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Prenatal Amphetamine-Induced Dopaminergic Alteration in a Gender- and Estrogen-Dependent Manner

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Abstract

Prenatal exposure to amphetamine induces changes in dopamine receptors in mesolimbic areas and alters locomotor response to amphetamine during adulthood. Sex differences have been reported in amphetamine-induced brain activity and stress sensitivity. We evaluated the effects of prenatal amphetamine exposure on locomotor activity, dopamine receptors and tyrosine hydroxylase mRNA expression in nucleus accumbens and caudate-putamen in response to amphetamine challenge in adult female and male rats. The role of estrogen in the response to restraint stress was analyzed in ovariectomized, prenatally amphetamine-exposed rats. Pregnant rats were treated with d-amphetamine during days 15–21 of gestation. Nucleus accumbens and caudate-putamen were processed for mRNA determination by real-time PCR. In nucleus accumbens, higher mRNA dopamine (D3) receptor expression was found in basal and d-amphetamine-challenge conditions in female than male, and prenatal amphetamine increased the difference. No sex differences were observed in caudate-putamen. Basal saline-treated females showed higher locomotor activity than males. Amphetamine challenge in prenatally amphetamine-exposed rats increased locomotor activity in males and reduced it in females. In nucleus accumbens, estrogen diminished mRNA D1, D2 and D3 receptor expression in basal, and D1 and D3 in ovariectomized stressed rats. Estrogen prevented the increase in tyrosine hydroxylase expression induced by stress in ovariectomized prenatally exposed rats. In conclusion, estrogen modulates mRNA levels of D1, D2 and D3 receptors and tyrosine hydroxylase expression in nucleus accumbens; prenatal amphetamine-exposure effects on D3 receptors and behavioral responses were gender dependent.

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Data Availability

The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are included in the paper.

Abbreviations

PEA:

Prenatal exposure to amphetamine

CPu:

Caudate-putamen

DA:

Dopamine

d-AMPH:

D-amphetamine

E2:

Estradiol

G15-21:

Day15-21 pregnancy

D1, D2, D3:

Dopamine receptors

NAcc:

Nucleus accumbens

OVX:

Ovariectomy

PND:

Postnatal day

TH:

Tyrosine hydroxylase

VTA:

Ventral tegmental area

References

  1. Purves-Tyson TD, Boerrigter D, Allen K, Zavitsanou K, Karl T, Djunaidi V, Double KL, Desai R, Handelsman DJ, Weickert CS (2015) Testosterone attenuates and the selective estrogen receptor modulator, raloxifene, potentiates amphetamine-induced locomotion in male rats. Horm Behav 70:73–84

    Article  CAS  PubMed  Google Scholar 

  2. Mattson BJ, Crombag HS, Mitchell T, Simmons DE, Kreuter JD, Morales M, Hope BT (2007) Repeated amphetamine administration outside the home cage enhances drug-induced Fos expression in rat nucleus accumbens. Behav Brain Res 185(2):88–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Paz MC, Marchese NA, Cancela LM, Bregonzio C (2013) Angiotensin II AT(1) receptors are involved in neuronal activation induced by amphetamine in a two-injection protocol. Biomed Res Int 2013:534817

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hope BT, Simmons DE, Mitchell TB, Kreuter JD, Mattson BJ (2006) Cocaine-induced locomotor activity and Fos expression in nucleus accumbens are sensitized for 6 months after repeated cocaine administration outside the home cage. Eur J Neurosci 24(3):867–875

    Article  PubMed  Google Scholar 

  5. Hope BT, Nye HE, Kelz MB, Self DW, Iadarola MJ, Nakabeppu Y, Duman RS, Nestler EJ (1994) Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13(5):1235–1244

    Article  CAS  PubMed  Google Scholar 

  6. Cullinan WE, Herman JP, Battaglia DF, Akil H, Watson SJ (1995) Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience 64(2):477–505

    Article  CAS  PubMed  Google Scholar 

  7. Rotllant D, Marquez C, Nadal R, Armario A (2010) The brain pattern of c-fos induction by two doses of amphetamine suggests different brain processing pathways and minor contribution of behavioural traits. Neuroscience 168(3):691–705

    Article  CAS  PubMed  Google Scholar 

  8. Hruba L, Schutova B, Slamberova R (2012) Sex differences in anxiety-like behavior and locomotor activity following prenatal and postnatal methamphetamine exposure in adult rats. Physiol Behav 105(2):364–370

    Article  CAS  PubMed  Google Scholar 

  9. Segarra AC, Agosto-Rivera JL, Febo M, Lugo-Escobar N, Menendez-Delmestre R, Puig-Ramos A, Torres-Diaz YM (2010) Estradiol: a key biological substrate mediating the response to cocaine in female rats. Horm Behav 58(1):33–43

    Article  CAS  PubMed  Google Scholar 

  10. Slamberova R, Macuchova E, Nohejlova K, Stofkova A, Jurcovicova J (2014) Effect of amphetamine on adult male and female rats prenatally exposed to methamphetamine. Prague Med Rep 115(1–2):43–59

    Article  CAS  PubMed  Google Scholar 

  11. Pennacchio GE, Neira FJ, Soaje M, Jahn GA, Valdez SR (2017) Effect of hyperthyroidism on circulating prolactin and hypothalamic expression of tyrosine hydroxylase, prolactin signaling cascade members and estrogen and progesterone receptors during late pregnancy and lactation in the rat. Mol Cell Endocrinol 442:40–50

    Article  CAS  PubMed  Google Scholar 

  12. Slamberova R, Yamamotova A, Pometlova M, Schutova B, Hruba L, Nohejlova-Deykun K, Nova E, Macuchova E (2012) Does prenatal methamphetamine exposure induce cross-sensitization to cocaine and morphine in adult male rats? Prague Med Rep 113(3):189–205

    Article  CAS  PubMed  Google Scholar 

  13. Casarsa BS, Marinzalda MA, Marchese NA, Paz MC, Vivas L, Baiardi G, Bregonzio C (2015) A previous history of repeated amphetamine exposure modifies brain angiotensin II AT1 receptor functionality. Neuroscience 307:1–13

    Article  CAS  PubMed  Google Scholar 

  14. Marchese NA, Occhieppo VB, Basmadjian OM, Casarsa BS, Baiardi G, Bregonzio C (2020) Angiotensin II modulates amphetamine-induced glial and brain vascular responses, and attention deficit via angiotensin type 1 receptor: evidence from brain regional sensitivity to amphetamine. Eur J Neurosci 51(4):1026–1041

    Article  PubMed  Google Scholar 

  15. Marchese NA, Artur de laVillarmois E, Basmadjian OM, Perez MF, Baiardi G, Bregonzio C (2016) Brain Angiotensin II AT1 receptors are involved in the acute and long-term amphetamine-induced neurocognitive alterations. Psychopharmacology 233(5):795–807

    Article  CAS  PubMed  Google Scholar 

  16. Fanous S, Lacagnina MJ, Nikulina EM, Hammer RP Jr (2011) Sensitized activation of Fos and brain-derived neurotrophic factor in the medial prefrontal cortex and ventral tegmental area accompanies behavioral sensitization to amphetamine. Neuropharmacology 61(4):558–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25(4):402–408

    Article  CAS  Google Scholar 

  18. Tan SE (2003) Prenatal amphetamine exposure alters behavioral reactivity to amphetamine in rats. Neurotoxicol Teratol 25(5):579–585

    Article  CAS  PubMed  Google Scholar 

  19. Lyon M, McClure WO (1994) Investigations of fetal development models for prenatal drug exposure and schizophrenia. Prenatal d-amphetamine effects upon early and late juvenile behavior in the rat. Psychopharmacology 116(2):226–236

    Article  CAS  PubMed  Google Scholar 

  20. Nasif FJ, Cuadra GR, Ramirez OA (1999) Permanent alteration of central noradrenergic system by prenatally administered amphetamine. Brain Res Dev Brain Res 112(2):181–188

    Article  CAS  PubMed  Google Scholar 

  21. Uban KA, Comeau WL, Bodnar T, Yu WK, Weinberg J, Galea LA (2015) Amphetamine sensitization and cross-sensitization with acute restraint stress: impact of prenatal alcohol exposure in male and female rats. Psychopharmacology 232(10):1705–1716

    Article  CAS  PubMed  Google Scholar 

  22. Uban KA, Comeau WL, Ellis LA, Galea LA, Weinberg J (2013) Basal regulation of HPA and dopamine systems is altered differentially in males and females by prenatal alcohol exposure and chronic variable stress. Psychoneuroendocrinology 38(10):1953–1966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Segal DM, Moraes CT, Mash DC (1997) Up-regulation of D3 dopamine receptor mRNA in the nucleus accumbens of human cocaine fatalities. Brain Res Mol Brain Res 45(2):335–339

    Article  CAS  PubMed  Google Scholar 

  24. Volkow ND, Chang L, Wang GJ, Fowler JS, Ding YS, Sedler M, Logan J, Franceschi D, Gatley J, Hitzemann R, Gifford A, Wong C, Pappas N (2001) Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry 158(12):2015–2021

    Article  CAS  PubMed  Google Scholar 

  25. Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, Dewey SL, Wolf AP (1993) Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14(2):169–177

    Article  CAS  PubMed  Google Scholar 

  26. Wang GJ, Smith L, Volkow ND, Telang F, Logan J, Tomasi D, Wong CT, Hoffman W, Jayne M, Alia-Klein N, Thanos P, Fowler JS (2012) Decreased dopamine activity predicts relapse in methamphetamine abusers. Mol Psychiatry 17(9):918–925

    Article  CAS  PubMed  Google Scholar 

  27. Sun H, Calipari ES, Beveridge TJ, Jones SR, Chen R (2015) The brain gene expression profile of dopamine D2/D3 receptors and associated signaling proteins following amphetamine self-administration. Neuroscience 307:253–261

    Article  CAS  PubMed  Google Scholar 

  28. Miyamoto Y, Nagayoshi I, Nishi A, Fukuda T (2019) Three divisions of the mouse caudal striatum differ in the proportions of dopamine D1 and D2 receptor-expressing cells, distribution of dopaminergic axons, and composition of cholinergic and GABAergic interneurons. Brain Struct Funct 224(8):2703–2716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev 16(3):223–244

    Article  CAS  PubMed  Google Scholar 

  30. Bartoletti M, Gaiardi M, Gubellini G, Bacchi A, Babbini M (1983) Long-term sensitization to the excitatory effects of morphine. A motility study in post-dependent rats. Neuropharmacology 22(10):1193–1196

    Article  CAS  PubMed  Google Scholar 

  31. Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 396(2):157–198

    Article  CAS  PubMed  Google Scholar 

  32. Antelman SM, Eichler AJ, Black CA, Kocan D (1980) Interchangeability of stress and amphetamine in sensitization. Science 207(4428):329–331

    Article  CAS  PubMed  Google Scholar 

  33. Piazza PV, Deminiere JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245(4925):1511–1513

    Article  CAS  PubMed  Google Scholar 

  34. 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 

  35. 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 

  36. Adinoff B, Williams MJ, Best SE, Harris TS, Chandler P, Devous MD Sr (2006) Sex differences in medial and lateral orbitofrontal cortex hypoperfusion in cocaine-dependent men and women. Gend Med 3(3):206–222

    Article  PubMed  PubMed Central  Google Scholar 

  37. van der Plas EA, Crone EA, van den Wildenberg WP, Tranel D, Bechara A (2009) Executive control deficits in substance-dependent individuals: a comparison of alcohol, cocaine, and methamphetamine and of men and women. J Clin Exp Neuropsychol 31(6):706–719

    Article  PubMed  Google Scholar 

  38. Weiss RD, Martinez-Raga J, Griffin ML, Greenfield SF, Hufford C (1997) Gender differences in cocaine dependent patients: a 6 month follow-up study. Drug Alcohol Depend 44(1):35–40

    Article  CAS  PubMed  Google Scholar 

  39. Schindler CW, Bross JG, Thorndike EB (2002) Gender differences in the behavioral effects of methamphetamine. Eur J Pharmacol 442(3):231–235

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Cailhol S, Mormede P (1999) Strain and sex differences in the locomotor response and behavioral sensitization to cocaine in hyperactive rats. Brain Res 842(1):200–205

    Article  CAS  PubMed  Google Scholar 

  42. Carlsson M, Svensson K, Eriksson E, Carlsson A (1985) Rat brain serotonin: biochemical and functional evidence for a sex difference. J Neural Transm 63(3–4):297–313

    Article  CAS  PubMed  Google Scholar 

  43. Gordon JH, Shellenberger K (1974) Regional catecholamine content in the rat brain: sex differences and correlation with motor activity. Neuropharmacology 13(2):129–137

    Article  CAS  PubMed  Google Scholar 

  44. Fleckenstein AE, Haughey HM, Metzger RR, Kokoshka JM, Riddle EL, Hanson JE, Gibb JW, Hanson GR (1999) Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function. Eur J Pharmacol 382(1):45–49

    Article  CAS  PubMed  Google Scholar 

  45. Rothman RB, Baumann MH (2003) Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 479(1–3):23–40

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to Ms. E. G de DiNasso and Mr. J. Rosales for their skillful technical assistance and Dr. Mariella Superina for her skillful assistance in manuscript language revision.

Funding

This work has been supported by grants SeCTy P J/492 and SIIP 06/J520 from the Universidad Nacional de Cuyo, Mendoza, Argentina and PIP 081-2015 from CONICET.

Author information

Author notes

  1. C. Bregonzio and M. Soaje have contributed equally to this work.

Authors and Affiliations

  1. Laboratorio de Reproducción y Lactancia, IMBECU-CONICET, Casilla de Correo 855, 5500, Mendoza, Argentina

    G. E. Pennacchio, F. E. Santonja, F. J. Neira & M. Soaje

  2. Instituto de Farmacología Experimental Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina

    C. Bregonzio

  3. Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina

    M. Soaje

Authors
  1. G. E. Pennacchio
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  3. F. J. Neira
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  4. C. Bregonzio
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  5. M. Soaje
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Contributions

PGE: conducted real time PCR, collaborated in methodology writing, reviewed the manuscript. SFE: participated in the animal experiment, collaborated in surgical procedure and locomotor activity recording. NFJ: participated in the animal experiment, collaborated in locomotor activity recording. BC: conceptualized and organized the experiments, data curation, writing-reviewing and editing the manuscript. SM: conceptualized and organized the experiments, data curation, writing-reviewing and editing the manuscript.

Corresponding author

Correspondence to M. Soaje.

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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Ethical Approval

All experimental procedures were approved by the Care and Use of Laboratory Animals Committee (CICUAL) of the Faculty of Medical Sciences, National University of Cuyo, Mendoza, Argentina.

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Pennacchio, G.E., Santonja, F.E., Neira, F.J. et al. Prenatal Amphetamine-Induced Dopaminergic Alteration in a Gender- and Estrogen-Dependent Manner. Neurochem Res 47, 1317–1328 (2022). https://doi.org/10.1007/s11064-022-03531-1

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