Abstract
Rationale
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.
Objectives
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.
Methods
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.
Results
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.
Conclusions
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.
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Acknowledgements
We wish to thank to Guillermo Chuliá for his editing of the manuscript.
Funding
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”. 
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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.
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Highlights
• Low-PPI mice present a lower sensitivity to cocaine’s conditioned rewarding effects
• Low-PPI mice display a stronger perseverant drug-seeking behaviour
• Low-PPI females show higher levels of D2R expression in the striatum
• The PPI paradigm predicts mice’s sensitivity to cocaine’s conditioned rewarding effects
• A PPI deficit could indicate a higher vulnerability to develop a substance use disorder
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Arenas, M.C., Navarro-Francés, C.I., Montagud-Romero, S. et al. Baseline prepulse inhibition of the startle reflex predicts the sensitivity to the conditioned rewarding effects of cocaine in male and female mice. Psychopharmacology 235, 2651–2663 (2018). https://doi.org/10.1007/s00213-018-4959-8
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DOI: https://doi.org/10.1007/s00213-018-4959-8