, Volume 235, Issue 9, pp 2651–2663 | Cite as

Baseline prepulse inhibition of the startle reflex predicts the sensitivity to the conditioned rewarding effects of cocaine in male and female mice

  • M. C. ArenasEmail author
  • C. I. Navarro-Francés
  • S. Montagud-Romero
  • J. Miñarro
  • C. Manzanedo
Original Investigation



Prepulse inhibition (PPI) of the startle reflex is a model of pre-attentional inhibitory function. The dopamine baseline in the nucleus accumbens plays a key role in PPI regulation as well as in the rewarding effects of cocaine.


The aim of this study was to evaluate the predictive ability of PPI to identify the more vulnerable mice of both sexes to the conditioned rewarding effects of cocaine.


Male and female OF1 mice were first tested in the PPI paradigm to classify them as high or low PPI. Afterwards, they were evaluated in the conditioned place preference (CPP) paradigm induced by cocaine (1, 6 and 12 mg/kg). Moreover, the D1R and D2R protein expressions in the striatum of high and low PPI animals were analysed by Western blot.


Only high-PPI mice acquired CPP induced by low doses of cocaine (1 and 6 mg/kg), while the low-PPI mice needed a higher dose of cocaine (12 mg/kg) to acquire the CPP, but once mice were conditioned, males did not extinguish the conditioned preference and females reinstated the preference with lower doses of cocaine than their control counterparts. Low-PPI animals, especially females, showed higher basal levels of D2R than those with a higher PPI.


Low-PPI mice presented a lower sensitivity to the conditioned rewarding effects of cocaine, but once they were conditioned with a higher dose, they displayed a stronger, perseverant conditioned preference. The predictive capacity of PPI to detect the more vulnerable mice to the conditioned effects of cocaine is discussed.


Prepulse inhibition Cocaine Conditioned place preference Dopamine Mice 



We wish to thank to Guillermo Chuliá for his editing of the manuscript.

Funding information

This work was supported by the following research grants: Ministerio de Economía y Competitividad. Proyecto I + D + i PSI2015-69649-R. Instituto de Salud Carlos III, Red de Trastornos Adictivos (RTA) RD16/0017/0007 and Unión Europea, Fondos FEDER “una manera de hacer Europa”. Open image in new window

Compliance with ethical standards

Procedures involving mice and their care conformed to national, regional, and local laws and regulations, which are in accordance with the Directive 2010/63/EU of the European Parliament and of the Council of September 22, 2010, on the protection of animals used for scientific purposes.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

213_2018_4959_MOESM1_ESM.pdf (103 kb)
ESM 1 (PDF 102 kb)


  1. Adams JU, Efferen TR, Duncan EJ, Rotrosen J (2001) Prepulse inhibition of the acoustic startle response in cocaine-withdrawn rats. Pharmacol Biochem Behav 68(4):753–759. CrossRefGoogle Scholar
  2. Aguilar MA, Rodríguez-Arias M, Miñarro J (2009) Neurobiological mechanisms of the reinstatement of drug-conditioned place preference. Brain Res Rev 59:253–277. CrossRefGoogle Scholar
  3. Arenas MC, Daza-Losada M, Vidal-Infer A, Aguilar MA, Miñarro J, Rodríguez-Arias M (2014) Capacity of novelty-induced locomotor activity and the hole-board test to predict sensitivity to the conditioned rewarding effects of cocaine. Physiol Behav 133:152–160. CrossRefGoogle Scholar
  4. Bergamini G, Sigrist H, Ferger B, Singewald N, Seifritz E, Pryce CR (2016) Depletion of nucleus accumbens dopamine leads to impaired reward and aversion processing in mice: relevance to motivation pathologies. Neuropharmacology 109:306–319. CrossRefGoogle Scholar
  5. Bitsios P, Giakoumaki SG, Frangou S (2005) The effects of dopamine agonists on prepulse inhibition in healthy men depend on baseline PPI values. Psychopharmacology 182(1):144–152. CrossRefGoogle Scholar
  6. Braff DL (2010) Prepulse inhibition of the startle reflex: a window on the brain in schizophrenia. Curr Top Behav Neurosci 4:349–371. CrossRefGoogle Scholar
  7. Braff DL, Geyer MA, Swerdlow NR (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology 156(2–3):234–258. CrossRefGoogle Scholar
  8. Broderick PA, Rosenbaum T (2013) Sex-specific brain deficits in auditory processing in an animal model of cocaine-related schizophrenic disorders. Brain Sci 3(2):504–520. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Byrnes JJ, Hammer RP (2000) The disruptive effect of cocaine on prepulse inhibition is prevented by repeated administration in rats. Neuropsychopharmacol 22(5):551–554. CrossRefGoogle Scholar
  10. Doherty JM, Masten VL, Powell SB, Ralph RJ, Klamer D, Low MJ, Geyer MA (2008) Contributions of dopamine D1, D2, and D3 receptor subtypes to the disruptive effects of cocaine on prepulse inhibition in mice. Neuropsychopharmacol 33(11):2648–2656. CrossRefGoogle Scholar
  11. Efferen TR, Duncan EJ, Szilagyi S, Chakravorty S, Adams JU, Gonzenbach S, Angrist B, Butler PD, Rotrosen J (2000) Diminished acoustic startle in chronic cocaine users. Neuropsychopharmacol 22(1):89–96. CrossRefGoogle Scholar
  12. Francis DD, Szegda K, Campbell G, Martin WD, Insel TR (2003) Epigenetic sources of behavioural differences in mice. Nat Neurosci 6:445–446. CrossRefGoogle Scholar
  13. Geyer MA, Wilkinson LS, Humby T, Robbins TW (1993) Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia. Biol Psychiatry 34:361–372. CrossRefGoogle Scholar
  14. Greenwood TA, Braff DL, Light GA, Cadenhead KS, Calkins ME, Dobie DJ, Freedman R, Green MF, Gur RE, Gur RC, Mintz J, Nuechterlein KH, Olincy A, Radant AD, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Swerdlow NR, Tsuang DW, Tsuang MT, Turetsky BI, Schork NJ (2007) Initial heritability analyses of endophenotypic measures for schizophrenia: the Consortium on the Genetics of Schizophrenia. Arch Gen Psychiatry 64:1242–1250. CrossRefGoogle Scholar
  15. Heffner TG, Hartman JA, Seiden LS (1980) A rapid method for the regional dissection of the rat brain. Pharmacol Biochem Behav 13(3):453–456. CrossRefGoogle Scholar
  16. Kedzior KK, Martin-Iverson MT (2006) Chronic cannabis use is associated with attention-modulated reduction in prepulse inhibition of the startle reflex in healthy humans. J Psychopharmacol 20:471–484. CrossRefGoogle Scholar
  17. Kim JH, Lawrence AJ (2014) Drugs currently in phase II clinical trials for cocaine addiction. Expert Opin Investig Drugs 23(8):1105–1122. CrossRefGoogle Scholar
  18. Kohl S, Heekeren K, Klosterkötten J, Kuhn J (2013) Prepulse inhibition in psychiatric disorders—apart from schizophrenia. J Psychiatr Res 47:445–452. CrossRefGoogle Scholar
  19. Labouesse MA, Stadlbauer U, Langhans W, Meyer U (2013) Chronic high fat diet consumption impairs sensorimotor gating in mice. Psychoneuroendocrinology 38:2562–2574CrossRefGoogle Scholar
  20. Lévesque A, Roy É, Jutras-Aswad D, Zang G, Artenie AA, Bruneau J (2016) Examining the link between psychological distress, mental health disorders and sharing behaviors among cocaine users. Addict Behav 62:54–59. CrossRefGoogle Scholar
  21. Leyton M (2017) Altered dopamine transmission as a familial risk trait for addictions. Curr Opin Behav Sci 13:130–138. CrossRefGoogle Scholar
  22. Leyton M, Vezina P (2014) Dopamine ups and downs in vulnerability to addictions: a neurodevelopmental model. TIPS 35:268–276. CrossRefGoogle Scholar
  23. Lipska B, Swerdlow NR, Geyer MA, Jaskiw GE, Braff DL, Weinberger DR (1995) Neonatal excitoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine. Psychopharmacology 122:35–43. CrossRefGoogle Scholar
  24. Maldonado C, Rodríguez-Arias M, Castillo A, Aguilar MA, Miñarro J (2006) Gamma-hydroxybutyric acid affects the acquisition and reinstatement of cocaine-induced conditioned place preference in mice. Behav Pharmacol 17:119–131. CrossRefGoogle Scholar
  25. Manzanedo C, Aguilar MA, Rodríguez-Arias M, Miñarro J (2001) Effects of dopamine antagonists with different receptor blockade profiles on morphine-induced place preference in male mice. Behav Brain Res 121:189–197. CrossRefGoogle Scholar
  26. Manzanedo C, García-Pardo MP, Rodríguez-Arias M, Miñarro J, Aguilar MA (2012) Pre-treatment with high doses of cocaine decreases the reinforcing effects of cocaine in the conditioned place preference paradigm. Neurosci Lett 516:29–33. CrossRefGoogle Scholar
  27. Marín M, Ponce G, Martínez-Gras I, Koeneke A, Curivil P, Jiménez-Arriero MA, Rubio G (2012) Impairments of prepulse inhibition of the startle response in abstinent alcoholic male patients. Alcohol Alcohol 47(5):545–551. CrossRefGoogle Scholar
  28. Martínez ZA, Ellison GD, Geyer MA, Swerdlow NR (1999) Effects of sustained cocaine exposure on sensorimotor gating of startle in rats. Psychopharmacology 142:253–260. CrossRefGoogle Scholar
  29. Mateos-García A, Roger-Sánchez C, Rodriguez-Arias M, Miñarro J, Aguilar MA, Manzanedo C, Arenas MC (2015) Higher sensitivity to the conditioned rewarding effects of cocaine and MDMA in high-novelty-seekers mice exposed to a cocaine binge during adolescence. Psychopharmacology 232:101–113. CrossRefGoogle Scholar
  30. Montagud-Romero S, Reguilon MD, Roger-Sanchez C, Pascual M, Aguilar MA, Guerri C, Miñarro J, Rodríguez-Arias M (2016) Role of dopamine neurotransmission in the long-term effects of repeated social defeat on the conditioned rewarding effects of cocaine. Prog Neuro-Psychopharmacol Biol Psychiatry 71:144–154. CrossRefGoogle Scholar
  31. Morales-Muñoz I, Jurado-Barba R, Ponce G, Martínez-Gras I, Jiménez-Arriero MA, Moratti S, Rubio G (2014) Characterizing cannabis-induced psychosis: a study with prepulse inhibition of the startle reflex. Psychiatry Res 220:535–540. CrossRefGoogle Scholar
  32. Mosher LJ, Frau R, Pardu A, Pes R, Devoto P, Bortolato M (2016) Selective activation of D1 dopamine receptors impairs sensorimotor gating in Long-Evans rats. Br J Pharmacol 173:2122–2134. CrossRefGoogle Scholar
  33. OEDT (2016) Encuesta sobre Uso de Drogas en Enseñanzas Secundarias en España. ESTUDES 2014Google Scholar
  34. Peleg-Raibstein D, Hauser J, Llano Lopez LH, Feldon J, Gargiulo PA, Yee BK (2013) Baseline prepulse inhibition expression predicts the propensity of developing sensitization to the motor stimulant effects of amphetamine in C57BL/6 mice. Psychopharmacology 225(2):341–352. CrossRefGoogle Scholar
  35. Preller KH, Ingold N, Hulka LM, Vonmoos M, Jenni D, Baumgartner MR, Vollenweider FX, Quednow BB (2013) Increased sensorimotor gating in recreational and dependent cocaine users is modulated by craving and attention-deficit/hyperactivity disorder symptoms. Biol Psychiatry 73(3):225–234. CrossRefGoogle Scholar
  36. Rohleder C, Wiedermann D, Neumaier B, Drzezga A, Timmermann L, Graf R, Leweke FM, Endepols H (2016) The functional networks of prepulse inhibition: neuronal connectivity analysis based on FDG-PET in awake and unrestrained rats. Front Behav Neurosci 10:148. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Scholes KE, Martin-Iverson MT (2009) Alterations to pre-pulse inhibition (PPI) in chronic cannabis users are secondary to sustained attention deficits. Psychopharmacology 207:469–484. CrossRefGoogle Scholar
  38. Scofield MD, Heinsbroek JA, Gipson CD, Kupchik YM, Spencer S, Smith AC et al (2016) The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev 68(3):816–871. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Seeman P (2013) Schizophrenia and dopamine receptors. Eur Neuropsychopharmacol 23(9):999–1009. CrossRefGoogle Scholar
  40. Swerdlow NR, Bhakta SG, Rana BK, Kei J, Chou HH, Talledo JA (2017) Sensorimotor gating in healthy adults tested over a 15 year period. Biol Psychol 123:177–186. CrossRefGoogle Scholar
  41. Swerdlow NR, Braff DL, Geyer MA (2016) Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next. J Psychopharmacol 30(11):1072–1081. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Swerdlow NR, Light GA (2016) Animal models of deficient sensorimotor gating in schizophrenia: are they still relevant? Curr Top Behav Neurosci 28:305–325. CrossRefGoogle Scholar
  43. Swerdlow NR, Stephany N, Wasserman LC, Talledo J, Shoemaker J, Auerbach PP (2003) Amphetamine effects on prepulse inhibition across-species: replication and parametric extension. Neuropsychopharmacol 28:640–650. CrossRefGoogle Scholar
  44. Swerdlow NR, Weber M, Qu Y, Light GA, Braff DL (2008) Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology 199(3):331–388. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Talledo JA, Sutherland Owens AN, Schortinghuis T, Swerdlow NR (2009) Amphetamine effects on startle gating in normal women and female rats. Psychopharmacology 204(1):165–175. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227–462. CrossRefGoogle Scholar
  47. UNODC United Nations Office on Drugs and Crime, World drug report (2014) United Nations publication, Sales No. E.14.XI.7.
  48. Valsamis B, Schmid S (2011) Habituation and prepulse inhibition of acoustic startle in rodents. J Vis Exp 55:1–10. CrossRefGoogle Scholar
  49. Vidal-Infer A, Arenas MC, Daza-Losada M, Aguilar MA, Miñarro J, Rodríguez-Arias M (2012) High novelty-seeking predicts greater sensitivity to the conditioned rewarding effects of cocaine. Pharmacol Biochem Behav 102:124–132. CrossRefGoogle Scholar
  50. Volkow ND, Wang GJ, Begleiter H, Porjesz B, Fowler JS, Telang F, Wong C, Ma Y, Logan J, Goldstein R, Alexoff D, Thanos PK (2006) High levels of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factors. Arch Gen Psychiatry 63:999–1008CrossRefGoogle Scholar
  51. Volkow ND, Morales M (2015) The brain on drugs: from reward to addiction. Cell 162(4):712–725. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Gifford A, Hitzemann R, Ding YS, Pappas N (1999) Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. Am J Psychiatry 156(9):1440–1443Google Scholar
  53. Wakabayashi C, Numakawa T, Ooshima Y, Hattori K, Kunugi H (2015) Possible role of the dopamine D1 receptor in the sensorimotor gating deficits induced by high-fat diet. Psychopharmacology 232(24):4393–4400CrossRefGoogle Scholar
  54. Yamashita M, Fukushima S, Shen HW, Hall FS, Uhl GR, Numachi Y, Kobayashi H, Sora I (2006) Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. Neuropsychopharmacol 31(10):2132–2139. CrossRefGoogle Scholar
  55. Yeomans JS, Lee J, Yeomans MH, Steidl S, Li L (2006) Midbrain pathways for prepulse inhibition and startle activation in rat. Neuroscience 142(4):921–929. CrossRefGoogle Scholar
  56. Zhang J, Forkstam C, Engel JA, Svensson L (2000) Role of dopamine in prepulse inhibition of acoustic startle. Psychopharmacology 149(2):181–188CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Unidad de investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de PsicologíaUniversitat de ValènciaValenciaSpain

Personalised recommendations