Concepción Maldonado

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 preference shown by the animals, abolished the acquisition and expression of the cocaine-induced CPP. Neither of the antagonists precipitated reinstatement of the preference induced by cocaine but memantine blocked the cocaine-primed reinstatement. Our results suggest that cocaine-induced CPP and reinstatement is largely dependent on glutamate neurotransmission, and confer a putative role for memantine among the tools useful for cocaine management and treatment.

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 conditioned aversion when administered in any phase. In a second experiment, the effects of these drugs were evaluated in the intensity of the physical signs of withdrawal, only memantine administration being efficient. In addition to these studies, the intensity of morphine dependence was investigated under the blockade of NMDA receptors, i.e. morphine was co-administered with memantine or MK-801. These animals did not develop CPA and present less intensity in the physical signs of morphine withdrawal. Our results support the idea that NMDA receptors are involved in the behavioural changes and therefore in the neural adaptations produced by repeated morphine administration.

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 avoidance task was affected only with the highest MDMA dose (20 mg/kg). Mice treated with MDMA did not present significant changes in brain monoamines, while those receiving MDMA and cocaine showed a decrease in DA in the striatum, which was accompanied by an increase in the serotonin concentration in the striatum and cortex 30 min after acute administration. In conclusion, the combined use of MDMA and cocaine produces a predominance of serotonin over DA, which is associated with an anxiolytic profile, defensive behaviours and fewer social contacts.

TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment

The adolescent brain undergoes important dynamic and plastic cell changes, including overproduction of axons and synapses, followed by rapid pruning along with ongoing axon myelination. These developmental changes make the adolescent brain particularly vulnerable to neurotoxic and behavioral effects of alcohol. Although the mechanisms of these effects are largely unknown, we demonstrated that ethanol by activating innate immune receptors toll-like receptor 4 (TLR4), induces neuroinflammation and brain damage in adult mice. The present study aims to evaluate whether intermittent ethanol treatment in adolescence promotes TLR4-dependent pro-inflammatory processes, leading to myelin and synaptic dysfunctions, and long-term cognitive impairments. Using wild-type (WT) and TLR4-deficient (TLR4-KO) adolescent mice treated intermittently with ethanol (3.0g/kg) for 2weeks, we show that binge-like ethanol treatment activates TLR4 signaling pathways (MAPK, NFκB) leading to the up-regulation of cytokines and pro-inflammatory mediators (COX-2, iNOS, HMGB1), impairing synaptic and myelin protein levels and causing ultrastructural alterations. These changes were associated with long-lasting cognitive dysfunctions in young adult mice, as demonstrated with the object recognition, passive avoidance and olfactory behavior tests. Notably, elimination of TLR4 receptors prevented neuroinflammation along with synaptic and myelin derangements, as well as long-term cognitive alterations. These results support the role of the neuroimmune response and TLR4 signaling in the neurotoxic and behavioral effects of ethanol in adolescence.

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

BackgroundNumerous 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, reinstatement of the preference was induced by 0.5 or 0.1 mg/kg of WIN.ResultsA low dose of WIN 55212-2 (0.1 mg/kg) increased the rewarding effects of low doses of MDMA (1.25 mg/kg), although a decrease in the preference induced by MDMA (5 and 2.5 mg/kg) was observed when the dose of WIN 55212-2 was raised (0.5 mg/kg). The CB1 antagonist SR 141716 also increased the rewarding effects of the lowest MDMA dose and did not block the effects of WIN. Animals treated with the highest WIN dose plus a non-neurotoxic dose of MDMA exhibited decreases of striatal DA and serotonin in the cortex. On the other hand, WIN 55212-2-induced CPP was reinstated by priming injections of MDMA, although WIN did not reinstate the MDMA-induced CPP.ConclusionsThese results confirm that the cannabinoid system plays a role in the rewarding effects of MDMA and highlights the risks that sporadic drug use can pose in terms of relapse to dependence. Finally, the potential neuroprotective action of cannabinoids is not supported by our data; on the contrary, they are evidence of the potential neurotoxic effect of said drugs when administered with MDMA.

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 cocaine did not develop preference after receiving the highest cocaine dose. In these mice, the motor activity in response to 50 mg/kg showed a small decrease. Although a reduced response to the highest cocaine dose can be argued, we suggest that the lack of preference obtained is more likely attributable to an increased sensitivity to the environmental cues associated during training to an aversive effect of this cocaine dose. The aversive properties of cocaine seem to be more apparent and to prevail over the rewarding action of the highest dose in exposed animals. These findings indicate that recurrent gestational cocaine exposure results in permanent (mal)adaptations of the structure and function of brain reward systems.

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 were administered 1 or 6 mg/kg of cocaine or 1 or 2.5 mg/kg MDMA. The results revealed a decrease in aggressive behaviors and an anxiolytic profile in HNS mice and longer latency to explore the novel object by LNS mice. Ethanol exposure enhanced the reinforcing effects of cocaine and MDMA in both groups when CPP was induced with a sub-threshold dose of the drugs. The extinguished cocaine-induced CPP (1 and 6 mg/kg) was reinstated after a priming dose in HNS animals only. Our results confirm that intermittent EtOH administration during adolescence induces long-lasting effects that are manifested in adult life, and that there is an association between these effects and the novelty-seeking phenotype.

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 monoamines revealed effects of housing conditions, isolated animals having fewer DOPAC but higher levels of HVA than those grouped, but in both groups there was a decrease in DOPAC in cocaine- and saline-treated mice. Prenatal cocaine exposure decreases the response to the rewarding properties of drugs in mature offspring. They also implicate cocaine consumption during pregnancy could affect the response of offspring to take other drugs of abuse.

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. After being exposed to MDMA plus cocaine, mice spent more time in social contacts during the interaction test, as well as exhibiting an anxiolytic profile in the elevated plus maze, with an increase in the time and number of entries in the open arms. The activity of mice treated with cocaine alone or plus MDMA remained constant; the decrease observed among the rest of the animals after the second hour was absent in their case. The level of dopamine in the striatum was diminished in mice treated with 20 mg/kg of MDMA, but this neurotransmitter was not affected in animals exposed to the same dose plus cocaine. The present results highlight pronounced alterations in the behaviour of adult mice after exposure to MDMA and cocaine during adolescence, and demonstrate that these long-term effects can occur without the dopaminergic system becoming affected.

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 exposed to social defeat during adulthood did not show conditioned place preference after conditioning with either dose of MDMA. Conversely, social defeat did not affect the anxiogenic and motor effects of MDMA. Adult mice exposed to social defeat showed higher levels of corticosterone than their controls and adolescent mice. Social stress did not induce behavioural effects in adolescent mice. Our results show that stress induced by social defeat decreases the sensitivity of adult mice to the rewarding effects of MDMA.