The negative allosteric modulator of mGluR5, MPEP, potentiates the rewarding properties of cocaine in priming-induced reinstatement of CPP. / El modulador alostérico negativo de los mGluR5, MPEP, potencia la reinstauración de la preferencia condicionada inducida con priming de cocaína.

Cocaine addiction is a chronic disorder with high relapse rates; therefore, understanding the neuronal mechanisms underlying drug-seeking during relapse is a priority to develop targeted pharmacotherapy. The metabotropic glutamate receptor 5 (mGluR5) seems to be involved in the reinstatement induced by cocaine-associated cues. The main objective of the study was to evaluate the efficacy of MPEP, a negative allosteric modulator of mGluR5, in attenuating or potentiating the reinstatement induced by priming doses of cocaine in the CPP paradigm, ultimately to further knowledge regarding the role of the mGluR5 in relapse into cocaine abuse. OF1 mice (48 female and 48 male) were conditioned in the CPP paradigm with cocaine (20 mg/kg) and were exposed to an extinction program. We evaluated the efficacy of MPEP (30 mg/kg) in blocking the successive cocaine-priming reinstatements in the CPP when extinction of the conditioning preference was confirmed. MPEP did not block the reinstatement of priming cocaine-induced CPP, but increased the potential of cocaine for reinstating conditioning preference. The contingent administration of MPEP with cocaine increased the drug-seeking behaviour and the number of reinstatements with priming doses of cocaine. Moreover, MPEP produced cross reinstatement of cocaine-induced CPP. Rather than preventing the reinstatements of conditioned preference induced by priming doses of cocaine, MPEP increased them. These findings may help to understand the role of mGluR5 in the relapse into cocaine abuse.

La adicción a la cocaína es un trastorno crónico con un alto índice de recaídas; por tanto, es prioritario entender los mecanismos neurales implicados en la búsqueda de la droga durante la recaída para desarrollar farmacoterapias eficaces. El receptor metabotrópico 5 del glutamato (mGluR5) parece estar implicado en la reinstauración inducida por las claves asociadas a la cocaína. El objetivo principal de este estudio fue profundizar en el papel del receptor mGluR5 en la recaída en el consumo de cocaína, evaluando el efecto del MPEP, un modulador alostérico negativo del mGluR5, sobre la reinstauración inducida por un priming de cocaína en el paradigma del condicionamiento de la preferencia de lugar (CPL). Ratones OF1 (48 machos y 48 hembras) fueron condicionados en el paradigma del CPL con cocaína (20 mg/kg) y expuestos a un programa de extinción. Cuando la extinción de la preferencia condicionada fue confirmada, se evaluó la eficacia del MPEP (30 mg/kg) para bloquear las sucesivas reinstauraciones mediante priming de cocaína en el CPL. La administración contingente de MPEP con la cocaína en el CPL incrementó la conducta de búsqueda de la droga y el número de reinstauraciones. Además, la administración solo de MPEP produjo reinstauración cruzada en el CPL inducido por cocaína. Por tanto, el MPEP no solo no previno, sino que incrementó las reinstauraciones de la preferencia condicionada inducida por priming de cocaína. Estos resultados pueden ayudar a entender el papel del mGluR5 en la recaída al consumo de cocaína.

El modulador alostérico negativo de los mGluR5, MPEP, potencia la reinstauración de la preferencia condicionada inducida con priming de cocaína / The negative allosteric modulator of mGluR5, MPEP, potentiates the rewarding properties of cocaine in priming-induced reinstatement of CPP

La adicción a la cocaína es un trastorno crónico con un alto índice de recaídas; por tanto, es prioritario entender los mecanismos neurales implicados en la búsqueda de la droga durante la recaída para desarrollar farmacoterapias eficaces. El receptor metabotrópico 5 del glutamato (mGluR5) parece estar implicado en la reinstauración inducida por las claves asociadas a la cocaína. El objetivo principal de este estudio fue profundizar en el papel del receptor mGluR5 en la recaída en el consumo de cocaína, evaluando el efecto del MPEP, un modulador alostérico negativo del mGluR5, sobre la reinstauración inducida por un priming de cocaína en el paradigma del condicionamiento de la preferencia de lugar (CPL). Ratones OF1 (48 machos y 48 hembras) fueron condicionados en el paradigma del CPL con cocaína (20 mg/kg) y expuestos a un programa de extinción. Cuando la extinción de la preferencia condicionada fue confirmada, se evaluó la eficacia del MPEP (30 mg/kg) para bloquear las sucesivas reinstauraciones mediante priming de cocaína en el CPL. La administración contingente de MPEP con la cocaína en el CPL incrementó la conducta de búsqueda de la droga y el número de reinstauraciones. Además, la administración solo de MPEP produjo reinstauración cruzada en el CPL inducido por cocaína. Por tanto, el MPEP no solo no previno, sino que incrementó las reinstauraciones de la preferencia condicionada inducida por priming de cocaína. Estos resultados pueden ayudar a entender el papel del mGluR5 en la recaída al consumo de cocaína

Cocaine addiction is a chronic disorder with high relapse rates; therefore, understanding the neuronal mechanisms underlying drug-seeking during relapse is a priority to develop targeted pharmacotherapy. The metabotropic glutamate receptor 5 (mGluR5) seems to be involved in the reinstatement induced by cocaine-associated cues. The main objective of the study was to evaluate the efficacy of MPEP, a negative allosteric modulator of mGluR5, in attenuating or potentiating the reinstatement induced by priming doses of cocaine in the CPP paradigm, ultimately to further knowledge regarding the role of the mGluR5 in relapse into cocaine abuse. OF1 mice (48 female and 48 male) were conditioned in the CPP paradigm with cocaine (20 mg/kg) and were exposed to an extinction program. We evaluated the efficacy of MPEP (30 mg/kg) in blocking the successive cocaine-priming reinstatements in the CPP when extinction of the conditioning preference was confirmed. MPEP did not block the reinstatement of priming cocaine-induced CPP, but increased the potential of cocaine for reinstating conditioning preference. The contingent administration of MPEP with cocaine increased the drug-seeking behaviour and the number of reinstatements with priming doses of cocaine. Moreover, MPEP produced cross reinstatement of cocaine-induced CPP. Rather than preventing the reinstatements of conditioned preference induced by priming doses of cocaine, MPEP increased them. These findings may help to understand the role of mGluR5 in the relapse into cocaine abuse

Differential Impact of Ad Libitum or Intermittent High-Fat Diets on Bingeing Ethanol-Mediated Behaviors.

BACKGROUND: Dietary factors have significant effects on the brain, modulating mood, anxiety, motivation and cognition. To date, no attention has been paid to the consequences that the combination of ethanol (EtOH) and a high-fat diet (HFD) have on learning and mood disorders during adolescence. The aim of the present work was to evaluate the biochemical and behavioral consequences of ethanol binge drinking and an HFD consumption in adolescent mice. METHODS: Animals received either a standard diet or an HFD (ad libitum vs. binge pattern) in combination with ethanol binge drinking and were evaluated in anxiety and memory. The metabolic profile and gene expression of leptin receptors and clock genes were also evaluated. RESULTS: Excessive white adipose tissue and an increase in plasma insulin and leptin levels were mainly observed in ad libitum HFD + EtOH mice. An upregulation of the Lepr gene expression in the prefrontal cortex and the hippocampus was also observed in ad libitum HFD groups. EtOH-induced impairment on spatial memory retrieval was absent in mice exposed to an HFD, although the aversive memory deficits persisted. Mice bingeing on an HFD only showed an anxiolytic profile, without other alterations. We also observed a mismatch between Clock and Bmal1 expression in ad libitum HFD animals, which were mostly independent of EtOH bingeing. CONCLUSIONS: Our results confirm the bidirectional influence that occurs between the composition and intake pattern of a HFD and ethanol consumption during adolescence, even when the metabolic, behavioral and chronobiological effects of this interaction are dissociated.

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, with particular focus on adolescent subjects. First, the different animal models of NS and the importance of this endophenotype in adolescence are discussed. Later, studies that have used the most common animal models of reward (self-administration, conditioned place preference paradigms) to evaluate how the NS trait influences the rewarding effects of psychostimulants are reviewed. Finally, possible explanations for the enhanced risk of developing substance dependence among HNS individuals are discussed. In conclusion, the studies referred to in this review show that the HNS trait is associated with: (1) increased initial sensitivity to the rewarding effects of psychostimulants, (2) a higher level of drug craving when the subject is exposed to the environmental cues associated with the drug, and (3) enhanced long-term vulnerability to relapse to drug consumption after prolonged abstinence.

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 to assess adolescent behaviour in rodents, the second is generally used to evaluate a wide repertoire of behaviours in adulthood and the latter is specific to aggressive behaviour. Throughout the review we will explore the most relevant studies carried out to date to evaluate the effects of alcohol, cocaine, opioids, 3,4-methylenedioxymethamphetamine (MDMA), cannabinoids, nicotine and other drugs of abuse on these three paradigms, taking into account the influence of different variables, such as social history, age and type of exposure. Drugs of diverse pharmacological classes induce alterations in social behaviour, although they can be contrasting depending on several factors (drug, individual differences and environmental conditions). Ethanol and nicotine increase social interaction at low doses but reduce it at high doses. Psychostimulants, MDMA and cannabinoids reduce social interaction, whereas opiates increase it. Ethanol and psychostimulants enhance aggression, whereas MDMA, opiates, cannabinoids and nicotine reduce it. Prenatal drug exposure alters social behaviour, whereas drug withdrawal decreases sociability and enhances aggression. As a whole, this evidence has improved our understanding of the social dimension of drug addiction.