Abstract
Prepulse inhibition (PPI) of the startle reflex is a measure of sensory-motor synchronization. A deficit in PPI has been observed in psychiatric patients, especially those with schizophrenia and vulnerable subjects, since the neural bases of this disorder are also involved in the regulation of PPI. Recently, we have reported that baseline PPI levels in mice can predict their sensitivity to the conditioned reinforcing effects of cocaine in the conditioned place preference (CPP) paradigm. Mice with a low PPI presented a lower sensitivity to the conditioned rewarding effects of cocaine; however, once they acquired conditioned preference with a higher dose of the drug, a more persistent associative effect of cocaine with respect to environmental cues was evident in these animals when compared with High-PPI mice. Therefore, we proposed that the PPI paradigm can determine subjects with a higher vulnerability to the effects of cocaine. Developing locomotor sensitization after pre-exposure to cocaine is considered an indicator of transitioning from recreational use to a compulsive consumption of the drug. Thus, the aim of the present study was to evaluate whether subjects with a low PPI display a higher locomotor sensitization induced by cocaine. First, male and female OF1 mice were classified as High- or Low-PPI according to their baseline PPI levels. Subsequently, the motor effects induced by an acute dose of cocaine (Experiments 1 and 2) and the development of locomotor sensitization induced by pre-exposure to this drug (Experiments 3 and 4) were recorded using two apparatuses (Ethovision and actimeter). Low-PPI mice presented low sensitivity to the motor effects of an acute dose of cocaine, but a high increase of activity after repeated administration of the drug, thus suggesting a great developed behavioral sensitization. Differences after pretreatment with cocaine vs. saline were more pronounced among Low-PPI subjects than among High-PPI animals. These results endorse our hypothesis that the PPI paradigm can detect subjects who are more likely to display behaviors induced by cocaine and which can increase the risk of developing a cocaine use disorder. Herein, we further discuss whether a PPI deficit can be considered an endophenotype for cocaine use disorder.
Highlights
Cocaine use is a serious health problem with important social and economic consequences
In a previous study (Arenas et al, 2018), we showed that the baseline prepulse inhibition (PPI) level of mice predicts their sensitivity to the conditioned reinforcing effects of cocaine in the conditioned place preference (CPP) paradigm
The results reveal for the first time that male and female mice with a low PPI display lower hyperactivity when administered an acute dose of cocaine (10 mg/kg), but that they seem to develop a higher motor sensitization to the drug after intermittent exposure
Summary
Cocaine use is a serious health problem with important social and economic consequences. Cocaine is the most widely consumed illegal stimulant drug in Europe and North America, mainly by the young adult population [European Monitoring Centre for Drugs and Drug Addiction (EMCDDA, 2019)] It is one of the drugs with the fastest transition from abuse to compulsive use (Flórez-Salamanca et al, 2013), and its addiction presents a persistent and high susceptibility to relapse (Volkow et al, 2016). An endophenotype is considered a biomarker of genetic vulnerability that can be measured reliably and indicates a possible risk of a psychiatric disorder with clinical state independency (Beauchaine, 2009) It must meet certain criteria, such as distinction from illness in the general population, inheritability, and presence at a higher rate in non-affected family members than in the general population (Gottesman and Gould, 2003)
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