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.

Cognitive profile of male mice exposed to a Ketogenic Diet.

In recent years, nutritional interventions for different psychiatric diseases have gained increasing attention, such as the ketogenic diet (KD). This has led to positive effects in neurological disorders such as Parkinson's disease, addiction, autism or epilepsy. The neurobiological mechanisms through which these effects are induced and the effects in cognition still warrant investigation, and considering that other high-fat diets (HFD) can lead to cognitive disturbances that may affect the results achieved, the main aim of the present work was to evaluate the effects of a KD to determine whether it can induce such cognitive effects. A total of 30 OF1 male mice were employed to establish the behavioral profile of mice fed a KD by testing anxiety behavior (Elevated Plus Maze), locomotor activity (Open Field), learning (Hebb Williams Maze), and memory (Passive Avoidance Test). The results revealed that the KD did not affect locomotor activity, memory or hippocampal-dependent learning, as similar results were obtained with mice on a standard diet, albeit with increased anxiety behavior. We conclude that a KD is a promising nutritional approach to apply in research studies, given that it does not cause cognitive alterations.

Effects of ketosis on cocaine-induced reinstatement in male mice.

In recent years, the benefits of the ketogenic diet (KD) on different psychiatric disorders have been gaining attention, but the substance abuse field is still unexplored. Some studies have reported that palatable food can modulate the rewarding effects of cocaine, but the negative metabolic consequences rule out the recommendation of using it as a complementary treatment. Thus, the main aim of this study was to evaluate the effects of the KD on cocaine conditioned place preference (CPP) during acquisition, extinction, and reinstatement. 41 OF1 male mice were employed to assess the effects of the KD on a 10 mg/kg cocaine-induced CPP. Animals were divided into three groups: SD, KD, and KD after the Post-Conditioning test. The results revealed that, while access to the KD did not block CPP acquisition, it did significantly reduce the number of sessions required to extinguish the drug-associated memories and it blocked the priming-induced reinstatement.

Ketogenic Diet Decreases Alcohol Intake in Adult Male Mice.

The classic ketogenic diet is a diet high in fat, low in carbohydrates, and well-adjusted proteins. The reduction in glucose levels induces changes in the body's metabolism, since the main energy source happens to be ketone bodies. Recent studies have suggested that nutritional interventions may modulate drug addiction. The present work aimed to study the potential effects of a classic ketogenic diet in modulating alcohol consumption and its rewarding effects. Two groups of adult male mice were employed in this study, one exposed to a standard diet (SD, n = 15) and the other to a ketogenic diet (KD, n = 16). When a ketotic state was stable for 7 days, animals were exposed to the oral self-administration paradigm to evaluate the reinforcing and motivating effects of ethanol. Rt-PCR analyses were performed evaluating dopamine, adenosine, CB1, and Oprm gene expression. Our results showed that animals in a ketotic state displayed an overall decrease in ethanol consumption without changes in their motivation to drink. Gene expression analyses point to several alterations in the dopamine, adenosine, and cannabinoid systems. Our results suggest that nutritional interventions may be a useful complementary tool in treating alcohol-use disorders.

A limited and intermittent access to a high-fat diet modulates the effects of cocaine-induced reinstatement in the conditioned place preference in male and female mice.

RATIONALE: Palatable food and drugs of abuse activate common neurobiological pathways and numerous studies suggest that fat consumption increases vulnerability to drug abuse. In addition, preclinical reports show that palatable food may relieve craving for drugs, showing that an ad libitum access to a high-fat diet (HFD) can reduce cocaine-induced reinstatement. OBJECTIVE: The main aim of the present study was to evaluate the effect of a limited and intermittent exposure to HFD administered during the extinction and reinstatement processes of a cocaine-induced conditioned place preference (CPP). METHODS: Male and female mice underwent the 10 mg/kg cocaine CPP. From post-conditioning onwards, animals were divided into four groups: SD (standard diet); HFD-MWF with 2-h access to the HFD on Mondays, Wednesdays, and Fridays; HFD-24h, with 1-h access every day; and HFD-Ext with 1-h access to the HFD before each extinction session. RESULTS: Our results showed that all HFD administrations blocked reinstatement in males, while only the HFD-MWF was able to inhibit reinstatement in females. In addition, HFD-Ext males needed fewer sessions to extinguish the preference, which suggests that administration of fat before being exposed to the environmental cues is effective to extinguish drug-related memories. HFD did not affect Oprµ gene expression but increased CB1r gene expression in the striatum in HFD-Ext males. CONCLUSIONS: These results support that palatable food could act as an alternative reward to cocaine, accelerating extinction and blocking reinstatement, these effects being sex specific.

Behavioral and neuroimmune characterization of resilience to social stress: Rewarding effects of cocaine. / Caracterización conductual y neuroinmune de la resiliencia al estrés social: Efectos reforzantes de la cocaína.

Preclinical studies have shown that social stress increases vulnerability to the reinforcing effects of cocaine. However, the results are not always homogeneous, revealing a subpopulation that does not show a preference for cocaine. Thus, the main aim of the present study was to characterize the behavioral profile of resilient mice to the stress-induced rewarding effects of cocaine using an animal model of repeated social defeat stress (SD). To this end, male adult mice of the C57/BL6 strain were exposed to SD and, three weeks later, assessed using the Conditioned Place Preference paradigm induced by an ineffective dose of cocaine (1mg/kg). Afterwards, the striatal levels of interleukin 6 were measured, as social stress usually induces a neuroinflammatory response. Control mice did not develop CPP, while defeated mice did overall develop a preference for the drug-paired compartment. Based on the conditioning score that they exhibited, the SD sample was subdivided into resilient (did not develop preference) and susceptible mice (developed preference). During the SD sessions, resilient animals showed less flight and submission behaviors than susceptible mice and they presented attack behaviors towards the residents, thereby showing their resistance to being defeated. There were no differences in the neuroinflammatory response, probably due to the long time elapsed after the last SD session. These results suggest that an active coping style to social stress may be decisive in protecting the individual from developing an addiction.

Numerosos estudios preclínicos han demostrado que el estrés social incrementa la vulnerabilidad a los efectos reforzantes de la cocaína. Sin embargo, los resultados obtenidos no son homogéneos, observándose siempre una subpoblación que no muestra dicho incremento. Utilizando el modelo de derrota social (DS) repetida en ratones, en este trabajo hemos querido caracterizar conductualmente a los ratones resilientes al incremento de los efectos reforzantes de la cocaína inducido por el estrés social. Utilizamos ratones adultos macho de la cepa C57/BL6 a los que sometimos al protocolo de DS repetida y tres semanas más tarde, realizamos el Condicionamiento de Preferencia de Lugar (CPL) inducido por una dosis no efectiva de cocaína (1mg/kg). Una vez finalizado este procedimiento se midieron los niveles estriatales de interleucina 6, ya que el estrés social produce una respuesta de neuroinflamación. No se observó CPL en los ratones controles, pero los animales derrotados tomados en conjunto desarrollaron preferencia. Sin embargo, esta muestra se pudo dividir en ratones resilientes (no desarrollaron preferencia) y susceptibles (presentaron CPL). Durante las derrotas sociales, los animales resilientes pasaron menos tiempo en las conductas de huida y sumisión que los catalogados como susceptible y presentaron conductas de ataque hacia el ratón residente, manifestando por tanto resistencia a ser derrotados. No se observaron diferencias en la respuesta de neuroinflamación, probablemente debido al largo periodo de tiempo trascurrido desde la última derrota social. Nuestros resultados sugieren que un estilo de afrontamiento activo al estrés social va a ser determinante en la protección del sujeto a desarrollar un trastorno por uso de drogas.

Caracterización conductual y neuroinmune de la resiliencia al estrés social: Efectos reforzantes de la cocaína / Behavioral and neuroimmune characterization of resilience to social stress: Rewarding effects of cocaine

Numerosos estudios preclínicos han demostrado que el estrés socialincrementa la vulnerabilidad a los efectos reforzantes de la cocaína.Sin embargo, los resultados obtenidos no son homogéneos, observándose siempre una subpoblación que no muestra dicho incremento.Utilizando el modelo de derrota social (DS) repetida en ratones, eneste trabajo hemos querido caracterizar conductualmente a los ratones resilientes al incremento de los efectos reforzantes de la cocaínainducido por el estrés social. Utilizamos ratones adultos macho de lacepa C57/BL6 a los que sometimos al protocolo de DS repetida y tressemanas más tarde, realizamos el Condicionamiento de Preferenciade Lugar (CPL) inducido por una dosis no efectiva de cocaína (1mg/kg). Una vez finalizado este procedimiento se midieron los nivelesestriatales de interleucina 6, ya que el estrés social produce una respuesta de neuroinflamación. No se observó CPL en los ratones controles, pero los animales derrotados tomados en conjunto desarrollaron preferencia. Sin embargo, esta muestra se pudo dividir en ratonesresilientes (no desarrollaron preferencia) y susceptibles (presentaronCPL). Durante las derrotas sociales, los animales resilientes pasaronmenos tiempo en las conductas de huida y sumisión que los catalogados como susceptible y presentaron conductas de ataque hacia elratón residente, manifestando por tanto resistencia a ser derrotados.No se observaron diferencias en la respuesta de neuroinflamación,probablemente debido al largo periodo de tiempo trascurrido desdela última derrota social. Nuestros resultados sugieren que un estilode afrontamiento activo al estrés social va a ser determinante en laprotección del sujeto a desarrollar un trastorno por uso de drogas. (AU)

Preclinical studies have shown that social stress increases vulnerability to the reinforcing effects of cocaine. However, the results are notalways homogeneous, revealing a subpopulation that does not show apreference for cocaine. Thus, the main aim of the present study wasto characterize the behavioral profile of resilient mice to the stress-induced rewarding effects of cocaine using an animal model of repeatedsocial defeat stress (SD). To this end, male adult mice of the C57/BL6 strain were exposed to SD and, three weeks later, assessed usingthe Conditioned Place Preference paradigm induced by an ineffectivedose of cocaine (1mg/kg). Afterwards, the striatal levels of interleukin6 were measured, as social stress usually induces a neuroinflammatory response. Control mice did not develop CPP, while defeated micedid overall develop a preference for the drug-paired compartment.Based on the conditioning score that they exhibited, the SD samplewas subdivided into resilient (did not develop preference) and susceptible mice (developed preference). During the SD sessions, resilientanimals showed less flight and submission behaviors than susceptible mice and they presented attack behaviors towards the residents,thereby showing their resistance to being defeated. There were nodifferences in the neuroinflammatory response, probably due to thelong time elapsed after the last SD session. These results suggest thatan active coping style to social stress may be decisive in protecting theindividual from developing an addiction. (AU)