Cognitive and behavioural effects induced by social stress plus MDMA administration in mice.

Adverse life experiences such as social stress may make an individual more vulnerable to drug addiction and mental disorders associated with drug consumption. The present work aimed to evaluate the effects of stress induced by acute social defeat combined with the administration of 3,4-methylenedioxymethamphetamine (MDMA) on depression-like behaviour, memory function and motor response to drug in late adolescent male mice. Two groups of mice were exposed to social defeat (SD) during four encounters with an aggressive co-specific, which took place on alternate days. Immediately after defeat, animals were treated with saline or MDMA 10mg/kg (SD+SAL and SD+MDMA). In control groups, mice were placed in a neutral cage without an opponent (Control+SAL, Control+MDMA). Corticosterone levels and temperature were measured on the last day of this phase. During the following days, the behaviour of the animals was evaluated in the tail suspension test (an animal model of depression), memory tasks (passive avoidance and object recognition) and, after administration of 5mg/kg of MDMA, in the open-field test. Exposure of adult mice to acute social defeat plus MDMA increased immobility in the tail suspension test (depression-like behaviour), produced cognitive impairment, and reduced the motor response to MDMA. An increase in corticosterone levels and a decrease of temperature were also observed. As hypothesised, a combination of social stress and consumption of MDMA increases the risk of developing mental and cognitive disorders. Our results support the idea that stress is a common contributing factor to the high rate of comorbidity between substance abuse and mental disease.

Corrigendum to "Effects of Cannabinoid Exposure during Adolescence on the Conditioned Rewarding Effects of WIN 55212-2 and Cocaine in Mice: Influence of the Novelty-Seeking Trait".

[This corrects the article DOI: 10.1155/2016/6481862.].

Role of dopamine neurotransmission in the long-term effects of repeated social defeat on the conditioned rewarding effects of cocaine.

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 30min 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 that was 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 25mg/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 3weeks 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.

`Up-regulation of histone acetylation induced by social defeat mediates the conditioned rewarding effects of cocaine.

Social defeat (SD) induces a long-lasting increase in the rewarding effects of psychostimulants measured using the self-administration and conditioned place procedures (CPP). However, little is known about the epigenetic changes induced by social stress and about their role in the increased response to the rewarding effects of psychostimulants. Considering that histone acetylation regulates transcriptional activity and contributes to drug-induced behavioral changes, we addressed the hypothesis that SD induces transcriptional changes by histone modifications associated with the acquisition of place conditioning. After a fourth defeat, H3(K9) acetylation was decreased in the hippocampus, while there was an increase of HAT and a decrease of HDAC levels in the cortex. Three weeks after the last defeat, mice displayed an increase in histone H4(K12) acetylation and an upregulation of histone acetyl transferase (HAT) activity in the hippocampus. In addition, H3(K4)me3, which is closely associated with transcriptional initiation, was also augmented in the hippocampus three weeks after the last defeat. Inhibition of HAT by curcumin (100mg/kg) before each SD blocked the increase in the conditioned reinforcing effects of 1mg/kg of cocaine, while inhibition of HDAC by valproic acid (500mg/kg) before social stress potentiated cocaine-induced CPP. Preference was reinstated when animals received a priming dose of 0.5mg/kg of cocaine, an effect that was absent in untreated defeated mice. These results suggest that the experience of SD induces chromatin remodeling, alters histone acetylation and methylation, and modifies the effects of cocaine on place conditioning. They also point to epigenetic mechanisms as potential avenues leading to new treatments for the long-term effects of social stress on drug addiction.

Effects of Cannabinoid Exposure during Adolescence on the Conditioned Rewarding Effects of WIN 55212-2 and Cocaine in Mice: Influence of the Novelty-Seeking Trait.

Adolescent exposure to cannabinoids enhances the behavioural effects of cocaine, and high novelty-seeking trait predicts greater sensitivity to the conditioned place preference (CPP) induced by this drug. Our aim was to evaluate the influence of novelty-seeking on the effects of adolescent cannabinoid exposure. Adolescent male mice were classified as high or low novelty seekers (HNS and LNS) in the hole-board test. First, we evaluated the CPP induced by the cannabinoid agonist WIN 55212-2 (0.05 and 0.075 mg/kg, i.p.) in HNS and LNS mice. Then, HNS and LNS mice were pretreated i.p. with vehicle, WIN 55212-2 (0.1 mg/kg), or cannabinoid antagonist rimonabant (1 mg/kg) and were subsequently conditioned with WIN 55212-2 (0.05 mg/kg, i.p.) or cocaine (1 or 6 mg/kg, i.p.). Only HNS mice conditioned with the 0.075 mg/kg dose acquired CPP with WIN 55212-2. Adolescent exposure to this cannabinoid agonist increased the rewarding effects of 1 mg/kg of cocaine in both HNS and LNS mice, and in HNS mice it also increased the reinstating effect of a low dose of cocaine. Our results endorse a role for individual differences such as a higher propensity for sensation-seeking in the development of addiction.

Cocaine enhances the conditioned rewarding effects of MDMA in adolescent mice.

Although the consumption of cocaine is frequent in young users of MDMA (3,4-methylenedioxymethamphetamine), the influence of exposure to cocaine on the rewarding effects of MDMA in adolescents has not been studied. The purpose of the present work was to evaluate the effect of co-administration of cocaine (1 and 10 mg/kg) and a sub-threshold dose of MDMA (1.25 mg/kg) on the acquisition of conditioned place preference (CPP) (experiment 1). In addition, the effect of pre-treatment with cocaine on MDMA-induced CPP was evaluated (experiment 2). Levels of monoamines in striatum, hippocampus and cortex were measured in both experiments. Our hypotheses were that cocaine co-administration or pre-treatment would increase the rewarding effects of MDMA, and that these effects would be related with changes in brain monoamine levels. Our results showed that cocaine potentiated the rewarding effects of MDMA, since a sub-threshold dose of MDMA, which did not induce CPP by itself, induced a significant CPP in adolescent mice when administered along with cocaine during conditioning (experiment 1). Moreover, pre-treatment with cocaine several days before conditioning also increased the rewarding effects of MDMA (experiment 2). No significant changes in the levels of biogenic amines, which correlated with these behavioural effects, were observed. Our results confirm the involvement of the dopaminergic system in MDMA-induced CPP in adolescent mice and suggest that combined consumption with or pre-exposure to cocaine increases the conditioned rewarding effects of MDMA, which may enhance the capacity of MDMA to induce dependence.

Higher sensitivity to the conditioned rewarding effects of cocaine and MDMA in High-Novelty-Seekers mice exposed to a cocaine binge during adolescence.

RATIONALE: Exposure to drugs during adolescence can induce alterations in the central nervous system. The novelty-seeking personality trait influences differences observed among individuals exposed to drugs of abuse. OBJECTIVES: Long-term effects of intensive pre-treatment with cocaine during adolescence or adulthood were evaluated in High- and Low-Novelty Seeker (HNS and LNS) mice. It was hypothesized that a cocaine binge during adolescence would increase sensitivity to the rewarding effects of cocaine and MDMA, especially in HNS animals, and modify the spontaneous behaviour of adult animals. METHODS: Adolescent (PND 33) and adult (PND 60) mice were identified as HNS or LNS according to their performance in the hole-board test. Subsequently, they received pre-treatment with cocaine (three injections per day of an increasing dose for 10 days) or saline. Three weeks later, the mice performed the hole-board, elevated plus maze, spontaneous locomotor activity and cocaine- (1 mg/kg) or MDMA- (1.25 mg/kg) induced conditioning place preference (CPP) tests. In another set of mice, the effects of pre-treatment of cocaine during adulthood on MDMA- or cocaine-induced CPP were also evaluated 3 weeks later. RESULTS: Only HNS mice treated with cocaine during adolescence acquired MDMA- or cocaine-induced CPP in adulthood. Moreover, pre-exposure to cocaine during adolescence caused subsequent behavioural alterations, including reduced exploratory behaviour and increased locomotor reactivity. CONCLUSIONS: Cocaine binge administration during adolescence induces a higher sensitivity to the rewarding effects of MDMA and cocaine in HNS mice in adulthood. This may explain the greater vulnerability often seen among individuals exposed early in life to drugs of abuse.

Effects of risperidone on the acquisition and reinstatement of the conditioned place preference induced by MDMA.

Some users of 3,4-methylenedioxymethylamphetamine (MDMA or ecstasy) abuse this drug and/or become concerned about their use. These individuals would benefit greatly from the development of pharmacological strategies to reduce MDMA consumption. We have previously observed that antipsychotics block acquisition and expression of the conditioned place preference (CPP) induced by MDMA, though they do not modify priming-induced reinstatement of MDMA-induced CPP after extinction. In the present study we have evaluated the capacity of the mixed serotonin (5-HT2A)/dopamine (DA D2) antagonist risperidone to block acquisition and reinstatement of MDMA induced-CPP. Adolescent male mice conditioned with 10mg/kg of MDMA were treated with 0.1 or 0.3mg/kg of risperidone during acquisition of conditioning (experiment 1) or before the reinstatement test (experiment 2). Risperidone was devoid of motivational effects in the CPP paradigm, but the higher dose blocked acquisition of the MDMA-induced CPP. This behavioural effect was accompanied by an increase in the level of dopamine transporters in the striatum. However, risperidone had no effects on reinstatement of the CPP induced by a priming of MDMA. Our results suggest that risperidone induces the same effects as other antipsychotics, in which case its efficacy for treating MDMA abuse is limited.

Neurochemical substrates of MDMA reward: effects of the inhibition of serotonin reuptake on the acquisition and reinstatement of MDMA-induced CPP.

Different neurotransmitter brain systems have been implicated in the rewarding effects of 3,4-methylenedioxymetamphetamine (MDMA), including dopamine or serotonin. Serotonin selective reuptake inhibitors (SSRI) are a commonly prescribed therapy for psychiatric disorders, and the SSRI fluoxetine is recommended for MDMA users due to its neuroprotective effect against MDMAinduced neurotoxicity. In the present work, we employed the conditioned place preference (CPP) paradigm to study how the inhibition of serotonin reuptake with fluoxetine affected the rewarding and reinstating effects of MDMA in adolescent male mice. Firstly, we evaluated the motivational effects of fluoxetine (1 and 10 mg/kg), administered alone or with a sub-threshold dose of MDMA (1.25 mg/kg). In a second experiment we evaluated the effects of a pretreatment with fluoxetine (1 and 10 mg/kg) on the subsequent acquisition of a CPP induced by MDMA (1.25 mg/kg). The effects of a priming dose of fluoxetine (1 and 10 mg/kg), MDMA (5 or 1.25 mg/kg) or both drugs together on the reinstatement of a previously extinguished CPP induced by MDMA (10 mg/kg) were studied in a third experiment. Fluoxetine did not induce motivational effects but did increase the rewarding effects of a sub-threshold dose of MDMA, and pretreatment with the high dose of fluoxetine had the same effect. Fluoxetine did not induce cross-reinstatement of the MDMA CPP, but the combination of an ineffective priming dose of MDMA and the highest dose of fluoxetine did induce reinstatement of CPP. Neurochemical experiments demonstrated alterations in monoamine levels of MDMA treated mice produced by fluoxetine. As a whole, these results show that the inhibition of serotonin reuptake potentiates the acquisition and reinstatement of MDMA-induced CPP and supports a role for serotonin in MDMA-induced reward.

Age- and sex-related differences in the acquisition and reinstatement of ethanol CPP in mice.

Many people begin to experiment with alcohol during adolescence, an important developmental period during which sex differences in the effects of ethanol appear. In the present study we evaluated the effect of ethanol (0, 0.625, 1.25 or 2.5 g/kg) on the acquisition of a conditioned place preference (CPP) in early and late adolescent male and female mice. In addition, we assessed the capacity of ethanol to induce reinstatement of the CPP after its extinction. CPP was induced in early and late adolescent females with 2.5 g/kg, and in early adolescent males with 1.25 or 2.5 g/kg of ethanol. No CPP was observed in late adolescent males. Priming with ethanol reinstated the CPP induced by the highest dose in early adolescent male and early and late adolescent female mice. Our data suggest that early adolescents of both sex and late adolescent females are particularly vulnerable to the effects of ethanol.