Food-induced behavioral sensitization, its cross-sensitization to cocaine and morphine, pharmacological blockade, and effect on food intake

Repeated administration of abused drugs sensitizes their stimulant effects and results in a drug-paired environment eliciting conditioned activity. We tested whether food induces similar effects. Food-deprived male mice were given novel food during 30 min tests in a runway (FR group) that measured locomotor activity. Whereas the activity of this group increased with repeated testing, that of a group exposed to the runways but that received the food in the home cage (FH group), or of a group satiated by prefeeding before testing (SAT group), decreased. When exposed to the runways in the absence of food, the paired group was more active than the other groups (conditioned activity); no activity differences were seen in an alternative, non-food-paired, apparatus. Conditioned activity survived a 3-week period without runway exposure. Conditioned activity was selectively reduced by the opiate antagonist naltrexone (10-20 mg/kg) and by the noncompetitive AMPA receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] (5-10 mg/kg). The D1 antagonist SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] (15-30 microg/kg) and D2 antagonist sulpiride (25-125 mg/kg) reduced activity nonspecifically. A single intraperitoneal dose of cocaine (10 mg/kg) or morphine (20 mg/kg) increased activity compared with saline, the stimulant effect being larger in the FR group, suggesting "cross-sensitization" to these drugs. However, pretreatment with GYKI 52466 or naltrexone at doses that suppressed conditioned activity in FR animals suppressed cross-sensitization to cocaine. When allowed ad libitum access to food in the runway, FR mice consumed more pellets in a time-limited test. Thus, many of the features of behavioral sensitization to drugs can be demonstrated using food reward and may contribute to excessive eating

Opium, opiacés, opioïdes (du remède millénaire à la physiologie des morphines endogènes)

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Long-term transcriptional consequences of drug exposure as cues to understand vulnerability to relapse: advances and perspectives

Quitting drug abuse represents a true challenge for addicted individuals because of the highly persistent vulnerability to relapse. Identifying long-lasting, drug-induced alterations in the brain-including at the transcriptome level-that underlie such vulnerability appears invaluable to improve relapse prevention. Despite substantial technological developments and research effort, however, the picture of drug-induced adaptations provided by high-throughput transcriptomics remains frustratingly partial, notably because of methodological issues. Major advances were made, however, regarding the time course and specificity of long-term transcriptional consequences of drug exposure as well as the recruitment of small, noncoding mRNAs (or miRNAs [microRNAs]) that were previously undetectable. Most importantly, high-throughput studies have benefited from systems biology approaches and shifted their interest toward regulations within functional gene networks rather than individual changes. Such network-based gene discovery approaches have proven informative to delineate the physiological processes, cellular signaling pathways, and neuronal populations altered by drug exposure. Provided the high-throughput effort will be pursued, together with the development of adapted bioinformatics tools, addiction transcriptomics should progressively integrate data across multiple scales (from epigenome to protein), allowing a better understanding of the genetics of drug abuse and opening novel therapeutic trails

Facilitating glutamate mGluR4 receptor signaling relieves autistic-like deficits in mice

International audienc

Food-induced behavioral sensitization, its cross-sensitization to cocaine and morphine, pharmacological blockade, and effect on food intake

Repeated administration of abused drugs sensitizes their stimulant effects and results in a drug-paired environment eliciting conditioned activity. We tested whether food induces similar effects. Food-deprived male mice were given novel food during 30 min tests in a runway (FR group) that measured locomotor activity. Whereas the activity of this group increased with repeated testing, that of a group exposed to the runways but that received the food in the home cage (FH group), or of a group satiated by prefeeding before testing (SAT group), decreased. When exposed to the runways in the absence of food, the paired group was more active than the other groups (conditioned activity); no activity differences were seen in an alternative, non-food-paired, apparatus. Conditioned activity survived a 3-week period without runway exposure. Conditioned activity was selectively reduced by the opiate antagonist naltrexone (10-20 mg/kg) and by the noncompetitive AMPA receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] (5-10 mg/kg). The D1 antagonist SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] (15-30 microg/kg) and D2 antagonist sulpiride (25-125 mg/kg) reduced activity nonspecifically. A single intraperitoneal dose of cocaine (10 mg/kg) or morphine (20 mg/kg) increased activity compared with saline, the stimulant effect being larger in the FR group, suggesting "cross-sensitization" to these drugs. However, pretreatment with GYKI 52466 or naltrexone at doses that suppressed conditioned activity in FR animals suppressed cross-sensitization to cocaine. When allowed ad libitum access to food in the runway, FR mice consumed more pellets in a time-limited test. Thus, many of the features of behavioral sensitization to drugs can be demonstrated using food reward and may contribute to excessive eating

Cues predicting drug or food reward restore morphine-induced place conditioning in mice lacking delta opioid receptors

International audienceThe exact role of delta opioid receptors in drug-induced conditioned place preference (CPP) remains debated. Under classical experimental conditions, morphine-induced CPP is decreased in mice lacking delta opioid receptors (Oprd1 (-/-)). Morphine self-administration, however, is maintained, suggesting that drug-context association rather than drug reward is deficient in these animals

Previous experience of ethanol withdrawal increases withdrawal-induced c-fos expression in limbic areas, but reduces withdrawal-induced anxiety and elevations in plasma corticosterone

No description supplie

Rôle du système opioidergique septal dans la modulation des processus émotionnels et mnésiques chez la souris

Le système opioïdergique endogène, connu pour son implication dans les processus motivationnels, émotionnels et mnésiques, est bien représenté au niveau de la région septale, considérée elle-même comme une interface possible entre ces différents processus. Nous avons mimé l'activation du système opioïdergique septal par l'injection de morphine dans le septum médian (SM) ou latéral (SL). Nous avons soumis les animaux à différentes épreuves comportementales et utilisé la technique de marquage de la protéine Fos pour identifier quelques unes des structures cérébrales recrutées par cette activation. Les souris s'auto-administrent la morphine dans les deux divisions septales. Dans le cas du SL, ce comportement dépend de mécanismes dopaminergiques et s'accompagne d'une activation de la voie mamillo-thalamique. Les animaux SM présentent des difficultés à s'auto-administrer en situation de discrimination spatiale, cette perturbation pouvant être d'origine soit mnésique, soit anxieuse. Nous avons alors évalué les effets de l'administration intraseptale de morphine sur les performances d'alternance spatiale spontanée ou renforcée. Les souris SM ne présentent de déficit mnésique que dans le protocole renforcé, et les souris SL que dans le protocole spontané. Or, chez des animaux naïfs soumis à un protocole d'alternance renforcée, il existe une corrélation positive entre l'expression de Fos dans l'hippocampe et les performances, suggérant que les difficultés rencontrées par les animaux SM résultent d'une altération de l'activité hippocampique. Enfin, nous avons mis en évidence, dans le labyrinthe en croix surélevé, un effet anxiogène de la morphine lorsqu'elle est administrée dans le SL, mais pas dans le SM. L'ensemble de nos résultats souligne l'implication différentielle du SM et du SL dans les processus motivationnels, émotionnels et mnésiques et permet d'identifier le système opioïdergique septal comme l'un des substrats de cette dissociation fonctionnelle.BORDEAUX1-BU Sciences-Talence (335222101) / SudocSudocFranceF

Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol

Unified theories of addiction are challenged by differing drug-seeking behaviors and neurobiological adaptations across drug classes, particularly for narcotics and psychostimulants. We previously showed that protracted abstinence to opiates leads to despair behavior and social withdrawal in mice, and we identified a transcriptional signature in the extended amygdala that was also present in animals abstinent from nicotine, Δ9-tetrahydrocannabinol (THC) and alcohol. Here we examined whether protracted abstinence to these four drugs would also share common behavioral features, and eventually differ from abstinence to the prototypic psychostimulant cocaine. We found similar reduced social recognition, increased motor stereotypies and increased anxiety with relevant c-fos response alterations in morphine, nicotine, THC and alcohol abstinent mice. Protracted abstinence to cocaine, however, led to strikingly distinct, mostly opposing adaptations at all levels, including behavioral responses, neuronal activation and gene expression. Together, these data further document the existence of common hallmarks for protracted abstinence to opiates, nicotine, THC and alcohol that develop within motivation/emotion brain circuits. In our model, however, these do not apply to cocaine, supporting the notion of unique mechanisms in psychostimulant abuse

Delta Opioid Receptors: Learning and Motivation

International audienceDelta opioid receptor (DOR) displays a unique, highly conserved, structure and an original pattern of distribution in the central nervous system, pointing to a distinct and specific functional roleamong opioid peptide receptors. Over the last 15 years, in vivo pharmacology and genetic models have allowed significant advances in the understanding of this role. In this review, we will focus on the involvement of delta opioid receptor in modulating different types of hippocampal-and striatal-dependent learning processes, as well as motor function, motivation and reward.Remarkably, DOR seems to play a key role in balancing hippocampal and striatal functions, with major implications for the control of cognitive performance and motor function under healthy and pathological conditions