Antagonism of corticotropin-releasing factor CRF1 receptors blocks the enhanced response to cocaine after social stress.

Numerous studies have shown that social defeat stress induces an increase in the rewarding effects of cocaine. In this study we have investigated the role played by the main hypothalamic stress hormone, corticotropin-releasing factor (CRF), in the effects that repeated social defeat (RSD) induces in the conditioned rewarding effects and locomotor sensitization induced by cocaine. A total of 220 OF1 mice were divided into experimental groups according to the treatment received before each social defeat: saline, 5 or 10 mg/kg of the nonpeptidic corticotropin-releasing factor CRF1 receptor antagonist CP-154,526, or 15 or 30 µg/kg of the peptidic corticotropin-releasing factor CRF2 receptor antagonist Astressin2-B. Three weeks after the last defeat, conditioned place preference (CPP) induced by 1 mg/kg of cocaine was evaluated. Motor response to 10 mg/kg of cocaine was also studied after a sensitization induction. Blockade of corticotropin-releasing factor CRF1 receptor reversed the increase in cocaine CPP induced by social defeat. Conversely, peripheral corticotropin-releasing factor CRF2 receptor blockade produced similar effects to those observed in socially stressed animals. The effect of RSD on cocaine sensitization was again blocked by the corticotropin-releasing factor CRF1 receptor antagonist, while peripheral CRF2 receptor antagonist did not show effect. Acute administration of Astressin2-B induced an anxiogenic response. Our results confirm that CRF modulates the effects of social stress on reinforcement and sensitization induced by cocaine in contrasting ways. These findings highlight CRF receptors as potential therapeutic targets to be explored by research about stress-related addiction problems.

Influencia del estrés social en el efecto reforzante del éxtasis bajo el paradigma de condicionamiento de preferencia de lugar: papel de la edad, la dosis y el tipo de estrés / The influence of social stress on the reinforcing effect of ecstasy under the conditioned place preference paradigm: the role played by age, dose and type of stress

Introducción. La adicción a las drogas es una enfermedad crónica con graves repercusiones para sus consumidores y que hasta el momento no tiene curación. Los psicoestimulantes, como el éxtasis, son las drogas ilegales más consumidas, tanto por los adolescentes como por los adultos jóvenes. Objetivos. Describir y analizar diferentes variables que pueden influir en los efectos del estrés social y las propiedades reforzantes del éxtasis. Asimismo, se pretende evaluar si los efectos del estrés social sobre el condicionamiento de preferencia de lugar (inducido por el éxtasis) son similares a los que ejercen otros psicoestimulantes, como la cocaína. Desarrollo. La derrota social evaluada a corto plazo sólo ejerce un efecto en animales adultos, disminuyendo la sensibilidad a los efectos reforzantes condicionados del éxtasis. Por el contrario, el estrés social a largo plazo incrementa los efectos reforzantes de esta droga en animales adolescentes y adultos. La dosis de éxtasis utilizada ejerce una escasa influencia en los efectos de la derrota social sobre el condicionamiento de preferencia de lugar. En comparación con los efectos del estrés social sobre las propiedades reforzantes de la cocaína, únicamente se observa un efecto diferente cuando la derrota es evaluada a corto plazo. Conclusiones. Existen diferentes variables que modulan los efectos reforzantes del éxtasis, como la edad de los animales, la dosis utilizada o la exposición al estrés. El estudio de todas estas variables es esencial para determinar los factores de vulnerabilidad neurobiológicos y ambientales que pueden influir en el desarrollo de dependencia al éxtasis (AU)

Introduction. Addiction to drugs is a chronic illness with severe repercussions for those that consume them and to date has no known cure. Psychostimulants, such as ecstasy, are the most widely consumed illegal drugs among adolescents and young adults. Aims. To describe and to analyse the different variables that can influence the effects of social stress and the reinforcing properties of ecstasy. Likewise, it also seeks to evaluate whether the effects of social stress on conditioned place preference (induced by ecstasy) are similar to those deriving from other psychostimulants, such as cocaine. Development. Social defeat evaluated in the short term has an effect only on adult animals by diminishing sensitivity to the conditioned reinforcing effects of ecstasy. Conversely, long-term social stress increases the reinforcing effects of this drug in adolescent and adult animals. The dose of ecstasy employed has little influence on the effects of social defeat on conditioned place preference. In comparison to the effects of social stress on the reinforcing properties of cocaine, a different effect is only observed when defeat is evaluated in the short term. Conclusions. Different variables modulate the reinforcing effects of ecstasy, such as the age of the animals, the dose employed or exposure to stress. It is essential to study these variables in order to determine the neurobiological and environmental vulnerability factors that can have an influence on the development of addiction to ecstasy (AU)

High novelty-seeking predicts greater sensitivity to the conditioned rewarding effects of cocaine.

Novelty-seeking in rodents, defined as enhanced specific exploration of novel situations, is considered to predict the response of animals to drugs of abuse and, thus, identify "drug-vulnerable" individuals. The main objective of this work was to determine the capacity of two animal models-the novel object recognition task and the novel environment test-for evaluating to what extent novelty-seeking can predict greater sensitivity to the rewarding properties of cocaine in young adult (PND 56) and adolescent (PND 35) OF1 mice of both sexes. Conditioned place preference, a useful tool for evaluating the sensitivity of individuals to the incentive properties of addictive drugs, was induced with a sub-threshold dose of cocaine (1 mg/kg, i.p.). Three factors that predispose individuals to addiction were considered: age, sex and novelty-seeking trait. CPP was detected only in the young adults that spent most time exploring the novel environment (High Novel Environment Seekers, High-Environment-NS). The novel environment test seemed to be more effective than the novel object recognition task in identifying young adults vulnerable to drugs; specifically, it revealed a distinction between High- and Low-Environment-NS mice that predicted greater sensitivity to the rewarding properties of cocaine among young adults but not among adolescents. Although our results reveal a higher novelty preference among young adult females than among their male counterparts in the two NS tests, both sexes showed similar susceptibility to the rewarding effects of a sub-threshold dose of cocaine in the CPP. These findings suggest that screening can identify humans at-risk of becoming drug users, and may contribute to the development of prevention strategies based on specific vulnerabilities.