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N-ethyl-pentylone (NEP), also known as "ephylone" and N-ethylnorpentylone, has been identified as one of the most recent novel psychostimulants to emerge into the illicit drug market and it has been associated with some intoxications and even fatalities. However, little is known about the consequences of its repeated consumption as well as the role of the monoaminergic system in such consequences. Thus, the aim of our study was to investigate the neurochemical profile and the behavioural effects after both acute and repeated NEP exposure. Male OF1 mice were acutely (1, 3, 10 mg/kg, i.p.) or repeatedly (1, 3, 10 mg/kg, i.p., 5 days, twice/day) exposed to NEP, and anxiety-like behaviour, aggressiveness, social interaction, depressive-like symptoms, body temperature, changes in monoaminergic enzymes and neurotransmitters levels as well as ΔFosB in striatum and prefrontal cortex (PFC) from post-mortem tissue were analysed short after drug-exposure or during drug-withdrawal. Acute administration of NEP induced anxiolytic effects but also an aggressive behaviour and social exploration deficits in mice, which persist during NEP-withdrawal. Moreover, NEP induced hyperthermia as well as depressive-like symptoms after repeated administrations that may be related to the decrease of serotonin and noradrenaline levels observed in striatum and PFC. Finally, the long-term increase in ΔFosB levels in striatum after NEP chronic exposure points to a high risk of dependence. Altogether indicates that NEP consumption induces different neurological and neuropsychiatric disorders accompanied by changes in the monoaminergic system, posing a threat to public health.

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., Highlights • Susceptible mice to depressive behaviors show a greater response to ethanol reward. • Social stress produces an increase in neuroinflammatory response in susceptible mice. • Environmental enrichment counteracts the effects induced by social stress. • Environmental enrichment increases resistance to the rewarding effects of ethanol. • Environmental enrichment decreases neuroinflammatory response.

N-ethyl-pentedrone (NEPD, 2-(ethylamino)-1-phenyl-1-pentanone) is one of the latest synthetic cathinone derivatives that emerged into the illicit drug market. This drug has psychostimulant properties and has been related with several intoxications and even fatalities. However, information about the consequences of its acute and repeated consumption is lacking. Thus, the aim of our study was to investigate the behavioral effects after both acute and repeated NEPD exposure as well as the neurochemical changes. Male OF1 mice were treated with an acute dose (1, 3 or 10 mg/kg, i.p.) or received repeated injections of these doses (twice/day, 5 days) of NEPD. Shortly after drug-exposure or during drug-withdrawal, anxiety-like behavior, aggressiveness, social interaction, depressive-like symptoms, body weight and temperature were assessed. Also, monoamine synthesis enzymes, levels of neurotransmitters and their precursors and main metabolites, as well as ΔFosB, were determined in striatum and prefrontal cortex from post-mortem tissue. Acute administration of NEPD induced anxiolytic effects and reduced social exploration whereas during withdrawal after repeated administration the anxiolytic effect had vanished, and the reduced social exploration was still present and accompanied with increased aggressive behavior. Moreover, NEPD (10 mg/kg) induced slight hyperthermia and reduced weight gain during the repeated administration, whereas increased locomotor activity and lack of depressive symptoms were found during withdrawal. This was accompanied by increased plasma corticosterone and decrease in striatal dopamine. Finally, the long-lasting and robust increase in ΔFosB levels found in striatum after NEPD chronic exposure suggests a high risk of dependence. The increased aggressivity and locomotor activity, together with this potential of inducing dependence justify a warning about the risks of consumption of NEPD if translated to humans. Keywords: Addiction; Aggressive behavior; Monoamine levels; N-ethyl-pentedrone; Synthetic cathinones.

The kynurenine (KYN) pathway of tryptophan (TRP) degradation is activated by stress and inflammatory factors. It is now well established that social stress induces the activation of the immune system, with central inflammation and KYN metabolism being two of the main factors linking stress with depression. The aim of the present study was to evaluate the long-lasting changes in the KYN pathway induced by social defeat (SD) associated with the resilience or susceptibility to an increase in the conditioned rewarding effects of cocaine. Mice were exposed to repeated SD and 3 weeks later, a conditioned place preference (CPP) induced by a subthreshold dose of cocaine (1.5 mg/kg) was developed. KYN levels in plasma, cerebellum, hippocampus, striatum and limbic forebrain were studied at the end of the CPP procedure. Changes in the KYN pathway after exposure to pharmacological (oxytocin and indomethacin) and environmental interventions (environmental enrichment) were also evaluated. Our results showed that defeated susceptible (SD-S) mice had higher conditioning scores than resilient mice (SD-R). In addition, although KYN concentration was elevated in all defeated mice, SD-R mice showed smaller increases in KYN concentration in the cerebellum than SD-S mice. Oxytocin or Indomethacin treatment before SD normalized cocaine-induced CPP, although the increase in the KYN pathway was maintained. However, environmental enrichment before SD normalized cocaine-induced CPP and prevented the increase in the KYN pathway. The present study highlights the role of the KYN pathway and anti-inflammatory drugs acting on TRP metabolism as pharmacological targets to potentiate resilience to social stress effects.

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.

Social stress modifies the activity of brain areas involved in the rewarding effects of psychostimulants, inducing neuroadaptations in the dopaminergic mesolimbic system and modifying the sensitivity of dopamine receptors. In the present study we evaluated the effect of the dopamine D1- and D2-like receptor antagonists (SCH23390 and raclopride, respectively) on the short-time effects of acute social defeat (ASD). Male OF1 mice were socially defeated before each conditioning session of the conditioned place preference (CPP) induced by 1mg/kg or 25mg/kg of cocaine plus the corresponding dopamine antagonist. A final experiment was designed to evaluate the effect of the dopamine antagonists on the CPP induced by 3mg/kg of cocaine with or without a stress experience. Mice exposed to ASD showed an increase in reinstatement of the conditioned reinforcing effects of cocaine that was blocked by all of the dopamine receptor antagonists. Blockade of dopamine D2-like receptors with raclopride specifically prevented the effects of stress without affecting the rewarding properties of cocaine. However, SCH23390 inhibited cocaine-induced preference in the control groups and even induced aversion in defeated mice conditioned with the lower dose of cocaine. Moreover, the lowest dose of SCH23390 blocked the rewarding effects of 3mg/kg of cocaine-induced CPP. Our results confirm that the dopamine D2 receptor is involved in the short-term effects of ASD on the rewarding effects of cocaine. The dopamine D1 receptor is clearly involved in the rewarding effects of cocaine, but its role in the effects of ASD remains to be demonstrated.

La Inhibición Pre-Pulso (IPP) es una medida operativa de la activación sensorio-motora que puede indicar alteraciones en el sistema dopaminérgico mesolímbico. Estudios previos han demostrado que el nivel basal de IPP puede predecir la vulnerabilidad a los efectos de sustancias de abuso como la cocaína. Existe una relación robusta entre el consumo de sustancias y los trastornos del estado de ánimo, y un estrés repetido puede incrementar tanto el consumo de drogas como desencadenar episodios depresivos. Así, el objetivo del presente trabajo fue evaluar si la IPP puede predecir los sujetos más vulnerables a los efectos a largo plazo que un estrés repetido provoca sobre el desarrollo de sintomatología depresiva. Ratones OF1 adultos (37 machos, 38 hembras) fueron clasificados en altos y bajos según su nivel de IPP. Posteriormente, fueron evaluados en el test tail suspension, prueba para determinar sintomatología depresiva, antes y 3 semanas después de aplicar un protocolo de estrés, consistente en cuatro sesiones de inmovilización (restraint) durante 30 ó 60 minutos. Los resultados mostraron una mayor puntuación en sintomatología depresiva en las hembras que en los machos (p

Social factors have a dual influence on addictive disorders. While social defeat stress in rodents increases the response to drug reward, positive social conditions, such as pair housing, increase stress resilience. The objective of the present study was to confirm whether oxytocin (OT) mediates this social buffering. To this end, male mice were housed in pairs and administered the OT receptor antagonist atosiban prior to each stress episode or for ten days after the stress protocol. The response to cocaine was assessed using a conditioned place preference paradigm. Our results confirmed that OT activity mediates the protective effect of pair housing and highlights its therapeutic potential.

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.

There is huge scientific interest in the neuropeptide oxytocin (OXT) due to its putative capacity to modulate a wide spectrum of physiological and cognitive processes including motivation, learning, emotion, and the stress response. The present review seeks to increase the understanding of the role of OXT in an individual’s vulnerability or resilience with regard to developing a substance use disorder. It places specific attention on the role of social stress as a risk factor of addiction, and explores the hypothesis that OXT constitutes a homeostatic response to stress that buffers against its negative impact. For this purpose, the review summarizes preclinical and clinical literature regarding the effects of OXT in different stages of the addiction cycle. The current literature affirms that a well-functioning oxytocinergic system has protective effects such as the modulation of the initial response to drugs of abuse, the attenuation of the development of dependence, the blunting of drug reinstatement and a general anti-stress effect. However, this system is dysregulated if there is continuous drug use or chronic exposure to stress. In this context, OXT is emerging as a promising pharmacotherapy to restore its natural beneficial effects in the organism and to help rebalance the functions of the addicted brain.

Oxytocin (OXT) modulates social interactions, attenuates stressful responses and can decrease drug-seeking and taking behaviors. In previous studies, we observed that social defeat (SD) induced a long-lasting increase in ethanol intake and neuroinflammation in male mice. We also know that OXT blocks the increase in cocaine reward induced by SD. Therefore, in the present study we aimed to evaluate the effect of 1 mg/kg of OXT administered 30 min before each episode of SD on ethanol consumption and the neuroinflammatory response in adult male mice. Three weeks after the last SD, mice underwent oral ethanol self-administration (SA) procedure, and striatal levels of the two chemokines CX3CL1 and CXCL12 were measured after the last SD and at the end of the ethanol SA. OXT administration blocked the increase in voluntary ethanol consumption observed in defeated mice, although it did not affect motivation for ethanol. An increase in the striatal levels of CX3CL1 and CXCL12 was observed in defeated animals immediately after the last defeat and after the ethanol SA. However, defeated mice treated with OXT did not show this increase in the neuroinflammatory response. In conclusion, OXT treatment can be a powerful therapeutic target to reduce the negative effects of social stress on ethanol consumption and the neuroinflammatory process.

Background Substance use disorders and social stress are currently associated with changes in the immune system response by which they induce a proinflammatory state in neurons and glial cells that eventually modulates the reward system. Aims The aim of the present work was to assess the role of the immune TLR4 (Toll-like receptors 4) and its signaling response in the increased contextual reinforcing effects of cocaine and reinforcing effects of ethanol (EtOH) induced by social defeat (SD) stress. Methods Adult male C57BL/6 J wild-type (WT) mice and mice deficient in TLR4 (TLR4-KO) were assigned to experimental groups according to stress condition (exploration or SD). Three weeks after the last SD, conditioned place preference (CPP) was induced by a subthreshold cocaine dose (1 mg/kg), while another set underwent EtOH 6% operant self-administration (SA). Several inflammatory molecules were analyzed in the hippocampus and the striatum. Results SD induced higher vulnerability to the conditioned rewarding effects of cocaine only in defeated WT mice. Similarly, defeated WT mice exhibited higher 6% EtOH consumption, an effect that was not observed in the defeated TLR4-KO group. However, the motivation to obtain the drug was observed in both genotypes of defeated animals. Notably, a significant upregulation of the protein proinflammatory markers NFkBp-p65, IL-1β, IL-17 A and COX-2 were observed only in the defeated WT mice, but not in their defeated TLR4-KO counterparts. Conclusions These results suggest that TLR4 receptors mediate the neuroinflammatory response underlying the increase in the rewarding effects of cocaine and EtOH induced by social stress.

Previous studies have shown that exposure to social defeat (SD), a model of social stress, produces a long-term increase in the consumption of ethanol, most likely through an increase in the neuroinflammation response. The aim of the present study was to evaluate whether exposure to physical activity in the form of voluntary wheel running (VWR) could block the increase in ethanol consumption and the neuroinflammatory response induced by social stress. Mice were exposed to either 4 sessions of repeated social defeat (RSD) or a non-stressful experience. During the whole procedure, half of the mice were exposed to controlled physical activity, being allowed 1 h access to a low-profile running wheel three times a week. Three weeks after the last RSD, animals started the oral self-administration (SA) of ethanol (6% EtOH) procedure. Biological samples were taken 4 h after the first and the fourth RSD, 3 weeks after the last RSD, and after the SA procedure. Brain tissue (striatum) was used to determine protein levels of the chemokines fractalkine (CX3CL1) and SDF-1 (CXCL12). RSD induced an increase in ethanol consumption and caused greater motivation to obtain ethanol. The striatal levels of CX3CL1 and CXCL12 were also increased after the last RSD. VWR was able to reverse the increase in ethanol intake induced by social stress and the neuroinflammatory response. In conclusion, our results suggest that VWR could be a promising tool to prevent and reduce the detrimental effects induced by social stress.

It is well established that repeated social defeat stress can induce negative long-term consequences such as increased anxiety-like behavior and enhances the reinforcing effect of psychostimulants in rodents. In the current study, we evaluated how the immune system may play a role in these long-term effects of stress. A total of 148 OF1 mice were divided into different experimental groups according to stress condition (exploration or social defeat) and pre-treatment (saline, 5 or 10 mg/kg of the anti-inflammatory indomethacin) before each social defeat or exploration episode. Three weeks after the last social defeat, anxiety was evaluated using an elevated plus maze paradigm. After this test, conditioned place preference (CPP) was induced by a subthreshold dose of cocaine (1 mg/kg). Biological samples were taken four hours after the first and the fourth social defeat, 3 weeks after the last defeat episode, and after the CPP procedure. Plasma and brain tissue (prefrontal cortex, striatum and hippocampus) were used to determine the levels of the pro-inflammatory cytokine interleukin 6 (IL-6). Results showed an increase of peripheral and brain IL-6 levels after the first and fourth social defeat that was reverted three weeks later. Intraperitoneal administration of the anti-inflammatory drug indomethacin before each episode of stress prevented this enhancement of IL-6 levels and also reversed the increase in the rewarding effects of cocaine in defeated mice. Conversely, this protective effect was not observed with respect to the anxiogenic consequences of social stress. Our results confirm the hypothesis of a modulatory proinflammatory contribution to stress-induced vulnerability to drug abuse disorders and highlight anti-inflammatory interventions as a potential therapeutic tool to treat stress-related addiction disorders.

Social interaction is known to be the main source of stress in human beings, which explains the translational importance of this research in animals. Evidence reported over the last decade has revealed that, when exposed to social defeat experiences (brief episodes of social confrontations during adolescence and adulthood), the rodent brain undergoes remodeling and functional modifications, which in turn lead to an increase in the rewarding and reinstating effects of different drugs of abuse. The mechanisms by which social stress cause changes in the brain and behavior are unknown, and so the objective of this review is to contemplate how social defeat stress induces longlasting consequences that modify the reward system. First of all, we will describe the most characteristic results of the short-and longterm consequences of social defeat stress on the rewarding effects of drugs of abuse such as psychostimulants and alcohol. Secondly, and throughout the review, we will carefully assess the neurobiological mechanisms underlying these effects, including changes in the dopaminergic system, corticotrophin releasing factor signaling, epigenetic modifications and the neuroinflammatory response. To conclude, we will consider the advantages and disadvantages and the translational value of the social defeat stress model, and will discuss challenges and future directions.

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 CRF

It is well established that repeated social defeat stress can induce negative long-term consequences such as increased anxiety-like behavior and enhances the reinforcing effect of psychostimulants in rodents. In the current study, we evaluated how the immune system may play a role in these long-term effects of stress. A total of 148 OF1 mice were divided into different experimental groups according to stress condition (exploration or social defeat) and pre-treatment (saline, 5 or 10 mg/kg of the anti-inflammatory indomethacin) before each social defeat or exploration episode. Three weeks after the last social defeat, anxiety was evaluated using an elevated plus maze paradigm. After this test, conditioned place preference (CPP) was induced by a subthreshold dose of cocaine (1 mg/kg). Biological samples were taken four hours after the first and the fourth social defeat, 3 weeks after the last defeat episode, and after the CPP procedure. Plasma and brain tissue (prefrontal cortex, striatum and hippocampus) were used to determine the levels of the pro-inflammatory cytokine interleukin 6 (IL-6). Results showed an increase of peripheral and brain IL-6 levels after the first and fourth social defeat that was reverted three weeks later. Intraperitoneal administration of the anti-inflammatory drug indomethacin before each episode of stress prevented this enhancement of IL-6 levels and also reversed the increase in the rewarding effects of cocaine in defeated mice. Conversely, this protective effect was not observed with respect to the anxiogenic consequences of social stress. Our results confirm the hypothesis of a modulatory proinflammatory contribution to stress-induced vulnerability to drug abuse disorders and highlight anti-inflammatory interventions as a potential therapeutic tool to treat stress-related addiction disorders.

Many vegetable extracts, essential oils, and their main constituents are active on the Central Nervous System (CNS). In fact, they have been used as sedatives, hypnotics, or tranquilizers for their activity in treating CNS disorders. In this research, we studied the possible activities of Lavandula angustifolia (LA) essential oil and of its main constituent, linalool, as anti-stress compounds on anxiety and social interaction and their in vitro effects on proteins (pERK and PKA) involved in the transmission of the signal. An acute intraperitoneal injection of linalool (100 mg/kg) and of LA essential oil (200 mg/kg) reduced motor activity without any anxiolytic effect, but significantly increased social interaction. Stressed mice, after being exposed to a social defeat encounter, showed heightened anxiety and social avoidance. Acute administration of LA essential oil blocked stress-induced anxiety, while linalool showed no effects. However, both compounds were capable of reversing social aversion, acting as antidepressant agents. Our results showed that linalool inhibits pERK and PKA expression in the SH-SY5Y cell, but no effect was detected with the LA essential oil. Therefore, the LA essential oil and linalool may be considered as useful alternative tools to the available traditional treatments for social stress-induced mental illnesses.

Numerous studies report that social defeat stress alters dopamine (DA) neurotransmission in several areas of the brain. Alterations of the mesolimbic dopaminergic pathway are believed to be responsible for the increased vulnerability to drug use observed as a result of social stress. In the present study, we evaluated the influence of DA receptors on the long-term effect of repeated social defeat (RSD) on the conditioned rewarding and reinstating effects of cocaine. For this purpose, the D1R antagonist SCH 23390 and the D1R antagonist raclopride were administered 30 min before each social defeat and a cocaine-induced CPP procedure was initiated three weeks later. The expression of the D1R and D2R was also measured in the cortex and hippocampus throughout the entire procedure. Mice exposed to RSD showed an increase in the conditioned rewarding effects of cocaine thatwas blocked by both DA receptors antagonists when a subthreshold dose of cocaine was employed. However, while the vulnerability to reinstatement of the preference induced by 25 mg/kg cocaine-induced CPP was abolished by the D1R antagonist, it was practically unaffected by raclopride. Increases in D2R receptor levels were observed in the cortex of defeated animals after the first and fourth social defeats and in the hippocampus 3-weeks later. Nevertheless, D1R receptor levels in the hippocampus decreased only after the last social defeat. Our results confirm that RSD enhances the conditioned rewarding effects of cocaine and that both DA receptors are involved in this enduring effect of social stress. (C) 2016 Elsevier Inc. All rights reserved.