the mesolimbic dopamine system. Neuroscience 68(4):969–979

    Article  PubMed  CAS  Google Scholar 

  • Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, Huganir RL, Hemmings HC Jr, Nairn AC, Greengard P (1999) Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402(6762):669–771

    Article  PubMed  CAS  Google Scholar 

  • Bibb JA, Chen J, Taylor JR, Svenningsson P, Nishi A, Snyder GL, Yan Z, Sagawa ZK, Ouimet CC, Nairn AC, Nestler EJ, Greengard P (2001) Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410(6826):376–380

    Article  PubMed  CAS  Google Scholar 

  • Caine SB, Bowen CA, Yu G, Zuzga D, Negus SS, Mello NK (2004) Effect of gonadectomy and gonadal hormone replacement on cocaine self-administration in female and male rats. Neuropsychopharmacology 29(5):929–942

    Article  PubMed  CAS  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(1):61–69

    Article  PubMed  CAS  Google Scholar 

  • Carroll ME, Morgan AD, Lynch WJ, Campbell UC, Dess NK (2002) Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: phenotype and sex differences. Psychopharmacology 161(3):304–313

    Article  PubMed  CAS  Google Scholar 

  • Carroll ME, Lynch WJ, Roth ME, Morgan AD, Cosgrove KP (2004) Sex and estrogen influence drug abuse. Trends Pharmacol Sci 25(5):273–279

    Article  PubMed  CAS  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(1–2):30–36

    Article  PubMed  CAS  Google Scholar 

  • Festa ED, Russo SJ, Gazi FM, Niyomchai T, Kemen LM, Lin SN, Foltz R, Jenab S, Quinones-Jenab V (2004) Sex differences in cocaine-induced behavioral responses, pharmacokinetics, and monoamine levels. Neuropharmacology 46(5):672–687

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Haney M, Maccari S, Le Moal M, Simon H, Piazza PV (1995) Social stress increases the acquisition of cocaine self-administration in male and female rats. Brain Res 698(1–2):46–52

    Article  PubMed  CAS  Google Scholar 

  • Harrod SB, Booze RM, Welch M, 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(1):170–181

    Article  PubMed  CAS  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(3):536–545

    Article  PubMed  CAS  Google Scholar 

  • Hu M, Becker JB (2003) Effects of sex and estrogen on behavioral sensitization to cocaine in rats. J Neurosci 23(2):693–699

    PubMed  CAS  Google Scholar 

  • Hu M, Crombag HS, Robinson TE, Becker JB (2004) Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology 29(1):81–85

    Article  PubMed  CAS  Google Scholar 

  • Hyman SE, Malenka RC (2001) Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2(10):695–703

    Article  PubMed  CAS  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

    PubMed  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(6):1604–1613

    Article  PubMed  CAS  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  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Lynch WJ, Taylor JR (2005a) Decreased motivation following cocaine self-administration under extended access conditions: effects of sex and ovarian hormones. Neuropsychopharmacology 30(5):927–935

    Article  PubMed  CAS  Google Scholar 

  • Lynch WJ, Taylor JR (2005b) 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(5):1214–1220

    Article  PubMed  CAS  Google Scholar 

  • Lynch WJ, Roth ME, Mickelberg JL, Carroll ME (2001) Role of estrogen in the acquisition of intravenously self-administered cocaine in female rats. Pharmacol Biochem Behav 68(4):641–646

    Article  PubMed  CAS  Google Scholar 

  • Lynch WJ, Roth ME, Carroll ME (2002) Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology 164(2):121–137

    Article  PubMed  CAS  Google Scholar 

  • McClung CA, Nestler EJ (2003) Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Nat Neurosci 6(11):1208–1215

    Article  PubMed  CAS  Google Scholar 

  • Miserendino MJ, Nestler EJ (1995) Behavioral sensitization to cocaine: modulation by the cyclic AMP system in the nucleus accumbens. Brain Res 674(2):299–306

    Article  PubMed  CAS  Google Scholar 

  • Nairn AC, Svenningsson P, Nishi A, Fisone G, Girault JA, Greengard P (2004) The role of DARPP-32 in the actions of drugs of abuse. Neuropharmacology 47(Suppl 1):14–23

    Article  PubMed  CAS  Google Scholar 

  • Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8(11):1445–1449

    Article  PubMed  CAS  Google Scholar 

  • Nishi A, Bibb JA, Snyder GL, Higashi H, Nairn AC, Greengard P (2000) Amplification of dopaminergic signaling by a positive feedback loop. Proc Natl Acad Sci USA 97(23):12840–12845

    Article  PubMed  CAS  Google Scholar 

  • Roche KW, O’Brien RJ, Mammen AL, Bernhardt J, Huganir RL (1996) Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 16(6):1179–1188

    Article  PubMed  CAS  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(1–2):214–220

    Article  PubMed  CAS  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(5):1848–1859

    PubMed  CAS  Google Scholar 

  • Snyder GL, Allen PB, Fienberg AA, Valle CG, Huganir RL, Nairn AC, Greengard P (2000) Regulation of phosphorylation of the GluR1 AMPA receptor in the neostriatum by dopamine and psychostimulants in vivo. J Neurosci 20(12):4480–4488

    PubMed  CAS  Google Scholar 

  • Sutton MA, McGibney K, Beninger RJ (2000) Conditioned locomotion in rats following amphetamine infusion into the nucleus accumbens: blockade by coincident inhibition of protein kinase A. Behav Pharmacol 11(5):365–376

    PubMed  CAS  Google Scholar 

  • Sutton MA, Schmidt EF, Choi KH, Schad CA, Whisler K, Simmons D, Karanian DA, Monteggia LM, Neve RL, Self DW (2003) Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour. Nature 421(6918):70–75

    Article  PubMed  CAS  Google Scholar 

  • Takahashi S, Ohshima T, Cho A, Sreenath T, Iadarola MJ, Pant HC, Kim Y, Nairn AC, Brady RO, Greengard P, Kulkarni AB (2005) Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling. Proc Natl Acad Sci USA 102(5):1737–1742

    Article  PubMed  CAS  Google Scholar 

  • Terwilliger RZ, Beitner-Johnson D, Sevarino KA, Crain SM, Nestler EJ (1991) A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res 548:100–110

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Zachariou V, Sgambato-Faure V, Sasaki T, Svenningsson P, Berton O, Fienberg AA, Nairn AC, Greengard P, Nestler EJ (2006) Phosphorylation of DARPP-32 at threonine-34 is required for cocaine action. Neuropsychopharmacology 31(3):555–562

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Svenningsson P, Picetti R, Schlussman SD, Nairn AC, Ho A, Greengard P, Kreek MJ (2006) Cocaine self-administration in mice is inversely related to phosphorylation at Thr34 (protein kinase A site) and Ser130 (kinase CK1 site) of DARPP-32. J Neurosci 26(10):2645–2651

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to acknowledge the Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) Scholar program (PI, Carolyn Mazure), the Specialized Centers of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health (PI, Rajita Sinha), and the NIH Office of Research on Women’s Health. The research described in the manuscript was supported by National Institutes on Health grants AR049469 (JRT and MRP), K01 DA 114038 (Carolyn Mazure, PI), K02 DA00436 (MRP), and R01 DA11717 (JRT).

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  1. Wendy J. Lynch

    Present address: Department of Psychiatric Medicine, University of Virginia, 1670 Discovery Drive, Charlottesville, VA, 22911, USA

Authors and Affiliations

  1. Division of Molecular Psychiatry and Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06508, USA

    Wendy J. Lynch, Drew D. Kiraly, Barbara J. Caldarone, Marina R. Picciotto & Jane R. Taylor

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  1. Wendy J. Lynch
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Correspondence to Wendy J. Lynch.

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Lynch, W.J., Kiraly, D.D., Caldarone, B.J. et al. Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats. Psychopharmacology 191, 263–271 (2007). https://doi.org/10.1007/s00213-006-0656-0

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  • DOI: https://doi.org/10.1007/s00213-006-0656-0

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