Bruno Ribeiro Do Couto

Changes in histone acetylation in the prefrontal cortex of ethanol-exposed adolescent rats are associated with ethanol-induced place conditioning.

Alcohol drinking during adolescence can induce long-lasting effects on the motivation to consume alcohol. Abnormal plasticity in reward-related processes might contribute to the vulnerability of adolescents to drug addiction. We have shown that binge-like ethanol treatment in adolescent rats induces alterations in the dopaminergic system and causes histone modifications in brain reward regions. Considering that histone acetylation regulates transcriptional activity and contributes to drug-induced alterations in gene expression and behavior, we addressed the hypothesis that ethanol is capable of inducing transcriptional changes by histone modifications in specific gene promoters in adolescent brain reward regions, and whether these events are associated with acquisition of place conditioning. After treating juvenile and adult rats with intermittent ethanol administration, we found that ethanol treatment upregulates histone acetyl transferase (HAT) activity in adolescent prefrontal cortex and increases histone (H3 or H4) acetylation and H3(K4) dimethylation in the promoter region of cFos, Cdk5 and FosB. Inhibition of histone deacetylase by sodium butyrate before ethanol injection enhances both up-regulation of HAT activity and histone acetylation of cFos, Cdk5 and FosB. Furthermore, co-administration of sodium butyrate with ethanol prolongs the extinction of conditioned place aversion and increased the reinstatement effects of ethanol in ethanol-treated adolescents, but not in ethanol-treated adult rats. These results indicate that ethanol exposure during adolescence induces chromatin remodeling, changes histone acetylation and methylation, and modify the effects of ethanol on place conditioning. They also suggest that epigenetic mechanisms might open up avenues to new treatments for binge drinking-induced drug addiction during adolescence.

Rewarding Effects and Reinstatement of MDMA-Induced CPP in Adolescent Mice

Although the rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in self-administration and conditioned place preference (CPP) procedures, its addictive potential (ie, the vulnerability to relapse, measured by its ability to induce reinstatement of an extinguished response), remains poorly understood. In this study, the effects of MDMA (5, 10, and 20 mg/kg) on the acquisition, extinction and reinstatement of CPP were evaluated in mice, using two different protocols during acquisition of CPP. In the first experiment, animals were trained using a two-session/day schedule (MDMA and saline for 4 consecutive days), whereas in the second experiment, they were trained using an alternating day schedule (MDMA and saline each 48 h). After extinction, the ability of drug priming to reinstate CPP was evaluated. In Experiment 1, MDMA did not significantly increase the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, although the preference was evident a week afterwards, lasting between 2 and 21 weeks. No reinstatement was observed after MDMA priming. In Experiment 2, all doses produced CPP in Post-C, which lasted between 1 and 4 weeks. MDMA induces reinstatement at doses up to 4 times lower than those used in conditioning. The analyses of brain monoamines revealed that the daily schedule of treatment induces a non-dose-dependent decrease in dopamine and serotonin (5-HT) in the striatum, whereas the alternating schedule produces a dose-dependent decrease of 5-HT in the cortex. These results demonstrate that MDMA produces long-lasting rewarding effects and reinstatement after extinction, suggesting the susceptibility of this drug to induce addiction.

Effects of NMDA receptor antagonists (MK-801 and memantine) on the acquisition of morphine-induced conditioned place preference in mice

Several studies have shown that the systemic administration of a variety of N-methyl-D-aspartate (NMDA) receptor antagonists can block the development or expression of conditioned place preference (CPP) induced by rewarding drugs such as morphine. In the present study, we examined the effects of different doses of two non-competitive NMDA receptor antagonists, MK-801 (0.1, 0.2 and 0.3 mg/kg) and memantine (2.5, 5, 10, 20 and 40 mg/kg), in CPP induced by 40 mg/kg of morphine in male mice. The CPP was carried out with an unbiased procedure in terms of initial spontaneous preference. Animals received the different doses of drugs in the conditioning sessions. MK-801 and memantine, at all doses used, produced neither place preference nor place aversion, but the higher doses of memantine (20 and 40 mg/kg) were able to completely block morphine-induced CPP. The present data show that the NMDA receptor antagonists MK-801 and memantine have no reinforcing properties but memantine is capable of preventing the acquisition of morphine-induced CPP. These results suggest that the development of morphine-induced CPP may be closely related to NMDA receptors and that the glutamatergic system can modulate opiate reward.

Effect of adolescent exposure to WIN 55212-2 on the acquisition and reinstatement of MDMA-induced conditioned place preference

The present study employs a conditioned place preference procedure (CPP) to examine the effects of exposure to the cannabinoid agonist WIN 55212-2 (WIN) (0.1 and 0.5mg/kg) during adolescence on the reinforcing properties of +/-3,4-methylenedioxymetamphetamine hydrochloride (MDMA) (1.25 and 2.5mg/kg) in mice. On postnatal day (PD) 27, animals received a daily injection of the assigned treatment on 5 consecutive days, and three days later the place conditioning procedure was initiated (PD 35). The results suggest that pre-exposure to cannabinoids strengthens the properties of MDMA and favors reinstatement of the craving for the drug, which endorses the gateway hypothesis.

Memantine blocks sensitization to the rewarding effects of morphine.

Knowledge regarding the specific brain changes and neural plasticity processes produced by repeated drug exposure may be used to advance the understanding of the neurobiology of addiction in order to design appropriate medications. In the present study, the influence of N-methyl-d-aspartate (NMDA) glutamatergic receptors on sensitization to the motor and rewarding effects of morphine was evaluated. The effects of pre-exposure to saline or 20 mg/kg morphine plus the NMDA receptor antagonist memantine (10 or 20 mg/kg) on motor activity and place conditioning induced by a low dose of morphine (2 mg/kg) were assessed. The dose of 2 mg/kg of morphine was ineffective in mice pre-exposed to saline but induced a clear conditioned place preference (CPP) in those pre-exposed to morphine. Conversely, animals pre-exposed to morphine plus memantine did not acquire CPP. Only those pre-exposed to morphine presented an increased motor response to morphine 2 mg/kg. Our results demonstrate that NMDA glutamatergic receptors are implicated in the development of sensitization to the conditioned rewarding effects of morphine.

Adolescent pre‐exposure to ethanol and 3,4‐methylenedioxymethylamphetamine (MDMA) increases conditioned rewarding effects of MDMA and drug‐induced reinstatement

Many adolescents often take ethanol (EtOH) in combination with 3,4‐methylenedioxymethylamphetamine (MDMA). In the present work, we used a mouse model to study the effect of repeated pre‐exposure during adolescence to EtOH (2 g/kg), MDMA (10 or 20 mg/kg) or EtOH + MDMA on the rewarding and reinstating effects of MDMA in the conditioned place preference (CPP) paradigm. Pre‐exposure to EtOH, MDMA or both increased the rewarding effects of a low dose of MDMA (1.25 mg/kg). These pre‐treatments did not affect the acquisition of the CPP induced by 5 mg/kg of MDMA. However, the CPP was more persistent in mice pre‐exposed to both doses of MDMA or to EtOH + MDMA20. After extinction of the CPP induced by 5 mg/kg of MDMA, reinstatement was observed in all groups with a priming dose of 2.5 mg/kg of MDMA, in the groups pre‐exposed to EtOH or MDMA alone with a priming dose of 1.25 mg/kg, and in the groups pre‐treated with MDMA alone with a priming dose of 0.625 mg/kg. Pre‐treatment during adolescence with MDMA or EtOH induced long‐term changes in the level of biogenic amines [dihydroxyphenyl acetic acid, homovanillic acid, dopamine turnover, serotonin (5‐hydroxytryptamine, 5‐HT) and 5‐hydroxyindole acetic acid (5‐HIAA) in the striatum, and 5‐HT and 5‐HIAA in the cortex] after the first reinstatement test, although these effects depended on the dose used during conditioning. These results suggest that exposure to EtOH and MDMA during adolescence reinforces the addictive properties of MDMA.

Involvement of nitric oxide synthesis in sensitization to the rewarding effects of morphine

Knowledge about the specific brain changes and neural plasticity processes produced by repeated exposure to a drug is essential to progress in the field of neurobiology of addiction and the development of effective medication. In the present study, the influence of nitric oxide synthesis on sensitization to the rewarding effects of morphine has been evaluated. The effects of pre-treatment of mice with saline or 20mg/kg of morphine plus the nitric oxide synthase inhibitor 7-nitroindazole (7NI) (12.5 or 25mg/kg) on the place conditioning induced by a low dose of morphine (2mg/kg) were assessed. The dose of 2mg/kg of morphine was ineffective in animals pre-treated with saline but induced a clear conditioned place preference (CPP) in those pre-treated with morphine. Conversely, animals pre-treated with morphine plus 7NI did not acquire CPP. Our results demonstrate that the nitric oxide pathway is implicated in the development of sensitization to the conditioned rewarding effects of morphine.

Impact of social stress in addiction to psychostimulants: what we know from animal models.

Psychostimulant addiction, most notably cocaine and amphetamine - type stimulants are an important public health problem worldwide. It appears that social factors may influence the initiation, maintenance and recovery from addictions. Several animal models have been developed to study addiction, highlighting drug self-administration (SA) and the conditioned place preference (CPP) paradigms. These models have been modified to accurately reflect the characteristics of drug addiction in its different stages. One factor that clearly plays a major role in addiction is stress, which is a risk factor not only for the initiation, maintenance and escalation of drug consumption, but also for relapse. In animal models, stress for itself can provoke reinstatement of self-administration or CPP. The relationship between stress and addiction is very tight. One example is the close anatomical relationship of some areas that share these two phenomena. It seems obvious to think that the main source of stress in humans is social interaction. The aim of the present review is to gather the current information regarding the role of social stress in the addiction to psychostimulant drugs in animal models. First, we briefly describe the mechanisms by which stress exerts its effects and the basic concepts of addiction. We will try to establish common pathways of stress and addiction, to address later social stress effects on different stages of addiction. Then, we will address pharmacological therapies and preventive factors that counteract the enhancing effects of social stress in addiction. Finally, we will analyze how negative environmental conditions may induce individuals to increased vulnerability to drugs, and how favorable environmental conditions may have protective and curative effects against addiction. In this sense, we also analyze the importance of social interactions and their ability to modulate the different stages of addiction. As a conclusion, and despite the scarcity of the research, social stress exposure increases the initiation of psychostimulant consumption and the vulnerability to relapse in animal models of addiction. Studies on the mechanisms underlying the effects of social stress and how it can be counteracted pharmacologically, are research areas that should be explored in the future. At the same time, translational research on the effects of environmental conditions and positive social interactions, which have been shown to have a critical role in addictions, should be encouraged.

Age and gender effects on the prevalence of poor sleep quality in the adult population.

OBJECTIVE Sleep quality has a significant impact on health and quality of life and is affected, among other factors, by age and sex. However, the prevalence of problems in this area in the general population is not well known. Therefore, our objective was to study the prevalence and main characteristics of sleep quality in an adult population sample. METHODS 2,144 subjects aged between 43 and 71 years belonging to the Murcia (Spain) Twin Registry. Sleep quality was measured by self-report through the Pittsburgh Sleep Quality Index (PSQI). Logistic regression models were used to analyse the results. RESULTS The prevalence of poor sleep quality stands at 38.2%. Univariate logistic regression analyses showed that women were almost twice as likely as men (OR: 1.88; 95% confidence interval [95%CI]: 1.54 to 2.28) to have poor quality of sleep. Age was directly and significantly associated with a low quality of sleep (OR: 1.05; 95%CI: 1.03 to 1.06). CONCLUSIONS The prevalence of poor sleep quality is high among adults, especially women. There is a direct relationship between age and deterioration in the quality of sleep. This relationship also appears to be more consistent in women.