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.
Subject(s)
Cocaine/pharmacology , Conditioning, Classical/drug effects , Dopamine Uptake Inhibitors/pharmacology , Prepulse Inhibition/drug effects , Reflex, Startle/drug effects , Reward , Animals , Conditioning, Classical/physiology , Dopamine/pharmacology , Female , Forecasting , Male , Mice , Nucleus Accumbens/drug effects , Nucleus Accumbens/physiology , Prepulse Inhibition/physiology , Reflex, Startle/physiologyABSTRACT
INTRODUCTION: Prepulse inhibition (PPI) of the startle response is an index used to evaluate how the pre-attention system works. PPI is altered in patients with a mental disorder such as schizophrenia and in subjects who are vulnerable to it. Likewise, cocaine users also frequently exhibit psychiatric disorders as schizophrenia. AIM: To know the alterations that cocaine produces on PPI. DEVELOPMENT: A comprehensive review is carried out, covering both clinical and preclinical studies with animal models that have evaluated the effects of cocaine exposure on the PPI paradigm. Underlying neural bases and mechanisms of action are suggested to explain these findings. CONCLUSIONS: Cocaine alters PPI through its action on the dopaminergic system. Acute exposure of cocaine decreases PPI by increasing dopamine, while with chronic use, depending on withdrawal time, PPI can be restored. However, the effects of cocaine on PPI appear to depend on the baseline levels of PPI shown by the individual. Thus, since a deficit in PPI has been associated with a greater vulnerability to developing mental pathologies such as schizophrenia, PPI level in subjects could be considered as a biomarker of psychiatric vulnerability. Therefore, a better understanding of the effect of drugs such as cocaine on PPI may help to understand the development of dual pathology.
TITLE: Efecto de la cocaina sobre la inhibicion por prepulso de la respuesta de sobresalto.Introduccion. La inhibicion por prepulso (IPP) de la respuesta de sobresalto es una medida de sincronizacion sensitivomotora basada en la respuesta del reflejo de sobresalto. Un deficit en la IPP se ha observado en pacientes psiquiatricos, especialmente con esquizofrenia, asi como en sujetos vulnerables a desarrollarla. Asimismo, los consumidores de cocaina presentan un alto indice de patologias psiquiatricas como la esquizofrenia. Objetivo. Conocer las alteraciones que el consumo de cocaina puede producir en la IPP. Desarrollo. Se realiza una revision exhaustiva de los estudios, tanto clinicos como con modelos animales, que hayan evaluado la IPP tras el consumo o la administracion de cocaina. Se sugieren bases neurales y mecanismos de accion subyacentes para explicar los resultados. Conclusiones. La cocaina altera la IPP a traves de su accion sobre el sistema dopaminergico. La administracion aguda de cocaina disminuye la IPP al aumentar la dopamina, mientras que con el consumo cronico, dependiendo del tiempo de abstinencia, la IPP puede restablecerse. Sin embargo, los efectos de la cocaina sobre la IPP parecen depender de los niveles basales de la IPP que muestre el individuo. Asi, dado que un deficit en la IPP se ha relacionado con una mayor vulnerabilidad a desarrollar patologias mentales como la esquizofrenia, los niveles de la IPP en los sujetos podrian considerarse como un biomarcador de vulnerabilidad psiquiatrica. Por ello, conocer mejor el efecto que drogas como la cocaina ejercen sobre la IPP puede ayudar a comprender el desarrollo de la patologia dual.
Subject(s)
Cocaine/pharmacology , Prepulse Inhibition/drug effects , Reflex, Startle/drug effects , HumansABSTRACT
RATIONALE: The practice of binge drinking is very common among adolescents of both sexes. It can have long-term consequences with respect to drug consumption during adulthood, but knowledge on these effects in females is limited. OBJECTIVES: The long-lasting effects of intermittent exposure to ethanol (EtOH) during adolescence on different cocaine-elicited behaviours, including locomotor reactivity, conditioned place preference (CPP) and intravenous self-administration, were evaluated in male and female adult mice. It was hypothesized that an EtOH binge during adolescence would increase sensitivity to the effects of a sub-threshold dose of cocaine and has a differential impact on the drug's effects in males and females. METHODS: Adolescent OF1 mice (postnatal day (PND) 26) underwent a 2-week pre-treatment schedule consisting of 16 doses of EtOH (2.5 g/kg) or saline (twice daily administrations separated by a 4-h interval i.p.) administered on two consecutive days separated by an interval of 2 days. Three weeks later (PND > 60), we assessed locomotor activity responses induced by an acute injection of different doses of cocaine in experiment 1 and the rewarding effects of cocaine on the CPP (1 mg/kg) and intravenous self-administration (1 mg/kg/infusion) paradigms in experiment 2. RESULTS: Pre-exposure to EtOH during adolescence altered motor reactivity to cocaine in a dose- and sex-dependent manner, increased sensitivity to cocaine in CPP and enhanced self-administration in adult mice. CONCLUSIONS: The effects of intermittent exposure to ethanol during adolescence are evident in adulthood, during which greater sensitivity and intake of cocaine is observed and differ in each sex.
