Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats.

GPR139 is an orphan G protein-coupled receptor (GPCR) that is expressed mainly in the brain, with the highest expression in the medial habenula. The modulation of GPR139 receptor function has been hypothesized to be beneficial in the treatment of some mental disorders, but behavioral studies have not yet provided causal evidence of the role of GPR139 in brain dysfunction. Because of the high expression of GPR139 in the habenula, a critical brain region in addiction, we hypothesized that GPR139 may play role in alcohol dependence. Thus, we tested the effect of GPR139 receptor activation using the selective, brain-penetrant receptor agonist JNJ-63533054 on addiction-like behaviors in alcohol-dependent male rats. Systemic administration of JNJ-63533054 (30 mg/kg but not 10 mg/kg, p.o.) reversed the escalation of alcohol self-administration in alcohol-dependent rats, without affecting water or saccharin intake in dependent rats or alcohol intake in nondependent rats. Moreover, systemic JNJ-63533054 administration decreased withdrawal-induced hyperalgesia, without affecting somatic signs of alcohol withdrawal. Further analysis demonstrated that JNJ-63533054 was effective only in a subgroup of dependent rats that exhibited compulsive-like alcohol drinking. Finally, site-specific microinjection of JNJ-63533054 in the habenula but not interpeduncular nucleus (IPN) reduced both alcohol self-administration and withdrawal-induced hyperalgesia in dependent rats. These results provide robust preclinical evidence that GPR139 receptor activation reverses key addiction-like behaviors in dependent animals, suggest that GPR139 may be a novel target for the treatment of alcohol use disorder, and demonstrate that GPR139 is functionally relevant in regulating mammalian behavior

Neuropharmacology

A major limitation of the most widely used current animal models of alcohol dependence is that they use forced exposure to ethanol including ethanol-containing liquid diet and chronic intermittent ethanol (CIE) vapor to produce clinically relevant blood alcohol levels (BAL) and addiction-like behaviors. We recently developed a novel animal model of voluntary induction of alcohol dependence using ethanol vapor self-administration (EVSA). However, it is unknown whether EVSA leads to an escalation of alcohol drinking per se, and whether such escalation is associated with neuroadaptations in brain regions related to stress, reward, and habit. To address these issues, we compared the levels of alcohol drinking during withdrawal between rats passively exposed to alcohol (CIE) or voluntarily exposed to EVSA and measured the number of Fos+ neurons during acute withdrawal (16 h) in key brain regions important for stress, reward, and habit-related processes. CIE and EVSA rats exhibited similar BAL and similar escalation of alcohol drinking and motivation for alcohol during withdrawal. Acute withdrawal from EVSA and CIE recruited a similar number of Fos+ neurons in the Central Amygdala (CeA), however, acute withdrawal from EVSA recruited a higher number of Fos+ neurons in every other brain region analyzed compared to acute withdrawal from CIE. In summary, while the behavioral measures of alcohol dependence between the voluntary (EVSA) and passive (CIE) model were similar, the recruitment of neuronal ensembles during acute withdrawal was very different. The EVSA model may be particularly useful to unveil the neuronal networks and pharmacology responsible for the voluntary induction and maintenance of alcohol dependence and may improve translational studies by providing preclinical researchers with an animal model that highlights the volitional aspects of alcohol use disorder. © 2022 The Author

Mécanismes psychobiologiques d'une recherche mal-adaptée de cocaïne

About 20% of cocaine users suffer with severe cocaine use disorder (CUD) or addiction, and to date, there are limited therapeutic options available. Due to this, there is an increased need to focus on the neurobiology surrounding key behavioral features of cocaine use disorder.My thesis focuses on understanding the psychobiological mechanisms of the emergence of maladaptive seeking- a key behavioral feature in those who suffer from CUD. Within my research, I use a model of CUD in the rat previously pioneered by our lab and acknowledged as a breakthrough in the field. In this model, 15% of rats develop an addiction-like behavior after protracted intravenous self-administration (SA). Critically, after early cocaine SA, a maladaptive seeking behavior emerges that is reliably predictive of the transition to addiction.The factors influencing the emergence of this maladaptive seeking behavior are explored in this manuscript.Combining behavioral methods, analytical chemistry and calcium imaging, I study the psychopharmacological and neurobiological determinants of this early maladaptive seeking behavior. I hypothesized and demonstrated that early maladaptive seeking results from an increased control of behavior by incentive internal cues at the expense of control by adaptive inhibitory external cues, which is related to altered recruitment of the prelimbic cortex (PL). Addiction is a relapsing disorder with 80% of users failing at remaining abstinent, making relapse a major clinical challenge. Therefore, I focused on how the mechanisms identified in the first two objectives modulate relapse, modeled in rats using the reinstatement procedure.This PhD work explores and identifies crucial psychopharmacological mechanisms that are involved in a key behavioral characteristic of the transition to addiction: maladaptive seeking. In addition, it detects neurobiological correlates of predictive markers of the vulnerability to addiction. Consequently, it sets an early foundation to explore potential treatment modalities that piggyback off of the psychopharmacological or neurobiological differences discovered.La consommation de cocaïne est en forte expansion en Europe. 20 % des usagers développent une addiction, représentant in fine des millions d'individus pour lesquels les solutions thérapeutiques sont limitées. Ma thèse porte sur la compréhension des mécanismes psychobiologiques impliqués dans l'émergence d’un usage maladapté de drogue - une caractéristique comportementale clé chez les sujets souffrant d’addiction. J'utilise un modèle d’addiction chez le rat mis au point par notre équipe et reconnucomme une avancée majeure dans le domaine. Après plusieurs mois d’auto-administration de cocaïne, 15 à 20 % des rats développent un comportement présentant les caractéristiques d’une addiction. Précocément une recherche de drogue inadaptée émerge qui prédit de façon fiable la transition vers le comportement d’addiction. En couplant comportement, chimie analytique et imagerie calcique, j'étudie lesdéterminants psychopharmacologiques (objectif 1) et neurobiologiques (objectif 2) de ce comportement précoce. J'ai émis l'hypothèse et démontré qu’il résulte d'un contrôle accru du comportement par des stimuli internes incitant à consommer, aux dépens du contrôle par des stimuli externes qui devraient inciter à inhiber le comportement, en lien avec un moindre recrutement du cortex prélimbique (PL). L’addiction est une pathologie chronique où 80 % des patients rechutent. Dans le troisième objectif, je me suis doncconcentrée sur la façon dont les mécanismes identifiés dans les deux premiers objectifs modulent ce défi clinique majeur. Mes données préliminaires, que je complète actuellement, indiquent que la rechute peut effectivement être contrôlée par des stimuli contextuels inhibiteurs via le recrutement du PL chez les rats résilients, mais pas chez les rats vulnérables

Mécanismes psychobiologiques d'une recherche mal-adaptée de cocaïne

La consommation de cocaïne est en forte expansion en Europe. 20 % des usagers développent une addiction, représentant in fine des millions d'individus pour lesquels les solutions thérapeutiques sont limitées. Ma thèse porte sur la compréhension des mécanismes psychobiologiques impliqués dans l'émergence d’un usage maladapté de drogue - une caractéristique comportementale clé chez les sujets souffrant d’addiction. J'utilise un modèle d’addiction chez le rat mis au point par notre équipe et reconnucomme une avancée majeure dans le domaine. Après plusieurs mois d’auto-administration de cocaïne, 15 à 20 % des rats développent un comportement présentant les caractéristiques d’une addiction. Précocément une recherche de drogue inadaptée émerge qui prédit de façon fiable la transition vers le comportement d’addiction. En couplant comportement, chimie analytique et imagerie calcique, j'étudie lesdéterminants psychopharmacologiques (objectif 1) et neurobiologiques (objectif 2) de ce comportement précoce. J'ai émis l'hypothèse et démontré qu’il résulte d'un contrôle accru du comportement par des stimuli internes incitant à consommer, aux dépens du contrôle par des stimuli externes qui devraient inciter à inhiber le comportement, en lien avec un moindre recrutement du cortex prélimbique (PL). L’addiction est une pathologie chronique où 80 % des patients rechutent. Dans le troisième objectif, je me suis doncconcentrée sur la façon dont les mécanismes identifiés dans les deux premiers objectifs modulent ce défi clinique majeur. Mes données préliminaires, que je complète actuellement, indiquent que la rechute peut effectivement être contrôlée par des stimuli contextuels inhibiteurs via le recrutement du PL chez les rats résilients, mais pas chez les rats vulnérables.About 20% of cocaine users suffer with severe cocaine use disorder (CUD) or addiction, and to date, there are limited therapeutic options available. Due to this, there is an increased need to focus on the neurobiology surrounding key behavioral features of cocaine use disorder.My thesis focuses on understanding the psychobiological mechanisms of the emergence of maladaptive seeking- a key behavioral feature in those who suffer from CUD. Within my research, I use a model of CUD in the rat previously pioneered by our lab and acknowledged as a breakthrough in the field. In this model, 15% of rats develop an addiction-like behavior after protracted intravenous self-administration (SA). Critically, after early cocaine SA, a maladaptive seeking behavior emerges that is reliably predictive of the transition to addiction.The factors influencing the emergence of this maladaptive seeking behavior are explored in this manuscript.Combining behavioral methods, analytical chemistry and calcium imaging, I study the psychopharmacological and neurobiological determinants of this early maladaptive seeking behavior. I hypothesized and demonstrated that early maladaptive seeking results from an increased control of behavior by incentive internal cues at the expense of control by adaptive inhibitory external cues, which is related to altered recruitment of the prelimbic cortex (PL). Addiction is a relapsing disorder with 80% of users failing at remaining abstinent, making relapse a major clinical challenge. Therefore, I focused on how the mechanisms identified in the first two objectives modulate relapse, modeled in rats using the reinstatement procedure.This PhD work explores and identifies crucial psychopharmacological mechanisms that are involved in a key behavioral characteristic of the transition to addiction: maladaptive seeking. In addition, it detects neurobiological correlates of predictive markers of the vulnerability to addiction. Consequently, it sets an early foundation to explore potential treatment modalities that piggyback off of the psychopharmacological or neurobiological differences discovered

Psychobiological Mechanisms of Maladaptive Cocaine Seeking

La consommation de cocaïne est en forte expansion en Europe. 20 % des usagers développent une addiction, représentant in fine des millions d'individus pour lesquels les solutions thérapeutiques sont limitées. Ma thèse porte sur la compréhension des mécanismes psychobiologiques impliqués dans l'émergence d’un usage maladapté de drogue - une caractéristique comportementale clé chez les sujets souffrant d’addiction. J'utilise un modèle d’addiction chez le rat mis au point par notre équipe et reconnucomme une avancée majeure dans le domaine. Après plusieurs mois d’auto-administration de cocaïne, 15 à 20 % des rats développent un comportement présentant les caractéristiques d’une addiction. Précocément une recherche de drogue inadaptée émerge qui prédit de façon fiable la transition vers le comportement d’addiction. En couplant comportement, chimie analytique et imagerie calcique, j'étudie lesdéterminants psychopharmacologiques (objectif 1) et neurobiologiques (objectif 2) de ce comportement précoce. J'ai émis l'hypothèse et démontré qu’il résulte d'un contrôle accru du comportement par des stimuli internes incitant à consommer, aux dépens du contrôle par des stimuli externes qui devraient inciter à inhiber le comportement, en lien avec un moindre recrutement du cortex prélimbique (PL). L’addiction est une pathologie chronique où 80 % des patients rechutent. Dans le troisième objectif, je me suis doncconcentrée sur la façon dont les mécanismes identifiés dans les deux premiers objectifs modulent ce défi clinique majeur. Mes données préliminaires, que je complète actuellement, indiquent que la rechute peut effectivement être contrôlée par des stimuli contextuels inhibiteurs via le recrutement du PL chez les rats résilients, mais pas chez les rats vulnérables.About 20% of cocaine users suffer with severe cocaine use disorder (CUD) or addiction, and to date, there are limited therapeutic options available. Due to this, there is an increased need to focus on the neurobiology surrounding key behavioral features of cocaine use disorder.My thesis focuses on understanding the psychobiological mechanisms of the emergence of maladaptive seeking- a key behavioral feature in those who suffer from CUD. Within my research, I use a model of CUD in the rat previously pioneered by our lab and acknowledged as a breakthrough in the field. In this model, 15% of rats develop an addiction-like behavior after protracted intravenous self-administration (SA). Critically, after early cocaine SA, a maladaptive seeking behavior emerges that is reliably predictive of the transition to addiction.The factors influencing the emergence of this maladaptive seeking behavior are explored in this manuscript.Combining behavioral methods, analytical chemistry and calcium imaging, I study the psychopharmacological and neurobiological determinants of this early maladaptive seeking behavior. I hypothesized and demonstrated that early maladaptive seeking results from an increased control of behavior by incentive internal cues at the expense of control by adaptive inhibitory external cues, which is related to altered recruitment of the prelimbic cortex (PL). Addiction is a relapsing disorder with 80% of users failing at remaining abstinent, making relapse a major clinical challenge. Therefore, I focused on how the mechanisms identified in the first two objectives modulate relapse, modeled in rats using the reinstatement procedure.This PhD work explores and identifies crucial psychopharmacological mechanisms that are involved in a key behavioral characteristic of the transition to addiction: maladaptive seeking. In addition, it detects neurobiological correlates of predictive markers of the vulnerability to addiction. Consequently, it sets an early foundation to explore potential treatment modalities that piggyback off of the psychopharmacological or neurobiological differences discovered

Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats.

GPR139 is an orphan G protein-coupled receptor (GPCR) that is expressed mainly in the brain, with the highest expression in the medial habenula. The modulation of GPR139 receptor function has been hypothesized to be beneficial in the treatment of some mental disorders, but behavioral studies have not yet provided causal evidence of the role of GPR139 in brain dysfunction. Because of the high expression of GPR139 in the habenula, a critical brain region in addiction, we hypothesized that GPR139 may play role in alcohol dependence. Thus, we tested the effect of GPR139 receptor activation using the selective, brain-penetrant receptor agonist JNJ-63533054 on addiction-like behaviors in alcohol-dependent male rats. Systemic administration of JNJ-63533054 (30 mg/kg but not 10 mg/kg, p.o.) reversed the escalation of alcohol self-administration in alcohol-dependent rats, without affecting water or saccharin intake in dependent rats or alcohol intake in nondependent rats. Moreover, systemic JNJ-63533054 administration decreased withdrawal-induced hyperalgesia, without affecting somatic signs of alcohol withdrawal. Further analysis demonstrated that JNJ-63533054 was effective only in a subgroup of dependent rats that exhibited compulsive-like alcohol drinking. Finally, site-specific microinjection of JNJ-63533054 in the habenula but not interpeduncular nucleus (IPN) reduced both alcohol self-administration and withdrawal-induced hyperalgesia in dependent rats. These results provide robust preclinical evidence that GPR139 receptor activation reverses key addiction-like behaviors in dependent animals, suggest that GPR139 may be a novel target for the treatment of alcohol use disorder, and demonstrate that GPR139 is functionally relevant in regulating mammalian behavior

Sales and collusion in a market with storage

Sales are a widespread and well-known phenomenon documented in several product markets. This paper presents a novel rationale for sales that does not rely on consumer heterogeneity, or on any form of randomness to explain such periodic price fluctuations. The analysis is carried out in the context of a simple repeated price competition model, and establishes that firms must periodically reduce prices in order to sustain collusion when goods are storable and the market is large. The largest equilibrium profits are characterized at any market size. A trade-o¤ between the size of the industry and its profits arises. Sales foster collusion, by magnifying the intertemporal links in consumers' decisions

Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats.

Previous studies showed that the glyoxalase 1 (Glo1) gene modulates anxiety-like behavior, seizure susceptibility, depression-like behavior, and alcohol drinking in the drinking-in-the-dark paradigm in nondependent mice. Administration of the small-molecule GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) decreased alcohol drinking in nondependent mice, suggesting a possible therapeutic strategy. However, the preclinical therapeutic efficacy of pBBG in animal models of alcohol dependence remains to be demonstrated. We tested the effect of pBBG (7.5 and 25 mg/kg) on operant alcohol self-administration in alcohol-dependent and nondependent rats. Wistar rats were trained to self-administer 10% alcohol (v/v) and made dependent by chronic intermittent passive exposure to alcohol vapor for 5 weeks. Pretreatment with pBBG dose-dependently reduced alcohol self-administration in both nondependent and dependent animals, without affecting water self-administration. pBBG treatment was more effective in dependent rats than in nondependent rats. These data extend previous findings that implicated Glo1 in alcohol drinking in nondependent mice by showing even more profound effects in alcohol-dependent rats. These results suggest that the pharmacological inhibition of GLO1 is a relevant therapeutic target for the treatment of alcohol use disorders

Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats.

Previous studies showed that the glyoxalase 1 (Glo1) gene modulates anxiety-like behavior, seizure susceptibility, depression-like behavior, and alcohol drinking in the drinking-in-the-dark paradigm in nondependent mice. Administration of the small-molecule GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) decreased alcohol drinking in nondependent mice, suggesting a possible therapeutic strategy. However, the preclinical therapeutic efficacy of pBBG in animal models of alcohol dependence remains to be demonstrated. We tested the effect of pBBG (7.5 and 25 mg/kg) on operant alcohol self-administration in alcohol-dependent and nondependent rats. Wistar rats were trained to self-administer 10% alcohol (v/v) and made dependent by chronic intermittent passive exposure to alcohol vapor for 5 weeks. Pretreatment with pBBG dose-dependently reduced alcohol self-administration in both nondependent and dependent animals, without affecting water self-administration. pBBG treatment was more effective in dependent rats than in nondependent rats. These data extend previous findings that implicated Glo1 in alcohol drinking in nondependent mice by showing even more profound effects in alcohol-dependent rats. These results suggest that the pharmacological inhibition of GLO1 is a relevant therapeutic target for the treatment of alcohol use disorders

Sci Rep

Despite the popularity of fiber photometry (FP), its integration with operant behavior paradigms is progressing slowly. This can be attributed to the complex protocols in operant behavior - resulting in a combination of diverse non-predictable behavioral responses and scheduled events, thereby complicating data analysis. To overcome this, we developed Pyfiber, an open-source python library which facilitates the merge of FP with operant behavior by relating changes in fluorescent signals within a neuronal population to behavioral responses and events. Pyfiber helps to 1. Extract events and responses that occur in operant behavior, 2. Extract and process the FP signals, 3. Select events of interest and align them to the corresponding FP signals, 4. Apply appropriate signal normalization and analysis according to the type of events, 5. Run analysis on multiple individuals and sessions, 6. Collect results in an easily readable format. Pyfiber is suitable for use with many different fluorescent sensors and operant behavior protocols. It was developed using Doric lenses FP systems and Imetronic behavioral systems, but it possesses the capability to process data from alternative systems. This work sets a solid foundation for analyzing the relationship between different dimensions of complex behavioral paradigms with fluorescent signals from brain regions of interest.Innovations instrumentales et procédurales en psychopathologie expérimentale chez le rongeurUniversity of Bordeaux Neurocampus Graduate Schoo