Stress inoculation during adolescence attenuates social stress-induced increase in ethanol intake in adult male mice.

Social stress exposure heightens the risk of substance abuse disorder development, especially when endured during adolescence, influencing long-term mental health. This study investigates early-life stress's potential to confer resilience against later-life stressors. To investigate this hypothesis, we examined the impact of a single social defeat (SD) incident during adolescent mice's lives on subsequent voluntary ethanol consumption following repeated adult social stress exposure. Half of the adolescent mice experienced SD at postnatal day 28. Three weeks later (postnatal day 49), defeated groups encountered four confrontations with aggressive residents every 72 h, while control groups were exposed to non-resident exploration. A day after the last SD, defeated mice were classified as resilient or susceptible based on their response to a social interaction test (SIT), a model for depressive behavior. To assess ethanol consumption during young adulthood, researchers used the 'drinking in the dark' and oral ethanol self-administration paradigms. Stress inoculation (IS) slightly increased resilient animals in the SIT. In mice without IS exposure during adolescence, susceptible defeated mice displayed higher ethanol consumption and motivation than control and resilient mice. IS in adolescence effectively counteracted this effect, as IS-SD groups, whether resilient or susceptible, showed no increase in ethanol intake. These groups also exhibited similar motivation to control, measured by the progressive ratio. Notably, elevated IL-6 levels seen in SD-S mice were absent in IS-exposed mice. Additionally, IS-exposed groups had lower prefrontal cortex IL-6 and CX3CL1 levels. These findings support the hypothesis that IS, induced by moderate-intensity stress during adolescence, can enhance resilience to more severe stressors in adulthood.

Voluntary wheel running during adolescence prevents the increase in ethanol intake induced by social defeat in male mice.

RATIONALE: Exposure to social defeat (SD) induces a depressive phenotype, increased ethanol seeking and consumption, accompanied by activation of the neuroinflammatory response. However, a resilient response can be potentiated through physical exercise in the form of voluntary wheel running (VWR) during or after exposure to social stress. Therefore, the aim of this study was to test whether physical exercise during adolescence prior to being exposed to SD can enhance resilience to the increase in ethanol intake. METHODS: Male mice had access to VWR during adolescence and the effects of social defeat (4 sessions every 72 h) on oral ethanol self-administration (SA) was evaluated. Based on the social interaction test, mice were classified as resilient or susceptible to depressive-like behavior. Two weeks after the last encounter, mice were subjected to the drinking in the dark and oral ethanol SA paradigms. Mice were then sacrificed to measure brain-derived neurotrophic factor (BDNF) levels in the striatum and hippocampus. RESULTS: As expected, susceptible mice increased ethanol intake in the oral SA protocol. However, susceptible mice in the exercise condition did not increase ethanol intake, showing similar consumption and motivation for ethanol than the control and resilient groups. On the other hand, decreased BDNF levels were observed in susceptible mice in both experimental conditions compared to the control groups after ethanol SA. CONCLUSIONS: The pre-exposure of VWR prevented the increase in consumption and motivation for ethanol induced by SD in susceptible mice. On the other hand, it appears that VWR did not exhibit any significant long-term effects on BDNF signaling, which is mainly affected in susceptible mice after ethanol intake.

Vicarious Social Defeat Increases Conditioned Rewarding Effects of Cocaine and Ethanol Intake in Female Mice.

Stress is a critical factor in the development of mood and drug use disorders. The social defeat model is not appropriate for female rodents due to their low level of aggression. Therefore, a robust female model of social stress needs to be developed and validated. The aim of the present study was to unravel the long-lasting effects of vicarious social defeat (VSD) on the conditioned rewarding effects of cocaine and ethanol intake in female mice. Although VSD seems to be a good model for inducing behavioral and physiologic endophenotypes induced by stress, there are no studies to date that characterize the effect of VSD on cocaine or alcohol use. The results confirm that VSD females showed an increase in corticosterone levels after a vicarious experience while also displaying an increase in anxiety- and anhedonic-like behaviors. Three weeks after the last VSD, vicariously defeated female mice showed an increased developed preference for a non-effective dose of cocaine in the conditioned place preference (CPP) paradigm and showed an increase in ethanol intake. Our results suggest that female mice vicariously experience a state of distress through the social observation of others suffering from adverse events, confirming the use of VSD as a valid model to study the response to social stress in females. The fact that VSD in females induced a comparable behavioral phenotype to that observed in physically defeated males could indicate a relationship with the higher rate of psychopathologies observed in women. Notwithstanding, more studies are needed to dissect the neurobiological and behavioral peculiarities of the female response to social stress.

Prepulse inhibition can predict the motivational effects of cocaine in female mice exposed to maternal separation.

The prepulse inhibition (PPI) of the startle response can identify the rodents that are more sensitive to the effects of cocaine. Mice with a lower PPI presented a higher vulnerability to the effects of cocaine and a higher susceptibility to developing a substance use disorder (SUD). Maternal separation with early weaning (MSEW) is a relevant animal model to induce motivational alterations throughout life. Nevertheless, only a few studies on females exist, even though they are more vulnerable to stress- and cocaine-related problems. Hence, the aim of the present study was to evaluate the ability of PPI to identify females with a greater vulnerability to the long-term consequences of early stress on the motivational effects of cocaine. Female mice underwent MSEW and were classified according to their high or low PPI. They were then assessed in the cocaine-induced locomotor sensitization test, the conditioned place preference paradigm or the operant self-administration paradigm. Additionally, they were also evaluated in the passive avoidance task, the tail-suspension and the splash tests. The results revealed that the females with lower PPI presented higher consequences of MSEW on the effects of cocaine and showed an increase in anhedonia-like behaviours. Our findings support that a PPI deficit could represent a biomarker of vulnerability to the effects of cocaine induced by MSEW.

Ethanol intake in male mice exposed to social defeat: Environmental enrichment potentiates resilience.

Large preclinical evidence shows that exposure to social defeat (SD) increases vulnerability to drug abuse, increasing the consumption of ethanol. However, not all subjects are equally affected by the changes induced by stress. Previous reports have evidenced that the resilient phenotype to depressive-like behaviors after SD is associated with the resistant phenotype to cocaine-increased rewarding effects and the smaller neuroinflammatory response. The aim of the present study was to further clarify whether the resilient profile to depressive-like behavior also predicts a protection against the increase in ethanol intake induced by SD. The neuroinflammatory profile was studied after the end of the oral ethanol self-administration (SA) procedure, measuring levels of the pro-inflammatory cytokine IL-6 and the chemokine CX3CL1 or fractalkine in the striatum and prefrontal cortex. Previous studies have shown that environmental enrichment (EE) is an effective mechanism to dimish the detrimental effects of social stress. In a second study, we aimed to evaluate if EE housing before exposure to SD could potentiate resilience. Our results showed that mice with a phenotype susceptible to SD-induced depressive-like behaviors showed increased ethanol consumption and increased neuroinflammatory signaling. In contrast, despite the lack of effect on depressive-like behaviors, defeated mice previously housed under EE conditions did not show an increase in ethanol SA or an increase in immune response. To sum up, the resilient phenotype to SD develops at different levels, such as depressive-like behaviors, ethanol consumption and the neuroinflammatory response. Our results also point to the protective role of EE in potentiating resilience to SD effects.

Sex differences in behavioral traits related with high sensitivity to the reinforcing effects of cocaine.

Cocaine is the most prevalent illegal stimulant drug in Europe among the adult population. Its abuse is characterized by a faster substance abuse disorder (SUD) development than other drugs, with high vulnerability to relapse. However, there does not exist an effective treatment for cocaine dependence. Sex differences have been reported in psychological disorders including SUD. For this reason, it is essential to identify risk factors that predict susceptibility or resilience to cocaine addiction for the development of effective prevention strategies considering sex differences. In the present study, the main objective was to determine more sensitive phenotypes to the conditioned reinforcing effects of cocaine in both sexes. Anxiety-like behavior and the locomotor response to novelty were evaluated in the elevated plus maze, and despair in the tail suspension test, as well as vulnerability traits linked with a high sensitivity to the reinforcing effects of a subthreshold dose of cocaine (1 mg/kg) in the conditioned place preference (CPP) paradigm in male and female mice. Our results indicated that only female mice with high anxiety, low locomotor response to novelty or low despair levels acquired CPP induced by cocaine, while male mice with low anxiety, high locomotor response to novelty or high despair levels presented a higher susceptibility to the rewarding effects of cocaine than others. These sex differences in the results reveal an opposite pattern in males and females on the relationship between anxiety- and depressive-like behaviors and cocaine vulnerability, demonstrating the need to include female mice in preclinical studies.

Cannabidiol prevents several of the behavioral alterations related to cocaine addiction in mice.

Cocaine dependence is a highly prevalent disease in modern society and lacks an effective treatment. Cannabidiol (CBD), a major non-psychoactive constituent of Cannabis sativa, has been shown to be a promising tool in the management of some neuropsychiatric disorders, including cocaine abuse. However, its therapeutic effects on the behavioral outcomes related to cocaine addiction remain unclear. The present research evaluates the effects of CBD (30, 60 and 120 mg/kg; injected intraperitoneally) on the acquisition, expression, extinction and reinstatement of cocaine (10 mg/kg)-induced conditioned place preference (CPP; Study 1); cocaine (25 mg/kg)-induced locomotor stimulation (Study 2); and cocaine withdrawal symptoms (Study 3) in male C57BL/6 J mice. The results show that CBD does not possess motivational properties in itself and does not modify the acquisition, expression or extinction of cocaine-induced CPP. Interestingly, when administered during the extinction phase of the cocaine-induced CPP, CBD (30 and 60 mg/kg) prevented priming-induced reinstatement of CPP. Moreover, CBD abolished cocaine-induced hyperactivity without altering the spontaneous locomotion of the animals. Furthermore, CBD (120 mg/kg) reduced the memory deficits induced by cocaine withdrawal in the object recognition test, though it did not reverse depressive-like symptoms measured in the tail suspension test. Overall, our data suggest that CBD can prevent the development of cocaine addiction, and, when administered during cocaine abstinence, may be of help in avoiding relapse to drug-seeking and in ameliorating the memory disturbances provoked by chronic consumption of cocaine.

Efecto del estrés sobre la inhibición por prepulso: revisión sistemática / Effect of stress on prepulse inhibition: a systematic review

INTRODUCCIÓN: La inhibición por prepulso, uno de los principales índices de la capacidad inhibitoria autónoma del sistema nervioso central, es deficitaria en patologías psiquiátricas asociadas con alteraciones del sistema dopaminérgico, como la esquizofrenia, el trastorno de estrés postraumático o el trastorno por uso de sustancias. El estrés es uno de los principales factores de riesgo relacionado con el desarrollo de estos trastornos psiquiátricos. OBJETIVO: Conocer la relación entre el estrés y la inhibición por prepulso como posible biomarcador y predictor de determinadas patologías asociadas a él, revisando la bibliografía reciente. Sujetos y métodos: Se realizó una revisión sistemática en las bases de datos PubMed y Web of Science desde 2011 hasta 2020. RESULTADOS: Tanto los estudios con modelos animales como clínicos han demostrado que un estrés intenso o repetido, ya sea social, físico o inducido por fármacos, produce un deterioro de la inhibición por prepulso, mientras que un estrés moderado parece mejorar sus niveles. CONCLUSIONES: Existe una clara relación entre el estrés y una disminución de la inhibición por prepulso, la cual se produce a través del sistema dopaminérgico, principalmente, y el factor liberador de corticotropina en la amígdala extendida. Los niveles de inhibición por prepulso reflejarían el estado de la actividad dopaminérgica cerebral y podrían señalar los sujetos más vulnerables a desarrollar patologías psiquiátricas relacionadas con el estrés

INTRODUCTION: Prepulse inhibition, one of the main indices of the autonomous inhibitory capacity of the central nervous system, is deficient in psychiatric pathologies associated with dopaminergic system alterations, such as schizophrenia, post-traumatic stress disorder, or substance use disorder. Stress is one of the main risk factors related to the development of these psychiatric disorders. AIM: To know the relationship between stress and prepulse inhibition as possible biomarker and predictor of related pathologies, based on recent literature. SUBJECTS AND METHODS: A systematic review was carried out in PubMed and Web of Science databases from 2011 to 2020. RESULTS. The studies reviewed, including both animal model studies and clinical articles, have shown that intense or repeated stress, whether social, physical or drug-induced, leads to a deterioration of prepulse inhibition, while moderate stress seems to improve its levels. CONCLUSIONS: The results demonstrate a clear relationship between stress and a deficit in prepulse inhibition, which occurs mainly through the dopaminergic system and the corticotropin-releasing factor in the extended amygdala. Prepulse inhibition levels reflect the state of brain dopaminergic activity, being able to identify the most vulnerable subjects to develop stress-related psychiatric pathologies

The negative allosteric modulator of mGluR5, MPEP, potentiates the rewarding properties of cocaine in priming-induced reinstatement of CPP. / El modulador alostérico negativo de los mGluR5, MPEP, potencia la reinstauración de la preferencia condicionada inducida con priming de cocaína.

Cocaine addiction is a chronic disorder with high relapse rates; therefore, understanding the neuronal mechanisms underlying drug-seeking during relapse is a priority to develop targeted pharmacotherapy. The metabotropic glutamate receptor 5 (mGluR5) seems to be involved in the reinstatement induced by cocaine-associated cues. The main objective of the study was to evaluate the efficacy of MPEP, a negative allosteric modulator of mGluR5, in attenuating or potentiating the reinstatement induced by priming doses of cocaine in the CPP paradigm, ultimately to further knowledge regarding the role of the mGluR5 in relapse into cocaine abuse. OF1 mice (48 female and 48 male) were conditioned in the CPP paradigm with cocaine (20 mg/kg) and were exposed to an extinction program. We evaluated the efficacy of MPEP (30 mg/kg) in blocking the successive cocaine-priming reinstatements in the CPP when extinction of the conditioning preference was confirmed. MPEP did not block the reinstatement of priming cocaine-induced CPP, but increased the potential of cocaine for reinstating conditioning preference. The contingent administration of MPEP with cocaine increased the drug-seeking behaviour and the number of reinstatements with priming doses of cocaine. Moreover, MPEP produced cross reinstatement of cocaine-induced CPP. Rather than preventing the reinstatements of conditioned preference induced by priming doses of cocaine, MPEP increased them. These findings may help to understand the role of mGluR5 in the relapse into cocaine abuse.

La adicción a la cocaína es un trastorno crónico con un alto índice de recaídas; por tanto, es prioritario entender los mecanismos neurales implicados en la búsqueda de la droga durante la recaída para desarrollar farmacoterapias eficaces. El receptor metabotrópico 5 del glutamato (mGluR5) parece estar implicado en la reinstauración inducida por las claves asociadas a la cocaína. El objetivo principal de este estudio fue profundizar en el papel del receptor mGluR5 en la recaída en el consumo de cocaína, evaluando el efecto del MPEP, un modulador alostérico negativo del mGluR5, sobre la reinstauración inducida por un priming de cocaína en el paradigma del condicionamiento de la preferencia de lugar (CPL). Ratones OF1 (48 machos y 48 hembras) fueron condicionados en el paradigma del CPL con cocaína (20 mg/kg) y expuestos a un programa de extinción. Cuando la extinción de la preferencia condicionada fue confirmada, se evaluó la eficacia del MPEP (30 mg/kg) para bloquear las sucesivas reinstauraciones mediante priming de cocaína en el CPL. La administración contingente de MPEP con la cocaína en el CPL incrementó la conducta de búsqueda de la droga y el número de reinstauraciones. Además, la administración solo de MPEP produjo reinstauración cruzada en el CPL inducido por cocaína. Por tanto, el MPEP no solo no previno, sino que incrementó las reinstauraciones de la preferencia condicionada inducida por priming de cocaína. Estos resultados pueden ayudar a entender el papel del mGluR5 en la recaída al consumo de cocaína.

El modulador alostérico negativo de los mGluR5, MPEP, potencia la reinstauración de la preferencia condicionada inducida con priming de cocaína / The negative allosteric modulator of mGluR5, MPEP, potentiates the rewarding properties of cocaine in priming-induced reinstatement of CPP

La adicción a la cocaína es un trastorno crónico con un alto índice de recaídas; por tanto, es prioritario entender los mecanismos neurales implicados en la búsqueda de la droga durante la recaída para desarrollar farmacoterapias eficaces. El receptor metabotrópico 5 del glutamato (mGluR5) parece estar implicado en la reinstauración inducida por las claves asociadas a la cocaína. El objetivo principal de este estudio fue profundizar en el papel del receptor mGluR5 en la recaída en el consumo de cocaína, evaluando el efecto del MPEP, un modulador alostérico negativo del mGluR5, sobre la reinstauración inducida por un priming de cocaína en el paradigma del condicionamiento de la preferencia de lugar (CPL). Ratones OF1 (48 machos y 48 hembras) fueron condicionados en el paradigma del CPL con cocaína (20 mg/kg) y expuestos a un programa de extinción. Cuando la extinción de la preferencia condicionada fue confirmada, se evaluó la eficacia del MPEP (30 mg/kg) para bloquear las sucesivas reinstauraciones mediante priming de cocaína en el CPL. La administración contingente de MPEP con la cocaína en el CPL incrementó la conducta de búsqueda de la droga y el número de reinstauraciones. Además, la administración solo de MPEP produjo reinstauración cruzada en el CPL inducido por cocaína. Por tanto, el MPEP no solo no previno, sino que incrementó las reinstauraciones de la preferencia condicionada inducida por priming de cocaína. Estos resultados pueden ayudar a entender el papel del mGluR5 en la recaída al consumo de cocaína

Cocaine addiction is a chronic disorder with high relapse rates; therefore, understanding the neuronal mechanisms underlying drug-seeking during relapse is a priority to develop targeted pharmacotherapy. The metabotropic glutamate receptor 5 (mGluR5) seems to be involved in the reinstatement induced by cocaine-associated cues. The main objective of the study was to evaluate the efficacy of MPEP, a negative allosteric modulator of mGluR5, in attenuating or potentiating the reinstatement induced by priming doses of cocaine in the CPP paradigm, ultimately to further knowledge regarding the role of the mGluR5 in relapse into cocaine abuse. OF1 mice (48 female and 48 male) were conditioned in the CPP paradigm with cocaine (20 mg/kg) and were exposed to an extinction program. We evaluated the efficacy of MPEP (30 mg/kg) in blocking the successive cocaine-priming reinstatements in the CPP when extinction of the conditioning preference was confirmed. MPEP did not block the reinstatement of priming cocaine-induced CPP, but increased the potential of cocaine for reinstating conditioning preference. The contingent administration of MPEP with cocaine increased the drug-seeking behaviour and the number of reinstatements with priming doses of cocaine. Moreover, MPEP produced cross reinstatement of cocaine-induced CPP. Rather than preventing the reinstatements of conditioned preference induced by priming doses of cocaine, MPEP increased them. These findings may help to understand the role of mGluR5 in the relapse into cocaine abuse

Social Housing Conditions Modulate the Long-Lasting Increase in Cocaine Reward Induced by Intermittent Social Defeat.

Social defeat is considered the most representative animal model for studying the consequences of social stress. Intermittent social defeat (ISD) has proved to enhance the response to cocaine hedonic properties. In the present research, we evaluated if different social housing conditions, as housing with a familiar conspecific or with a female, exert a protective effect modulating the negative consequences of ISD as the increased sensitivity to cocaine and the induction of anxiety-like behavior. To achieve this objective, non-stressed or ISD OF1 male mice were divided into five different experimental groups according to their social environment: standard housing (four adult males per cage); male adolescent or adult in pairs (two males per cage); and adult males housed with a female for a short or long period (3 days vs. the whole duration of the study). Anxiety-like behavior was evaluated 19 days after the last episode of ISD using an elevated plus maze (EPM), and 24 h later the animals underwent a conditioned place preference paradigm (CPP) induced by a sub-threshold dose of cocaine (1 mg/kg). Following CPP, biological samples were taken to measure striatal levels of interleukin 6 (IL-6) and plasmatic levels of oxytocin (OT). Our results confirmed that ISD animals housed in standard condition displayed an anxious phenotype, developed CPP and had increased levels of IL-6 in the striatum. However, animals housed with a female or with a familiar male since adolescence did not develop CPP and were protected against the anxiogenic and neuroinflammatory potential of ISD stress. In the group of animals paired with a female throughout the experimental procedure, an increase in OT levels may have underlain this buffering effect, while the protective effect of being housed with a familiar male mouse seems to be related with a better resolution of the stress response. The present results expand our knowledge of the neurobiology of vulnerability to drug addiction and highlight the benefit of social support for recovery from the adverse effects of social stress.

Prepulse Inhibition of the Startle Reflex as a Predictor of Vulnerability to Develop Locomotor Sensitization to Cocaine.

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.

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.

Efecto de la cocaína sobre la inhibición por prepulso de la respuesta de sobresalto / Effects of cocaine on prepulse inhibition of the startle response

Introducción. La inhibición por prepulso (IPP) de la respuesta de sobresalto es una medida de sincronización sensitivomotora basada en la respuesta del reflejo de sobresalto. Un déficit en la IPP se ha observado en pacientes psiquiátricos, especialmente con esquizofrenia, así como en sujetos vulnerables a desarrollarla. Asimismo, los consumidores de cocaína presentan un alto índice de patologías psiquiátricas como la esquizofrenia. Objetivo. Conocer las alteraciones que el consumo de cocaína puede producir en la IPP. Desarrollo. Se realiza una revisión exhaustiva de los estudios, tanto clínicos como con modelos animales, que hayan evaluado la IPP tras el consumo o la administración de cocaína. Se sugieren bases neurales y mecanismos de acción subyacentes para explicar los resultados. Conclusiones. La cocaína altera la IPP a través de su acción sobre el sistema dopaminérgico. La administración aguda de cocaína disminuye la IPP al aumentar la dopamina, mientras que con el consumo crónico, dependiendo del tiempo de abstinencia, la IPP puede restablecerse. Sin embargo, los efectos de la cocaína sobre la IPP parecen depender de los niveles basales de la IPP que muestre el individuo. Así, dado que un déficit en la IPP se ha relacionado con una mayor vulnerabilidad a desarrollar patologías mentales como la esquizofrenia, los niveles de la IPP en los sujetos podrían considerarse como un biomarcador de vulnerabilidad psiquiátrica. Por ello, conocer mejor el efecto que drogas como la cocaína ejercen sobre la IPP puede ayudar a comprender el desarrollo de la patología dual (AU)

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 (AU)

Adolescent Exposure to the Synthetic Cannabinoid WIN 55212-2 Modifies Cocaine Withdrawal Symptoms in Adult Mice.

Chronic cannabinoid consumption is an increasingly common behavior among teenagers and has been shown to cause long-lasting neurobehavioral alterations. Besides, it has been demonstrated that cocaine addiction in adulthood is highly correlated with cannabis abuse during adolescence. Cocaine consumption and subsequent abstinence from it can cause psychiatric symptoms, such as psychosis, cognitive impairment, anxiety, and depression. The aim of the present research was to study the consequences of adolescent exposure to cannabis on the psychiatric-like effects promoted by cocaine withdrawal in adult mice. We pre-treated juvenile mice with the cannabinoid CB1 receptor agonist WIN 55212-2 (WIN) and then subjected them to a chronic cocaine treatment during adulthood. Following these treatments, animals were tested under cocaine withdrawal in the following paradigms: pre-pulse inhibition, object recognition, elevated plus maze, and tail suspension. The long-term psychotic-like actions induced by WIN were not modified after cocaine cessation. Moreover, the memory impairments induced by cocaine withdrawal were not altered by previous adolescent WIN intake. However, WIN pre-treatment prevented the anxiogenic effects observed after cocaine abstinence, and led to greater depressive-like symptoms following cocaine removal in adulthood. This study is the first to show the long-lasting behavioral consequences of juvenile exposure to WIN on cocaine withdrawal in adult mice.

Effects of acute social stress on the conditioned place preference induced by MDMA in adolescent and adult mice.

Exposure to social defeat stress increases the rewarding effects of psychostimulants in animal models, but its effect on 3,4-methylenedioxymethylamphetamine (MDMA) reward has received little attention. In the present study, we evaluated the influence of social defeat on the rewarding effects of MDMA in adolescent [postnatal day (PND) 29-40] and adult (PND 50-61) male mice using the conditioned place preference paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1.25 or 10 mg/kg of MDMA. The effects of social defeat on corticosterone levels and the motor or the anxiogenic effects of MDMA were also evaluated. Mice exposed to social defeat during adulthood did not show conditioned place preference after conditioning with either dose of MDMA. Conversely, social defeat did not affect the anxiogenic and motor effects of MDMA. Adult mice exposed to social defeat showed higher levels of corticosterone than their controls and adolescent mice. Social stress did not induce behavioural effects in adolescent mice. Our results show that stress induced by social defeat decreases the sensitivity of adult mice to the rewarding effects of MDMA.

Rhodiola rosea Impairs Acquisition and Expression of Conditioned Place Preference Induced by Cocaine.

A novel approach to the treatment of adverse effects of drugs of abuse is one which makes use of natural products. The present study investigated the effect of Rhodiola rosea L. hydroalcoholic extract (RHO) on cocaine-induced hyperactivity and conditioned place preference (CPP) in mice. In a first experiment, mice received RHO (15, 20 or 25 mg/kg, IG), cocaine (25 mg/kg, i.p.) (COC), or a combination of both drugs (COC + RHO15, COC + RHO20, and COC + RHO25), and their locomotor activity was evaluated. In a second experiment, the effects of RHO on the acquisition, expression, and reinstatement of cocaine CPP (induced by drug priming or social defeat stress) were evaluated. RHO alone did not increase activity but potentiated the hyperactivity induced by cocaine. Rhodiola did not induce motivational effects by itself but attenuated the acquisition and expression of cocaine-induced CPP. Moreover, it was found that RHO did not block reinstatement. The results indicate that RHO is effective in reducing the rewarding properties of cocaine but is ineffective in preventing priming or stress-induced cocaine reinstatement. In light of these findings, the benefits of Rhodiola rosea L. as a treatment of cocaine addiction would seem to be limited.

Sex-dependent effects of early maternal deprivation on MDMA-induced conditioned place preference in adolescent rats: possible neurochemical correlates.

The early neonatal stage constitutes a sensitive period during which exposure to adverse events can increase the risk of neuropsychiatric disorders. Maternal deprivation (MD) is a model of early life stress that induces long-term behavioural and physiological alterations, including susceptibility to different drugs of abuse. In the present study we have used the conditioned place preference (CPP) paradigm to address the influence of MD on the rewarding effects of 3,4-methylenedioxymetamphetamine (MDMA) in adolescent animals of both sexes. We have previously observed in adolescent rats that MD induces modifications in the serotonergic and endocannabinoid systems, which play a role in the rewarding effects of MDMA. In light of this evidence, we hypothesized that MD would alter the psychobiological consequences of exposure to MDMA. Neonatal Wistar rats underwent MD (24h, on PND 9) or were left undisturbed (controls). The animals were conditioned with 2.5mg/kg MDMA during the periadolescent period (PND 34-PND 43) and were tested in the open-field test at the end of adolescence (PND 60). Animals were sacrificed on PND 68-75 and levels of serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid were measured in the striatum, hippocampus and cortex, while the expression of hippocampal CB1 cannabinoid receptor (CB1R) and circulating levels of corticosterone and leptin were also measured. Control males showed CPP after administration of MDMA. However, no MDMA-induced CPP was detected in control females or MD males, and MD had no effect on open field activity in any group. A reduction in striatal and cortical 5-HT levels, increased expression of hippocampal CB1R and a marked trend towards higher circulating leptin levels were observed in MDMA-treated MD males. Our results demonstrate for the first time that MD reduces the rewarding effects of MDMA in a sex-dependent manner. We propose that this effect is related, at least in part, with alterations of the serotonergic and cannabinoid systems.

Pre-treatment with high doses of cocaine decreases the reinforcing effects of cocaine in the conditioned place preference paradigm.

The aim of the present study was to determine if pre-exposure to high doses of cocaine can subsequently alter the rewarding effects of this drug. Adult male mice received a pretreatment of physiological saline, or 12.5 or 25 mg/kg of cocaine (one injection a day for five days). After an interval of six days without injections, the rewarding effects of low doses of cocaine (0.5, 1 or 1.5 mg/kg) were evaluated in the conditioned place preference (CPP) paradigm. Doses of 1 and 1.5 mg/kg induced a clear CPP in animals pre-treated with saline but were ineffective in those pre-treated with 25 mg/kg of cocaine. Only the dose of 1.5 mg/kg induced CPP in mice pre-treated with 12.5 mg/kg of cocaine. Our results, which reveal a decrease in the conditioned rewarding effects of threshold doses of cocaine, demonstrate that exposure to high doses of this drug can alter the reward system.

Effects of CNQX and MPEP on sensitization to the rewarding effects of morphine.

The present study was conducted to evaluate the influence of the glutamatergic receptors α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and metabotropic glutamate 5 (mGlu5) receptors on sensitization to the rewarding effects of morphine. The effects of pre-treatment with saline or 20mg/kg morphine plus the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (5 or 10mg/kg) or the metabotropic Glu5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) (5 or 10mg/kg) on the place conditioning induced by a low dose of morphine (2mg/kg) were assessed. The 2mg/kg dose of morphine was ineffective in animals pre-treated with saline but induced a clear conditioned place preference (CPP) in mice pre-treated with morphine alone and morphine plus any of the MPEP doses or the lowest dose of CNQX. Conversely, animals pre-treated with morphine plus 10mg/kg of CNQX did not acquire CPP. Our results suggest that AMPA glutamate receptors are involved in the development of sensitization to the conditioned rewarding effects of morphine.