P-70REPEATED SOCIAL STRESS REVERSED ETHANOL-INDUCED CONDITIONED PLACE AVERSION IN MALE MICE

Exposure to stressors can produce behavioural and neurochemical adaptations that render individuals more prone to drug-seeking and drug-taking behaviours. It is well know that stress experiences are a risk factor for alcohol abuse in humans and recent studies in animal models reported that repeated social stress increased alcohol consumption. The aim of the present work is to evaluate the long-term …

P-69TLR4 ELIMINATION PREVENTS LONG-LASTING ETHANOL EFFECTS ON COCAINE-INDUCED CONDITIONED PLACE PREFERENCE IN ADOLESCENT MICE

Our previous studies indicated that binge-like ethanol treatment in adolescent rats induces an increase in the conditioned rewarding effects of cocaine. Ethanol induces the production of cytokines and inflammatory mediators, that cause brain damage by activating the toll-like receptor 4 (TLR4) signaling response. To test if these receptor mediated the observed increased in cocaine-induced conditioned …

Role of N-methyl-D-aspartate receptors in the long-term effects of repeated social defeat stress on the rewarding and psychomotor properties of cocaine in mice.

Abstract Exposure to social stress increases the vulnerability of experimental animals to the rewarding effects of cocaine and it has been suggested that the glutamatergic system could be involved in these effects of stress. The aim of this work is to determine the role of N-methyl- d -aspartate (NMDA) glutamate receptors in the influence of social stress on the conditioned place preference and locomotor sensitization induced by cocaine. Mice treated with saline or NMDA antagonist memantine (5 or 10 mg/kg) underwent repeated social defeat or were kept in the exploration control condition. After three weeks, all groups (SAL + RSD, M5 + RSD, M10 + RSD, SAL + EXP, M5 + EXP and M10 + EXP) were …

Effects of DA D1 and D2 antagonists on the sensitisation to the motor effects of morphine in mice

Abstract Acute morphine administration produces hyperactivity in mice and repeated treatment induces an enhancement of this effect. In this experiment, we study the sensitisation to the hyperactivity induced by intermittent morphine administration (40 mg/kg) and the effects of dopamine (DA) antagonists on this phenomenon. Animals received three injections, separated by 48 h, and after each injection, their activity was registered between 30 and 60 min. In Experiment 1, animals were divided into two groups, which received saline and morphine (S–S–M) or only morphine (M–M–M). In Experiment 2, animals were divided into 12 groups. Half, which was designed to study the effects of DA antagonists …

Effects of CGS 10746B on hyperactivity and place preference induced by morphine

The effects of CGS 10746B, a dopamine release inhibitor, on spontaneous locomotor activity, morphine-induced hyperactivity, acquisition of conditioned place paradigm and morphine-induced conditioned place preference (CPP) was evaluated in male mice. In experiment 1, animals treated with CGS 10746B (0.5, 1, 2, 4, 8, 16, 24 and 32 mg/kg), morphine (40 mg/kg) or morphine (40 mg/kg) plus CGS 10746B (0.5, 1, 2, 4, 8, 16, 24 and 32 mg/kg) were placed in an actimeter during a period of 90 min. In experiment 2, animals treated with CGS 10746B (0.5, 1, 3 and 10 mg/kg), morphine (40 mg/kg) or morphine (40 mg/kg) plus CGS 10746B (0.5, 1, 3 and 10 mg/kg) were conditioned following a procedure unbiased …

Pharmacological modulation of protein kinases as a new approach to treat addiction to cocaine and opiates.

Drug addiction shares brain mechanisms and molecular substrates with learning and memory processes, such as the stimulation of glutamate receptors and their downstream signalling pathways. In the present work we provide an up-to-date review of studies that have demonstrated the implication of the main memory-related calcium-dependent protein kinases in opiate and cocaine addiction. The effects of these drugs of abuse in different animal models of drug reward, dependence and addiction are altered by manipulation of the mitogen-activated protein kinase (MAPK) family, particularly extracellular signal regulated kinase (ERK), calcium/calmodulin-dependent kinase II (CaMKII), the protein kinase C…

Reinstatement of Morphine-Induced Conditioned Place Preference in Mice by Priming Injections

To construct a model of relapse of drug abuse in mice, the induction, we evaluated the extinction and reinstatement of morphine-induced place preference. In Experiment 1, we examined the effects of morphine (0, 2, 3, 5, 10, 20 and 40 mg/kg) in the conditioned place preference (CPP) paradigm. Mice showed CPP with 5, 10, 20 and 40 mg/kg. In Experiment 2, we evaluated the effects of two different extinction procedures. After conditioning with 40 mg/kg of morphine, the mice underwent daily extinction sessions of 60 or 15 min of duration. CPP was extinguished after seven and nine sessions, respectively. In Experiment 3, we tested the reinstating effects of several priming doses of morphine. Mice…

Sensitization to the rewarding effects of morphine depends on dopamine

The influence of dopamine (DA) on sensitization to the rewarding effects of morphine was evaluated. The effects of pre-treatment with saline or morphine plus naloxone, CGS 10746B, haloperidol, SCH 23390 and raclopride, on the place conditioning induced by 2 mg/kg morphine were evaluated. This dose was ineffective in saline pre-treated animals but induced a clear conditioned place preference in mice pre-treated with morphine, CGS 10746B or haloperidol. Conversely, animals pre-treated with morphine plus naloxone, CGS 10746B, SCH 23390, raclopride and the high dose of haloperidol did not acquire place preference. Our results demonstrated that DA release and subsequent DA D1 and D2 receptor act…

Prenatal cocaine exposure alters spontaneous and cocaine-induced motor and social behaviors.

The abuse of cocaine in pregnant women could affect emotional behaviors in their descendents. The aim of this work was to evaluate the effects of prenatal cocaine exposure on spontaneous and cocaine-induced motor and social behaviors in mice. Three kinds of prenatal treatment were used: non-treated animals; mice treated daily with physiological saline during the last week of pregnancy; and finally, those treated with cocaine (25 mg/kg) during the same period. Behavioral studies took place on adult males, which were housed in two different conditions: grouped (non-aggressive), or isolated (aggressive). Cocaine-pretreated animals exhibited slight differences in spontaneous motor activity, but…

Reinstatement of Drug-seeking in Mice Using the Conditioned Place Preference Paradigm

The present protocol describes the Conditioned Place Preference (CPP) as a model of relapse in drug addiction. In this model, animals are first trained to acquire a conditioned place preference in a drug-paired compartment, and after the post-conditioning test, they perform several sessions to extinguish the established preference. The CPP permits the evaluation of the conditioned rewarding effects of drugs related to environmental cues. Then, the extinguished CPP can be robustly reinstated by the non-contingent administration of a priming dose of the drug, and by exposure to stressful stimuli. Both methods will be explained here. When the animal reinitiates the behavioral response, a reins…

CB1 cannabinoid receptor-mediated aggressive behavior

This study examined the role of cannabinoid CB1 receptors (CB1r) in aggressive behavior. Social encounters took place in grouped and isolated mice lacking CB1r (CB1KO) and in wild-type (WT) littermates. Cognitive impulsivity was evaluated in the delayed reinforcement task (DRT). Gene expression analyses of monoaminooxidase-A (MAO-A), catechol-o-methyl-transferase (COMT), 5-hydroxytriptamine transporter (5-HTT) and 5-HT1B serotonergic receptor (5HT1Br) in the median and dorsal raphe nuclei (MnR and DR, respectively) and in the amygdala (AMY) were performed by real time-PCR. Double immunohistochemistry studies evaluated COMT and CB1r co-localization in the raphe nuclei and in the cortical (AC…

Cannabidiol prevents priming- and stress-induced reinstatement of the conditioned place preference induced by cocaine in mice

[Background]: Cocaine dependence is an important problem without any effective pharmacological treatment. Some preclinical studies have suggested that cannabidiol (CBD), a component of the Cannabis sativa plant, could be useful for the treatment of cocaine use disorders.

Memantine presents different effects from MK-801 in motivational and physical signs of morphine withdrawal

Adaptive changes in neural systems due to chronic opiate exposure are related to the neural plasticity phenomenon, NMDA receptors being implicated in these processes, e.g. tolerance, dependence or withdrawal. In this work, we investigated the effect of two non-competitive NMDA antagonists, memantine and MK-801, in motivational (Conditioned Place Aversion paradigm, CPA) and physical aspects of morphine withdrawal. After the induction of morphine dependence, animals in which the CPA was studied, received memantine (5 and 10 mg/kg) or MK-801 (0.3-0.006 mg/kg) either during the acquisition (conditioning) or expression (test) phase of this procedure. Both drugs were capable of inhibiting conditi…

The novelty-seeking phenotype modulates the long-lasting effects of adolescent MDMA exposure.

Exposure to drugs such as ethanol or cocaine during adolescence induces alterations in the central nervous system that are modulated by the novelty-seeking trait. Our aim was to evaluate the influence of this trait on the long-term effects of MDMA administration during adolescence on spontaneous behavior and conditioned rewarding effects in adulthood. Adolescent mice were classified as high or low novelty seekers (HNS or LNS) according to the hole-board test and received either MDMA (0, 10 or 20mg/kg PND 33-42) or saline. Three weeks later, having entered adulthood (PND>68), one set of mice performed the elevated plus maze and social interaction tests, while another set performed the condit…

CB1 Cannabinoid Receptors and Aggression

Abstract The relation between the use of cannabis and violent behavior is controversial, partly owing to the complexity of the concept of aggression and variability among the studies performed. The primary psychoactive compound of cannabis, Δ9-tetrahydrocannabinol, acts on G-protein-coupled receptors such as the cannabinoid type 1 (CB1) receptor, the most important of the endocannabinoid system. Although historically suspected of instigating aggressive behaviors, the findings of research about cannabis use in humans are mixed. While cannabis intoxication seems to reduce the likelihood of violence, mounting evidence associates withdrawal with an increase in aggression. Acute or chronic canna…

Environment associated with morphine and experience of aggression modulate behaviors of postdependent mice

Contexts associated with drug use can acquire secondary reinforcing properties. Furthermore, context-specific withdrawal has been observed to reflect a relatively long-lasting learned response. The aim of this study was to evaluate the effect of the environment paired with morphine after 15 days of abstinence. In the first experiment, isolated male mice received saline or morphine either in their home cage or in the distinctive environment, performing two agonistic encounters in the distinctive environment during spontaneous withdrawal. Similar groups were assigned but without aggression encounters during withdrawal. In the second experiment, animals received saline or morphine as previousl…

Behavioural and neurotoxic long-lasting effects of MDMA plus cocaine in adolescent mice

The poly-drug pattern is the most common among MDMA users, with cocaine being a frequently associated drug. The aim of the present work was to evaluate the behavioural and neurotoxic long-term effects of exposure during adolescence to MDMA alone or plus cocaine. Mice of 28 to 30 days of age received a treatment of two daily injections of an identical dose of MDMA (5, 10 or 20 mg/kg), alone or plus cocaine (25 mg/kg), for 3 days (6 administrations). Three weeks after receiving MDMA, an increase in the time dedicated by the animals to social contacts with their conspecifics was observed, whilst their behaviour in the elevated plus maze showed no differences from that of non-treated mice. Afte…

Gestational exposure to cocaine alters cocaine reward

Exposure of the developing foetus to drugs of abuse during pregnancy may lead to persistent abnormalities of brain systems involved in drug addiction. Mice prenatally exposed to cocaine (25 mg/kg), physiological saline or non-treated during the last 7 days of pregnancy were evaluated in adulthood for the rewarding properties of cocaine (3, 25 and 50 mg/kg), using the conditioned place preference procedure. Dams treated with physiological saline gained significantly less weight over the course of gestation than controls; no other differences were observed in the maternal and offspring data. All the animals developed preference to 3 and 25 mg/kg of cocaine, but those treated prenatally with c…

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 30 min before each social defeat and a cocaine-induced CPP procedure was initiated three weeks later. The expression of the D1R a…

Effects of risperidone on conditioned avoidance responding in male mice

The effects of risperidone (0.1, 0.5 and 1 mg/kg) on active avoidance behaviour of BALB/C mice were explored in three acquisition sessions and in one subsequent performance session. In the acquisition phase, risperidone-treated animals showed a decrease in avoidances and in crossings in the adaptation period and in the intertrial intervals (ITIs), and an increase in non-responses; intermediate and high doses also decreased defecation. In the performance phase, 0.5 and 1 mg/kg risperidone decreased avoidance responses, crossings in the adaptation period and ITI crossing, which also decreased with 0.1 mg/kg. Moreover, 0.5 mg/kg of risperidone increased escape responses and 1 mg/kg increased n…

Role of acute social stress in the rewarding effects of MDMA in adolescent mice

Drug use among adolescents is a serious problem in our society, as some individuals develop dependence and addiction. MDMA/Esctasy is one of the most typically used substances by this age group. It is well known that environmental factors can alter the rewarding properties of drugs and the propensity to drug-related disorders. In this sense, exposure to social stress induces long-term effects in mice, enhancing the rewarding effects of MDMA in the conditioned place preference (CPP) paradigm. On the other hand, previous research has not provided conclusive results regarding the short-term effects of social defeat on MDMA reward in adolescent animals, probably due to the use of very low or ve…

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)…

Effects of extended cocaine conditioning in the reinstatement of place preference.

Rats allowed extended access to cocaine self-administration develop a number of symptoms of addiction, such as greater susceptibility to drug-induced relapse. Using the conditioned place preference (CPP), the number of conditioning training sessions was increased in order to augment exposure to contextual cues associated with the effects of a drug. Mice were conditioned with a steady dose of 6 or 25 mg/kg of cocaine for 4, 8, 12, 16, 20 or 40 days. Weekly sessions of extinction followed the establishment of preference, after which a priming dose of cocaine was administered to reinstate the extinguished preference. The magnitude of the place preference effect was equal in all groups, indepen…

Increased ethanol consumption after interruption of fat bingeing

There is a marked comorbidity between alcohol abuse and eating disorders, especially in the young population. We have previously reported that bingeing on fat during adolescence increases the rewarding effects of ethanol (EtOH). The aim of the present work was to study if vulnerability to EtOH persists after cessation of binge eating. OF1 mice binged on fat (HFB: high-fat binge) during adolescence (PND 25-43) and were tested for 15 days after the last access to HFB (on PND 59) using the self-administration paradigm, the conditioned place preference (CPP) and locomotor sensitization to ethanol. Our results showed that after 15 days of cessation of fat ingestion, mice increased their consumpt…

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.

Role of the dopaminergic system in the acquisition, expression and reinstatement of MDMA-induced conditioned place preference in adolescent mice.

Background The rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in conditioned place preference (CPP) procedures, but the involvement of the dopaminergic system in MDMA-induced CPP and reinstatement is poorly understood. Methodology/Principal Findings In this study, the effects of the DA D1 antagonist SCH 23390 (0.125 and 0.250 mg/kg), the DA D2 antagonist Haloperidol (0.1 and 0.2 mg/kg), the D2 antagonist Raclopride (0.3 and 0.6 mg/kg) and the dopamine release inhibitor CGS 10746B (3 and 10 mg/kg) on the acquisition, expression and reinstatement of a CPP induced by 10 mg/kg of MDMA were evaluated in adolescent mice. As expected, MDMA significantly increa…

7-Nitroindazole blocks conditioned place preference but not hyperactivity induced by morphine.

The effects of 7-nitroindazole (7-NI), a neural nitric oxide synthase (nNOS) inhibitor, on spontaneous locomotor activity, morphine-induced hyperactivity, acquisition of place conditioning and morphine-induced conditioned place preference (CPP) were evaluated in male mice. In experiment 1, animals treated with 7-NI (25, 50 and 100 mg/kg), morphine (40 mg/kg) or morphine (40 mg/kg) plus 7-NI (25, 50 or 100 mg/kg) were placed in an actimeter for 3 h. In experiment 2, animals treated with the same drugs and doses were conditioned following an unbiased procedure. 7-NI did not affect the spontaneous locomotor activity or hyperactivity induced by morphine. However, the moderate and high doses of …

Behavioral Traits Associated With Resilience to the Effects of Repeated Social Defeat on Cocaine-Induced Conditioned Place Preference in Mice

The relationship between stress and drug use is well demonstrated. Stress-induced by repeated social defeat (RSD) enhances the conditioned place preference (CPP) induced by cocaine in mice. The phenomenon of resilience understood as the ability of subjects to overcome the negative effects of stress is the focus of increasing interest. Our aim is to characterize the behavior of resilient animals with respect to the effects of RSD on the CPP induced by cocaine. To this end, 25 male C57BL/6 mice were exposed to stress by RSD during late adolescence, while other 15 male mice did not undergo stress (controls). On the 2 days following the last defeat, all the animals carried out the elevated plus…

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

Abstract 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 i…

GHB differentially affects morphine actions on motor activity and social behaviours in male mice

There are several reports suggesting that gamma-hydroxybutyric acid (GHB) influences the endogenous opioid system. The present study aimed to investigate the effects of GHB on motor and social activities and to examine its influence on morphine's actions on these behaviours. In a first experiment, several doses of GHB were studied but only the highest (200 and 400 mg/kg) produced a decrease in spontaneous motor activity measured in an actimeter cage. When hyperactivity induced by injecting 50 mg/kg of morphine was evaluated, all the GHB doses efficiently counteracted this morphine action. Using the paradigm of isolation-induced aggression, administration of 200 mg/kg of GHB significantly de…

Housing conditions modulate the reinforcing properties of cocaine in adolescent mice that binge on fat

Abstract Binge eating is a specific form of overeating characterized by intermittent, excessive eating. To date, several studies have addressed the effects that bingeing on fat has on the rewarding effects of drugs of abuse, but they have found contradictory and highly variable results. Housing conditions could modulate these results, as most studies employ isolated animals to measure the exact amount of food that is ingested. The aim of this study was to evaluate the effects of housing conditions on the response of mice to cocaine, modulated by bingeing on a high-fat diet during adolescence. After 40 days of binge-eating for 2 h, three days a week (PND 29–69), the reinforcing effects of a …

The rewarding effects of ethanol are modulated by binge eating of a high-fat diet during adolescence

Abstract Binge-eating is considered a specific form of overeating characterized by intermittent and high caloric food intake in a short period of time. Epidemiologic studies support a positive relation between the ingestion of fat and ethanol (EtOH), specifically among adolescent subjects. The aim of this work was to clarify the role of the compulsive, limited and intermittent intake of a high-fat food during adolescence on the rewarding effects of EtOH. After binge-eating for 2 h, three days a week from postnatal day (PND) 29, the reinforcing effects of EtOH were tested with EtOH self-administration (SA), conditioned place preference (CPP) and ethanol locomotor sensitization procedures in …

Hypericum perforatum L. prevents the acquisition of and promotes resilience against stress-induced reinstatement of the conditioned place preference induced by cocaine.

Abstract Cocaine use disorder is a serious problem worldwide, and there are no approved medications for its treatment. A novel approach to the treatment of drug addiction is the use of natural products, and, in this context, preclinical evidence suggests that Hypericum perforatum L. (Hypericum) is effective against alcohol and other substance use disorders. We hypothesised that Hypericum could also be useful as a treatment for cocaine use disorder, and so we set out to test its effectiveness in a mice model of cocaine addiction. In the first experiment we evaluated its effects on the acquisition of cocaine-induced conditioned place preference (CPP). Adult male mice were conditioned with coc…

Social defeat in adolescent mice increases vulnerability to alcohol consumption

This study employs an oral operant conditioning paradigm to evaluate the effects of repeated social defeat during adolescence on the reinforcing and motivational actions of ethanol in adult OF1 mice. Social interaction, emotional and cognitive behavioral aspects were also analyzed, and real-time polymerase chain reaction (PCR) experiments were performed to study gene expression changes in the mesocorticolimbic and hypothalamus-hypophysis-adrenal (HHA) axis. Social defeat did not alter anxiety-like behavior in the elevated plus maze or cognitive performance in the passive avoidance and Hebb-Williams tests. A social interaction test revealed depression-like symptoms and social subordination b…

'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, whil…

A Methanol Extract ofBrugmansia arboreaAffects the Reinforcing and Motor Effects of Morphine and Cocaine in Mice

Previous reports have shown that several of the effects of morphine, including the development of tolerance and physical withdrawal symptoms, are reduced by extracts ofBrugmansia arborea(L.) Lagerheim (Solanaceae) (B. arborea). In the present study we evaluate the action of the methanol extract ofB. arborea(7.5–60 mg/kg) on the motor and reinforcing effects of morphine (20 and 40 mg/kg) and cocaine (25 mg/kg) using the conditioned place preference (CPP) procedure. At the doses employed,B. arboreadid not affect motor activity or induce any effect on CPP. The extract partially counteracted morphine-induced motor activity and completely blocked the CPP induced by 20 mg/kg morphine. On the othe…

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)…

Memantine does not block antiaggressive effects of morphine in mice.

The action of the noncompetitive N-methyl-D-aspartate (NMDA) receptor blocker memantine (5, 10, 20 and 40 mg/kg) was evaluated during social encounters in mice. Although a dose-dependent increase in locomotion was observed, only with the highest dose did it reach statistical significance. Aggressive behavior was decreased with 20 and 40 mg/kg of memantine, social contacts being increased only with 20 mg/kg. Subsequently, the effect of these memantine doses on the antiaggressive actions of morphine (10 mg/kg) was evaluated. None of the doses affected the antiaggressive action of morphine. As memantine administration produced an antiaggressive effect only at doses that affected locomotion, it…

Dopamine D2 receptors mediate the increase in reinstatement of the conditioned rewarding effects of cocaine induced by acute social defeat

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 …

Cross-reinstatement by cocaine and amphetamine of morphine-induced place preference in mice

The cross-reinstatement by psychostimulants of a conditioned place preference (CPP) induced by morphine was evaluated in mice. In Experiment 1, we examined the effects of a single dose of cocaine and amphetamine on a previously extinguished morphine CPP. After acquisition of CPP induced by morphine (40 mg/kg), animals underwent daily extinction sessions of 15 min duration until the CPP was extinguished. Subsequently, animals received a non-contingent injection of cocaine (25 mg/kg) or amphetamine (4 mg/kg), which produced the reinstatement of the extinguished morphine-induced CPP. In Experiment 2, we evaluated the reinstating effects of several priming doses of cocaine (Experiment 2A) or am…

Acquisition and reinstatement of MDMA-induced conditioned place preference in mice pre-treated with MDMA or cocaine during adolescence

Those who take ecstasy are more likely to consume other drugs than non-users with cocaine abuse being reported by 75.5% of high school student MDMA (+/- 3,4-methylenedioxymetamphetamine hydrochloride) users. The aim of this work was to evaluate the effects of exposure during adolescence to MDMA, cocaine or to both drugs on the MDMA-induced conditioned place preference (CPP) in adult mice. Animals received two daily administrations of saline, 10 mg/kg of MDMA, 25 mg/kg of cocaine or 10 mg/kg of MDMA plus 25 mg/kg of cocaine over 3 days (from PD28 to 30). Three weeks after pre-treatment, the MDMA-induced CPP procedure was initiated (PD52). Acquisition of CPP was induced with a sub-threshold d…

Involvement of 5-hydroxytryptamine 5-HT3 serotonergic receptors in the acquisition and reinstatement of the conditioned place preference induced by MDMA

Some MDMA (3,4-methylenedioxymethamphetamine) users develop dependence as a result of chronic consumption. The present study evaluated the role of 5-hydroxytryptamine 5-HT₃ receptors in the acquisition, expression and reinstatement of the conditioned place preference (CPP) induced by MDMA. Adolescent male mice were conditioned with 10 mg/kg of MDMA and then treated with 1 or 3mg/kg of the 5-hydroxytryptamine 5-HT₃ antagonist MDL72222 during acquisition of conditioning (experiment 1), before expression of CPP in a post-conditioning test (experiment 2) or before a reinstatement test (experiment 3). MDL72222 was devoid of motivational effects but blocked acquisition of the MDMA-induced CPP. Mo…

Role of NMDA and AMPA glutamatergic receptors in the effects of social defeat on the rewarding properties of MDMA in mice

Exposure to social stress alters the response to drugs of abuse of experimental animals. Changes in the glutamatergic system seem to play a role in the effects of social defeat stress on the rewarding properties of cocaine and amphetamine. The aim of the present study was to evaluate the involvement of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors in the effects of social defeat on the conditioned place preference induced by 3,4-methylenedioxymethamphetamine (MDMA). Our hypothesis was that changes in these receptors could mediate the effects of social defeat on MDMA reward. Young adult male mice were exposed to an episode…

Effect of memantine and CNQX in the acquisition, expression and reinstatement of cocaine-induced conditioned place preference

The present study evaluates the effect of memantine, a non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist and CNQX, an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist on the rewarding effects of cocaine in mice, using the conditioned place preference (CPP) paradigm. Cocaine-induced CPP was studied pairing this drug with different memantine or CNQX doses during either the acquisition or the expression phase of the procedure. Once CPP was established, and the preference extinguished, reinstatement was induced by a priming dose of cocaine. Both antagonists, which in themselves do not present motivational actions on the preferen…

Role of AMPA glutamate receptors in the conditioned rewarding effects of MDMA in mice

Abstract Currently, there is not an effective treatment for 3,4-methylenedioxymethamphetamine (MDMA) dependence but pharmacotherapies targeting glutamate neurotransmission are a promising strategy. Previously, we showed that blockade of glutamate NMDA and AMPA receptors impairs the conditioned rewarding effects of MDMA and cocaine, respectively. In this study we evaluated the role of AMPA receptors in the rewarding effects of MDMA in mice using the conditioned place preference (CPP) paradigm. Mice were conditioned with MDMA (1.25 mg/kg) 60 min after the treatment with saline or different doses (0.25, 1 and 5 mg/kg) of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dion…

Acute social defeat stress increases the conditioned rewarding effects of cocaine in adult but not in adolescent mice.

Stressful experiences modify activity in areas of the brain involved in the rewarding effects of psychostimulants. In the present study we evaluated the influence of acute social defeat (ASD) on the conditioned rewarding effects of cocaine in adolescent (PND 29-32) and adult (PND 50-53) male mice in the conditioned place preference (CPP) paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1mg/kg or 25mg/kg of cocaine. The effects of social defeat on corticosterone levels were also evaluated. Adult mice exposed to ASD showed an increase in the conditioned reinforcing effects of cocaine. Only these mice developed cocaine…

Social behavioural profile of cocaine in isolated and grouped male mice

Studies concerning the relationship between cocaine and aggression in humans as well as in animals have discrepant outcomes. Increases, decreases, or no changes, have been reported after single or chronic cocaine administration in animal models. To clarify, at least in part, the complex behavioural actions of cocaine, the present study evaluated cocaine effects on social behaviours of mice exposed to different situations (isolated or group housed) using confrontations between two male mice in a neutral area. Different doses of cocaine (6, 25 and 50 mg/kg) were administered in a single or binge pattern (three doses in 24 h) and the behavioural test was performed 20 min after the last injecti…

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. …

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-tre…

Effects of dopamine antagonists with different receptor blockade profiles on morphine-induced place preference in male mice.

The effects of dopamine (DA) antagonists with different selectivity for the DA receptors (SCH 23390, 0.5, 0.25, 0.125 mg/kg; haloperidol, 0.2, 0.1 mg/kg; raclopride, 1.2, 0.6, 0.3 mg/kg; risperidone, 0.4, 0.2, 0.1 mg/kg; U-99194A maleate, 40, 20 mg/kg; clozapine, 2.5, 1.25, 0.625 mg/kg) on the acquisition of place conditioning and morphine-induced conditioned place preference (CPP) were explored in male mice. Morphine (40 mg/kg) produced CPP while SCH 23390, haloperidol and clozapine (highest dose) and risperidone (lowest dose) produced conditioned place aversion (CPA). Raclopride and U-99194A maleate did not produce CPP or CPA. Morphine-induced CPP was reversed by the administration of SCH…

The effects of dopamine D 2 and D 3 antagonists on spontaneous motor activity and morphine-induced hyperactivity in male mice

Rationale: Dopaminergic neurotransmission, in particular the mesolimbic pathway, is involved in spontaneous locomotor activity and in morphine-induced hyperactivity, since the drugs acting on DA receptors can modify the action of morphine and this effect could be dependent on the type of DA receptor affected. Objective: In this study, the action of U-99194A maleate, haloperidol, sulpiride and morphine (5, 10, 20, 40 mg/kg) on locomotor activity in male mice was evaluated. Likewise, the effects of these dopaminergic antagonists on morphine-induced hyperactivity were studied. Methods: Animals treated with U-99194A maleate (2.5, 5, 10, 20 mg/kg), haloperidol (0.075, 0.1 mg/kg), sulpiride (20, …

Neurobiological mechanisms of the reinstatement of drug-conditioned place preference.

Drug addiction is a chronic disorder characterized by a high rate of relapse following detoxification. There are two main versions of the reinstatement model that are employed to study relapse to drug abuse; one based on the operant self-administration procedure, and the other on the classical conditioned place preference procedure. In the last seven years, the use of the latter version has become more widespread, and the results obtained complement those obtained in self-administration studies. It has been observed that the conditioned place preference induced by opioids, psychostimulants, nicotine, ethanol and other drugs of abuse can be extinguished and reinstated by drug priming or expo…

Long-term effects of repeated social stress on the conditioned place preference induced by MDMA in mice.

Previous studies have demonstrated that social defeat stress increases the rewarding effects of psychostimulant drugs such as cocaine and amphetamine. In the present study we evaluated the long-term effects of repeated social defeat (RSD) on the rewarding effects of ±3,4-methylenedioxymethamphetamine (MDMA) hydrochloride in the conditioned place preference (CPP) paradigm. Adolescent and young adult mice were exposed to four episodes of social defeat (on PND 29-40 and PND 47-56, respectively) and were conditioned three weeks later with 1.25 or 10mg/kg i.p. of MDMA (experiment 1). The long-term effects of RSD on anxiety, social behavior and cognitive processes were also evaluated in adult mic…

Antiaggressive and motor effects of the DA release inhibitor CGS 10746B

In the present study the effects of a wide range of doses of the dopamine release inhibitor CGS 10746B were evaluated in spontaneous activity and in aggressive behaviour using the paradigm of isolation-induced aggression. The two higher doses (8 and 16 mg/kg) produced a decrease in spontaneous motor activity. Antiaggressive effects were observed after administration of doses from 4 mg/kg upwards. At this dose, CGS 10746B diminished threat and attack, and although an increase in immobility was observed, no impairment of other motor behaviours was presented. With higher doses, aggression was practically abolished but with a concomitant effect on many other behaviours. When animals were separa…

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 p…

Isolation decreases physical and motivational aspects of morphine withdrawal

Environmental manipulations such as social housing conditions of animals may play a role in the expression of individual differences in response to drugs. This study aimed to evaluate whether isolated and grouped mice develop different degrees of morphine dependence. Isolated and grouped mice were rendered morphine dependent employing two different methods of induction: a fast or slow protocol, both reaching the same maximum daily dose (100 mg/kg). Naloxone-induced morphine withdrawal was assessed using a modified Gellert-Holtzman scale and a conditioned place aversion (CPA) procedure. Isolated animals manifested fewer signs of physical dependence than grouped mice and only those receiving …

Influence of Social Defeat Stress on the Rewarding Effects of Drugs of Abuse

Effect of the CB1 cannabinoid agonist WIN 55212-2 on the acquisition and reinstatement of MDMA-induced conditioned place preference in mice

AbstractBackgroundNumerous reports indicate that MDMA users consume other psychoactive drugs, among which cannabis is one of the most common. The aim of the present study was to evaluate, using the conditioned place preference, the effect of the cannabinoid agonist WIN 55,212-2 on the rewarding effects of MDMA in mice.MethodsIn the first experiment adolescent mice were initially conditioned with 1.25, 2.5 or 5 mg/kg of MDMA or 0.1 or 0.5 mg/kg of WIN and subsequently with both drugs. Reinstatement of the extinguished preference by priming doses was performed in the groups that showed CPP. In the second experiment, animals were conditioned with 2.5 or 5 mg/kg of MDMA and, after extinction, r…

Predicting how equipotent doses of chlorpromazine, haloperidol, sulpiride, raclopride and clozapine reduce locomotor activity in mice

Distinguishing the specific effects of neuroleptics on one particular behaviour from its non-specific effects on motility is not easy. In this study, the effects of five neuroleptics on spontaneous motor activity were compared and the ED(50) values of these drugs to impair activity were calculated. Male and female mice were evaluated in an actimeter or in a shuttle-box used as an open field after the administration of chlorpromazine (0.4, 1.2, 3.6 mg/kg), haloperidol (0.1, 0.3, 0.9 mg/kg), raclopride (0.1, 0.3, 0.9 mg/kg), sulpiride (10, 30, 90 mg/kg) and clozapine (0.4, 1.2, 3.6 mg/kg), and two automatic and two observational activity measures were obtained. A very high correlation between…

Therapies in early development for the treatment of opiate addiction.

Opiate drugs are psychoactive substances used to manage severe pain. However, their chronic use is associated with the development of addiction. Opiate addiction represents a significant public health concern.This review focuses on the most recent advances in the pharmacological treatment of opiate addiction, from those being tested in clinical trials (Phase I and II), to preclinical studies that point to new targets. Readers will gain knowledge of the wide variety of treatments used to treat opiate addiction, including their strengths and weaknesses, and the promising pharmacological targets identified by preclinical research.Among the currently available agonist therapies, new dosage form…

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…

Acute behavioural and neurotoxic effects of MDMA plus cocaine in adolescent mice.

The poly-drug pattern is the most common among those observed in MDMA users, with cocaine being a frequently associated drug. This study evaluates the acute effects of MDMA (5, 10 and 20 mg/kg), alone or in combination with cocaine (25 mg/kg), on motor activity, anxiety (elevated plus maze and social interaction test), memory and brain monoamines in adolescent mice, Both drugs, administered alone or concurrently, produced hyperactivity and a decrease in social contacts. However, an anxiolytic effect, studied by means of the elevated plus maze and expressed as an increase in the time spent on the open arms, was observed only in those animals treated with cocaine and MDMA. The passive avoidan…

Blockade of nitric oxide signalling promotes resilience to the effects of social defeat stress on the conditioned rewarding properties of MDMA in mice

Abstract MDMA abuse continues being a serious problem in our society. Environmental factors, such as stress, increase the vulnerability of individuals to develop drug abuse and we have observed that exposure to social defeat (SD) stress alters the sensitivity of mice to the rewarding effects of MDMA in the conditioned place preference (CPP) paradigm. In the present study, we evaluated the role of the nitric oxide (NO) pathway in the effects of SD on the rewarding properties of MDMA. Three groups of mice were treated with an inhibitor of NO synthesis, 7-nitroindazole (0, 7.25 and 12.5 mg/kg), before each exposure to SD and place conditioning with MDMA (1.25 mg/kg) on PND 54, 56, 58, and 60. …

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…

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 con…

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 ofRhodiola roseaL. 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 in…

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 hig…

The dopamine release inhibitor CGS 10746B blocks conditioned physical signs of morphine withdrawal

Environment previously paired with morphine withdrawal leads to conditioned physical signs of withdrawal, this effect being modulated by additional exposition to morphine administration. In this study, the putative role of dopamine in conditioned withdrawal signs is evaluated by administering the dopamine release inhibitor CGS 10746B prior to suffering two naloxone-induced withdrawals in a distinctive environment associated or not with morphine administration. The results show that dopamine seems to be necessary for the development of conditioned somatic signs of morphine withdrawal, as animals which received CGS 10746B do not present paw tremor or body shakes when they are placed in the en…

Dose-dependent impairing effects of morphine on avoidance acquisition and performance in male mice.

The effects of morphine (6.3, 12.6, and 25.2 mg/kg) on active avoidance behavior of BALB/C mice are explored in three acquisition sessions and in two subsequent performance sessions. Morphine-treated animals showed an increase in avoidance acquisition with respect to control group without differences in performance. However, a dramatical, concomitant rise in the locomotor activity of the animals (increase in the number of crossings during the intertrial intervals) prompted us to transform the data employing a formula with which a measure of actual learning was obtained. Applying this formula, we have observed that morphine administration impairs, dose-dependently, acquisition and performanc…

Prenatal cocaine alters later responses to morphine in adult male mice.

Mice prenatally exposed to cocaine (25 mg/kg), physiological saline or non-treated during the last 6 days of pregnancy were evaluated as adults for the rewarding properties of 2 mg/kg of morphine, using the conditioned place preference (CPP) procedure. Likewise, isolated animals underwent a social interaction test with conspecifics after receiving the same morphine dose. Unlike control or animals pre-treated with saline, subjects prenatally treated with cocaine did not develop CPP with this dose of morphine. Only cocaine-exposed animals showed increased threat, avoidance and fleeing during the social encounter. No differences in motor effects of morphine were observed. Analysis of monoamine…

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 adolescen…

Role of dopamine and glutamate receptors in cocaine-induced social effects in isolated and grouped male OF1 mice.

Cocaine administration in paired male mice decreases social contacts as well as increases avoidance and flee elements. As dopamine (DA) and glutamate seem to be involved in some of cocaine's effects, an attempt was made to assess whether a range of associated receptors influenced the social impacts of this drug of abuse. The NMDA antagonist memantine (10 and 40 mg/kg); the AMPA antagonist CNQX (1 and 20 mg/kg); the DA release inhibitor CGS 10746b (2 and 8 mg/kg): the DA D1 antagonist SCH 23390 (0.05 and 0.5 mg/kg); and the DA D2/D3 antagonist raclopride (0.03 and 0.3 mg/kg) were administered prior to 25 mg/kg of cocaine and behaviour was evaluated during an encounter between an experimental…

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 trai…

Cocaine exposure during adolescence affects anxiety in adult mice.

Psychostimulant drugs such as cocaine have profound and long-lasting neurobiological effects, which may affect anxiety or social behaviors. These actions could be greater when cocaine is administered during a developmental period such as adolescence. The present work attempts to further clarify the long-lasting effects of cocaine administration on mice, examining three major variables: age; pattern of drug administration; and housing conditions. Adolescent (postnatal day 26) or early adult mice (postnatal day 46) were exposed to a daily or binge cocaine administration and 15 days later their behavior was evaluated, the mice being housed either in isolation or in groups during this stage. Af…

Cannabidiol Treatment Might Promote Resilience to Cocaine and Methamphetamine Use Disorders: A Review of Possible Mechanisms

Currently, there are no approved pharmacotherapies for addiction to cocaine and other psychostimulant drugs. Several studies have proposed that cannabidiol (CBD) could be a promising treatment for substance use disorders. In the present work, the authors describe the scarce preclinical and human research about the actions of CBD on the effects of stimulant drugs, mainly cocaine and methamphetamine (METH). Additionally, the possible mechanisms underlying the therapeutic potential of CBD on stimulant use disorders are reviewed. CBD has reversed toxicity and seizures induced by cocaine, behavioural sensitization induced by amphetamines, motivation to self-administer cocaine and METH, context- …

Effect of intermittent exposure to ethanol and MDMA during adolescence on learning and memory in adult mice

Abstract Background Heavy binge drinking is increasingly frequent among adolescents, and consumption of 3,4-methylenedioxymethamphetamine (MDMA) is often combined with ethanol (EtOH). The long-lasting effects of intermittent exposure to EtOH and MDMA during adolescence on learning and memory were evaluated in adult mice using the Hebb-Williams maze. Methods Adolescent OF1 mice were exposed to EtOH (1.25 g/kg) on two consecutive days at 48-h intervals over a 14-day period (from PD 29 to 42). MDMA (10 or 20 mg/kg) was injected twice daily at 4-h intervals over two consecutive days, and this schedule was repeated six days later (PD 33, 34, 41 and 42), resulting in a total of eight injections. …

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

Abstract 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 (Stud…

Role of nitric oxide pathway in the conditioned rewarding effects of MDMA in mice.

It is estimated that 2.1 million young adults used MDMA/Ecstasy in the last year in Europe. Vulnerable subjects can develop dependence after MDMA abuse but currently there does not exist an effective treatment for this disorder. The nitric oxide (NO) pathway seems to have an important role on the rewarding effects of different drugs and has been proposed as a new pharmacological treatment for psychostimulant addiction. In the present study, we intend to evaluate whether the blockade of the NO synthesis (NOS) interferes with the rewarding effects of MDMA in the conditioned preference place (CPP) paradigm in young adult male mice. Our results indicated that mice treated with 7-nitroindazole (…

Adolescent pre-exposure to ethanol or MDMA prolongs the conditioned rewarding effects of MDMA

Adolescents often take ethanol (EtOH) in combination with MDMA (3,4-methylenedioxymethylamphetamine). In the present work we studied the effect of repeated intermittent adolescent pre-exposure to both drugs on the behavioral and neurochemical effects of MDMA in mice. Sixteen days after pre-treatment, the rewarding and reinstating effects of MDMA in the conditioned place preference (CPP) paradigm were evaluated, along with the levels of biogenic amines, basal motor activity and corticosterone response to different challenges. Pre-exposure to EtOH, MDMA or EtOH+MDMA did not affect the CPP induced by 10mg/kg of MDMA. However, adolescent exposure to EtOH or MDMA increased the duration of the co…

Effects of repeated social defeat on adolescent mice on cocaine-induced CPP and self-administration in adulthood: integrity of the blood-brain barrier

Social stress in adulthood enhances cocaine self-administration, an effect that has been related with an increase in extracellular signal-regulated kinase and p38α mitogen-activated protein kinase phosphorylation. A detrimental effect of cocaine on blood-brain barrier (BBB) integrity has also been reported. This study evaluates the effects of repeated social defeat (RSD) during adolescence on the reinforcing and motivational effects of cocaine in adult mice and the changes induced by RSD on BBB permeability. Cocaine self-administration, conditioned place preference and quantitative analysis of claudin-5, laminin, collagen-IV and IgG immunoreactivity took place 3 weeks after RSD. Mice social…

Effects of bingeing on fat during adolescence on the reinforcing effects of cocaine in adult male mice

Binge eating is a specific form of overeating characterized by intermittent excessive eating. In addition to altering the neurobiological reward system, several studies have highlighted that consumption of palatable food increases vulnerability to drug use. The aim of the present study was to evaluate the effects of a high-fat diet consumed in a binge pattern during adolescence on the reinforcing effects of cocaine. After 40 days of binge-eating for 2 h, three days a week (PND 29–69), the reinforcing effects of cocaine on conditioning place preference and intravenous self-administration paradigm were evaluated in adolescent male mice. Circulating leptin and ghrelin levels and the effects of…

Individual differences in the induction of sensitisation or tolerance to the motor effects of morphine in mice

Acute morphine administration produces hyperactivity in most strains of mice and some studies indicate that repeated treatment can induce a potentiation of this effect (sensitisation). With the object of determining whether the hyperactivity induced by morphine in OF1 mice shows sensitisation after repeated administration, we tested the effect of the pre-exposure to six daily injections of morphine on the subsequent hyperactivity induced by the same dose of this drug. Animals were treated with 40 mg/kg of morphine for seven days. After the last injection they were tested in an actimeter at different points at time (15, 30, 45 and 60 min). This repeated schedule of treatment produced sensiti…

Editorial: Neurobehavioural Mechanisms of Resilience and Vulnerability in Addictive Disorders

The novelty-seeking phenotype modulates the long-lasting effects of intermittent ethanol administration during adolescence.

The aim of the present study was to investigate if a novelty-seeking phenotype mediates the long-lasting consequences of intermittent EtOH intoxication during adolescence. The hole board test was employed to classify adolescent mice as High- or Low-Novelty Seekers. Subsequently, animals were administered ethanol (1.25 or 2.5 g/kg) on two consecutive days at 48-h intervals over a 14-day period. Anxiety levels - measured using the elevated plus maze- spontaneous motor activity and social interaction test were studied 3 weeks later. A different set of mice underwent the same procedure, but received only the 2.5 g/kg dose of ethanol. Three weeks later, in order to induce CPP, the same animals w…

Effect of adolescent exposure to MDMA and cocaine on acquisition and reinstatement of morphine-induce CPP

It is well known that an elevated percentage of ecstasy users also consume cocaine. Recently, it has been reported that a high frequency of heroin smokers first consumed heroin under the effects of ecstasy with the hope of reducing the stimulant effects of the latter drug. The aim of the present study was to evaluate the effect of exposure to MDMA and cocaine during adolescence on morphine-induced conditioned place preference (CPP) and reinstatement in adulthood. In the first experiment, adolescent mice were exposed to six injections of MDMA and three weeks later their response to the reinforcing properties of 40 mg/kg of morphine was evaluated using the CPP paradigm. All the treatment grou…

Effect of drugs of abuse on social behaviour: a review of animal models.

Social behaviour is disturbed in many substance abuse and psychiatric disorders. Given the consensus that social behaviours of lower mammals may help to understand some human emotional reactions, the aim of the present work was to provide an up-to-date review of studies on the changes in social behaviour induced by drugs of abuse. Various animal models have been used to study the relationship between drugs of abuse and social behaviour. Herein, we describe the effects of different substances of abuse on the three most commonly used animal models of social behaviour: the social play test, the social interaction test and the resident-intruder paradigm. The first is the most widely used test t…

Assessment of the abuse potential of MDMA in the conditioned place preference paradigm: Role of CB1 receptors

Numerous reports have highlighted the role of the endocannabinoid system in the addictive potential of MDMA (3,4-methylenedioxy-methamphetamine). A previous report showed that CB1 knockout (KOCB1) mice do not acquire MDMA self-administration, despite developing conditioned place preference (CPP). This contradiction could be due to the particular procedure of place conditioning used. The present work compares MDMA-induced CPP in KOCB1 mice using unbiased and biased procedures of place conditioning. In the unbiased procedure, MDMA induced CPP and reinstatement of the extinguished preference in wild type (WT) mice, but not in KOCB1 mice. In contrast, in a biased protocol of CPP, MDMA produced …

Chronic Moderate Hyperammonemia Impairs Active and Passive Avoidance Behavior and Conditional Discrimination Learning in Rats

Abstract The cerebral dysfunction associated with hepatic encephalopathy is generally considered to have hyperammonemia as one of its main causes. Hyperammonemia impairs the neuronal glutamate–nitric oxide–cyclic GMP pathway and the induction of NMDA receptor-dependent long-term potentiation in the hippocampus. We studied the performance of pre/neonatally and postnatally exposed rats to hyperammonemia on active avoidance, passive avoidance, and conditional discrimination tasks. Pre/neonatal hyperammonemia slowed learning of active avoidance behaviors and impaired memory for the passive avoidance task while postnatal hyperammonemia impaired learning on the conditional discrimination task. Hy…

Ascorbic acid antagonizes ethanol-induced locomotor activity in the open-field.

Abstract It has been reported that ascorbic acid (AA) antagonizes the physiological and behavioral effects of dopamine (DA). AA reduces locomotor activity induced by dopaminergic agonist drugs. Also, AA amplifies the action of antidopaminergic drugs. Ethanol, like other drugs, produces a release of DA in the mesolimbic pathway, and at some doses, induces locomotor activity in mice. The ethanol-induced locomotor activity could be dopamine-dependent because it can be reduced by antidopaminergic drugs. In the present study, we investigated whether an acute administration of AA reduces ethanol-induced locomotor behavior. AA, at doses (0.0, 21.85, 87.5, 175, 350, and 1400 mg/kg) was injected IP …

Adolescent but not adult ethanol binge drinking modulates cocaine withdrawal symptoms in mice.

Background Ethanol (EtOH) binge drinking is an increasingly common behavior among teenagers that induces long-lasting neurobehavioral alterations in adulthood. An early history of EtOH abuse during adolescence is highly correlated with cocaine addiction in adulthood. Abstinence of cocaine abuse can cause psychiatric symptoms, such as anxiety, psychosis, depression, and cognitive impairments. This study assessed the consequences of adolescent exposure to EtOH on the behavioral alterations promoted by cocaine withdrawal in adulthood. Methods We pretreated juvenile (34-47 days old) or adult (68-81 days old) mice with EtOH (1.25 g/kg) following a binge-drinking pattern. Then, after a three-week…

Morphine potentiates the impairing effects of neuroleptics on two-way active conditioned avoidance response in male mice

The dopaminergic and opioid systems have effects on the conditioned avoidance response (CAR), although the possible interaction between these systems on this behaviour has not been studied. The effects of morphine (12.6 mg/kg), haloperidol (0.075 mg/kg), sulpiride (20 mg/kg) and risperidone (0.1 mg/kg) alone as well as morphine combined with these dopamine (DA) antagonists on the acquisition and performance of the CAR were explored in mice. Morphine increased avoidances but this seemed secondary to a rise in activity levels. All DA antagonists impaired CAR in the acquisition phase but only haloperidol disrupted performance. The combination of morphine plus neuroleptics impaired acquisition …

Gamma-hydroxybutyric acid affects the acquisition and reinstatement of cocaine-induced conditioned place preference in mice

Cocaine addicts very often use different combinations of cocaine and other drugs of abuse such as gamma-hydroxybutyric acid. The objective of the present work was to evaluate the impact of gamma-hydroxybutyric acid administration on the rewarding actions of cocaine, using the conditioned place preference procedure. Cocaine-induced conditioned place preference (50 mg/kg) was studied after pairing this drug with different gamma-hydroxybutyric acid doses (6.25, 12.5, 25, 50 and 100 mg/kg) during either the acquisition or the expression phase of the procedure. After conditioned place preference had been established, and the preference was extinguished, a reinstatement was induced by a dose of c…

Cannabidiol treatment might promote resilience to cocaine and methamphetamine use disorders: A review of possible mechanisms

Currently, there are no approved pharmacotherapies for addiction to cocaine and other psychostimulant drugs. Several studies have proposed that cannabidiol (CBD) could be a promising treatment for substance use disorders. In the present work, the authors describe the scarce preclinical and human research about the actions of CBD on the effects of stimulant drugs, mainly cocaine and methamphetamine (METH). Additionally, the possible mechanisms underlying the therapeutic potential of CBD on stimulant use disorders are reviewed. CBD has reversed toxicity and seizures induced by cocaine, behavioural sensitization induced by amphetamines, motivation to self-administer cocaine and METH, context- …

Role of CB2 cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine.

This study was aimed to evaluate the involvement of CB2 cannabinoid receptors (CB2r) in the rewarding, reinforcing and motivational effects of nicotine. Conditioned place preference (CPP) and intravenous self-administration experiments were carried out in knockout mice lacking CB2r (CB2KO) and wild-type (WT) littermates treated with the CB2r antagonist AM630 (1 and 3 mg/kg). Gene expression analyses of tyrosine hydroxylase (TH) and α3- and α4-nicotinic acetylcholine receptor subunits (nAChRs) in the ventral tegmental area (VTA) and immunohistochemical studies to elucidate whether CB2r colocalized with α3- and α4-nAChRs in the nucleus accumbens and VTA were performed. Mecamylamine-precipitat…

Apparent vs real effects of scopolamine on the learning of an active avoidance task.

The effects of scopolamine hydrobromide (0.5 and 2 mg/ kg) administered intraperitoneally to Balb/c male mice before or after training in active avoidance were explored in four training sessions and in a subsequent test session, free of drug. Animals given scopolamine prior to training performed better than controls, an effect that was reversed in the session free of drug. However, a deeper analysis of the data permits us to interpret this increment in the number of avoidance responses as a consequence of the increase in activity produced by the drug and not as learning. In the animals injected with scopolamine after sessions no effects were observed. In conclusion, the results of the prese…

Conditioned place preference paradigm can be a mouse model of relapse to opiates

With the object of determining the usefulness of the conditioned place preference (CPP) paradigm as a model of relapse to opiates, the effects of the re-exposure to morphine are explored in male mice which had undergone a process of extinction of conditioning. Morphine (40 mg/kg) produces a CPP which lasts up to 15 days after conditioning. When it has completely extinguished (45 days), a non contingent re-exposure to the drug again produces the same preference. These results suggest that the CPP paradigm may be used in mice to study the mechanisms of relapse to opiates in addicts.

Acute blockade of CB1 receptor leads to reinstatement of MDMA-induced conditioned place preference

Cannabis is one of the drugs most commonly consumed in combination with ecstasy (3,4-methylenedioxymethamphetamine, MDMA). Although numerous studies have attempted to further our understanding of the role of the cannabinoid system in drug abuse, few have focused on how it influences the rewarding effects of MDMA. The aim of the present study was to evaluate the role of the CB1 cannabinoid receptor in vulnerability to reinstatement of a MDMA-induced conditioned place preference (CPP). Mice were first conditioned with 5mg/kg of MDMA. Once the preference had been extinguished, a priming dose of MDMA, alone or plus the CB1 cannabinoid agonist WIN 55,212-2 (0.1 and 0.5mg/kg) or the CB1 cannabino…

Preclinical evidence of new opioid modulators for the treatment of addiction.

Addiction to opiates is one of the most severe forms of substance dependence, and despite a variety of pharmacological approaches to treat it, relapse is observed in a high percentage of subjects. New pharmacological compounds are necessary to improve the outcome of treatments and reduce adverse side effects. Moreover, drugs that act on the opioid system can also be of benefit in the treatment of alcohol or cocaine addiction. AREA COVERED BY THIS REVIEW: Recent preclinical studies of pharmacological agents for the treatment of opiate addiction (2008 to the present date).The reader will be informed of the latest drugs shown in animal models to modify dependence on opiates and the reinforcing…

Effects of risperidone and SCH 23390 on isolation-induced aggression in male mice.

In this study, the antiaggressive effects of risperidone and SCH 23390 have been explored. Using the paradigm of isolation-induced aggression, 150 albino male mice of the OF1 strain were allocated to control and experimental groups which received three doses of risperidone (0.01, 0.05 and 0.1 mg/kg) or two doses of SCH 23390 (0.05 and 0.1 mg/kg). Only the highest doses of risperidone decreased threat and attack behaviours but all doses significantly impaired motor behaviour. SCH 23390 decreased attack with the two doses used and also produced significant increases in immobility. Although both antipsychotics are antiaggressive, this action seems to be more specific in the case of risperidone…

Capacity of novelty-induced locomotor activity and the hole-board test to predict sensitivity to the conditioned rewarding effects of cocaine

Novelty-seeking in rodents, defined as enhanced specific exploration of novel situations, is considered to predict the response of animals to drugs of abuse and, thus, allow "drug-vulnerable" individuals to be identified. The main objective of this study was to assess the predictive ability of two well-known paradigms of the novelty-seeking trait - novelty-induced locomotor activity (which distinguishes High- and Low-Responder mice, depending on their motor activity) and the hole-board test (which determines High- and Low-Novelty Seeker mice depending on the number of head dips they perform) - to identify subjects that would subsequently be more sensitive to the conditioned rewarding effect…

SY29-3SOCIAL DEFEAT IN ADOLESCENT MICE INCREASES VULNERABILITY TO ALCOHOL CONSUMPTION

Background. Stressful life situations have been widely linked to drug-seeking. Several studies in humans and animal models have demonstrated that exposure to different kinds of stress increases abuse and relapse to abuse of certain drugs such as alcohol. Methods. This study employs an oral operant conditioning paradigm to evaluate the …

NMDA glutamate but not dopamine antagonists blocks drug-induced reinstatement of morphine place preference.

The effects of dopaminergic and glutamatergic antagonists on the drug-induced reinstatement of a previously extinguished morphine conditioned place preference (CPP) in mice were evaluated. Following extinction of a place preference induced by morphine (40 mg/kg), a non-contingent injection of the dopaminergic antagonists SCH 23390 (0.125, 0.5 mg/kg), raclopride (0.3, 1.2 mg/kg), haloperidol (0.1, 0.2 mg/kg) and the dopamine (DA) release inhibitor CGS 10746B (1, 10 mg/kg) or glutamatergic NMDA antagonists memantine (10, 20, 40 mg/kg) and MK-801 (0.1, 0.2, 0.3 mg/kg) alone or with 10 mg/kg morphine was given. Neither the dopaminergic nor the glutamatergic antagonists alone reinstated the plac…

Neurochemical substrates of the rewarding effects of MDMA: implications for the development of pharmacotherapies to MDMA dependence.

In recent years, studies with animal models of reward, such as the intracranial self-stimulation, self-administration, and conditioned place preference paradigms, have increased our knowledge on the neurochemical substrates of the rewarding effects of 3,4-methylenedioxymetamphetamine (MDMA) in rodents. However, pharmacological and neuroimaging studies with human participants are scarce. Serotonin [5-hydroxytryptamine (5-HT)], dopamine (DA), endocannabinoids, and endogenous opiates are the main neurotransmitter systems involved in the rewarding effects of MDMA in rodents, but other neurotransmitters such as glutamate, acetylcholine, adenosine, and neurotensin are also involved. The most impo…

Long-lasting rewarding effects of morphine induced by drug primings.

To evaluate the persistence of the rewarding effects of morphine, the acquisition, maintenance, extinction and reinstatement of a conditioned place preference (CPP) was assessed in OF1 mice. In Experiment 1, the persistence of morphine-induced CPP was evaluated weekly. Mice showed CPP after four sessions of conditioning with 5, 10, 20 and 40 mg/kg of morphine, which lasted 0, 1, 2 and 4 weeks, respectively. In Experiment 2, after four sessions of conditioning with 40 mg/kg of morphine, the effects of four schedules of extinction differing in the time interval (2, 4, 6 or 8 weeks) between sessions were evaluated. CPP was no longer evident after 8 weeks for the groups examined each 2 or 8 wee…

Influence of the Novelty-Seeking Endophenotype on the Rewarding Effects of Psychostimulant Drugs in Animal Models

Novelty seeking (NS), defined as a tendency to pursue novel and intense emotional sensations and experiences, is one of the most relevant individual factors predicting drug use among humans. High novelty seeking (HNS) individuals present an increased risk of drug use compared to low novelty seekers. The NS endophenotype may explain some of the differences observed among individuals exposed to drugs of abuse in adolescence. However, there is little research about the particular response of adolescents to drugs of abuse in function of this endophenotype, and the data that do exist are inconclusive. The present work reviews the literature regarding the influence of NS on psychostimulant reward…

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 20 mg/kg morphine plus the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (5 or 10 mg/kg) or the metabotropic Glu5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) (5 or 10 mg/kg) on the place conditioning induced by a low dose of morphine (2 mg/kg) were assessed. The 2 mg/kg dose of morphine was ineffective in animals pre-treated with saline but induced a clear con…

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 expose…

P-71ADOLESCENT ETHANOL EXPOSURE INDUCES LONG-TERM MEMORY DEFICITS AND POTENTIATES THE MEMORY IMPAIRMENT INDUCED BY COCAINE WITHDRAWAL IN ADULT MICE

Ethanol (EtOH) heavy-binge drinking during pubertal development elicits long-lasting neurobehavioral alterations in the adulthood such as memory impairments. An early history of EtOH consumption is correlated with higher rates of cocaine addiction in the adulthood. One consequence of cocaine withdrawal is the induction of memory deficits. The aim of the present investigation was to study the consequences of adolescent exposure …

Involvement of NMDA glutamate receptors in the acquisition and reinstatement of the conditioned place preference induced by MDMA.

Some 3,4-methylenedioxymethamphetamine (MDMA) users become dependent as a result of chronic consumption. A greater understanding of the neurobiological basis of the rewarding effects of MDMA could contribute to developing effective pharmacotherapies for MDMA-related problems. The present study evaluated the role of N-methyl-D-aspartate (NMDA) glutamate receptors (NMDARs) in the acquisition and reinstatement of conditioned place preference (CPP) induced by MDMA. Adolescent male mice were conditioned with 1 or 10 mg/kg MDMA and pretreated with 5 or 10 mg/kg of the NMDAR antagonist memantine during acquisition of conditioning (experiment 1), or before a reinstatement test (experiment 2). In ad…

Potencial adictivo del éxtasis: una visión desde los modelos animales

Resumen La 3,4-metilendioximetanfetamina (MDMA) es el principio activo del “extasis”, un psicoestimulante de gran popularidad entre los adolescentes y los adultos jovenes. La actividad farmacologica del extasis esta mediada por la serotonina (5-HT) y la dopamina (DA), esta ultima fuertemente implicada en la modulacion de los efectos reforzantes de las drogas de abuso. Aunque escasos, los estudios realizados en consumidores de extasis indican que un porcentaje de ellos cumplirian los criterios de dependencia a esta sustancia. La presente revision analiza los resultados mas relevantes obtenidos hasta el momento sobre los efectos reforzantes de la MDMA, principalmente aquellos obtenidos a part…

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

Abstract 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 20 mg/kg of morphine plus the nitric oxide synthase inhibitor 7-nitroindazole (7NI) (12.5 or 25 mg/kg) on the 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 animals pre-treated with saline but …

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…