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Le trouble de la consommation d'alcool (AUD) est une maladie chronique et mortelle. Le principal obstacle au traitement par AUD est une forte probabilité de rechute à l'abus d'alcool, même après une abstinence prolongée. Les mécanismes moléculaires de la rechute induite par les signaux ne sont pas bien établis, malgré le fait qu'ils peuvent offrir de nouvelles cibles pour le traitement de l'AUD. En utilisant un modèle animal complet d'AUD, des manipulations génétiques à médiation virale et ciblées sur l'amygdale par la technologie CRISPR/Cas9 et l'électrophysiologie ex vivo, nous identifions un mécanisme qui contrôle sélectivement la rechute d'alcool induite par les signaux et la gravité des symptômes d'AUD. Ce mécanisme est basé sur l'activité régulée de la protéine associée au cytosquelette (ARC)/plasticité dépendante de l'Arg3.1 des synapses de l'amygdale. Chez l'homme, nous avons identifié des polymorphismes mononucléotidiques dans le gène ARC et leur méthylation prédisant non seulement la taille de l'amygdale, mais aussi la fréquence de la consommation d'alcool, même au début de la consommation régulière. Cibler l'arc pendant l'exposition à l'alcool peut donc être un nouveau mécanisme sélectif pour la prévention des rechutes. El trastorno por consumo de alcohol (TCA) es una enfermedad crónica y mortal. El principal impedimento de la terapia AUD es una alta probabilidad de recaída en el abuso de alcohol incluso después de una abstinencia prolongada. Los mecanismos moleculares de la recaída inducida por señales no están bien establecidos, a pesar de que pueden ofrecer nuevas dianas para el tratamiento de la AUD. Utilizando un modelo animal integral de AUD, manipulaciones genéticas mediadas por virus y dirigidas a la amígdala mediante tecnología CRISPR/Cas9 y electrofisiología ex vivo, identificamos un mecanismo que controla selectivamente la recaída de alcohol inducida por señales y la gravedad de los síntomas de AUD. Este mecanismo se basa en la actividad regulada de la proteína asociada al citoesqueleto (ARC)/plasticidad dependiente de Arg3.1 de las sinapsis de la amígdala. En humanos, identificamos polimorfismos de un solo nucleótido en el gen ARC y su metilación prediciendo no solo el tamaño de la amígdala, sino también la frecuencia del consumo de alcohol, incluso al inicio del consumo regular. Dirigirse a Arc durante la exposición al alcohol puede ser, por lo tanto, un nuevo mecanismo selectivo para la prevención de recaídas. Alcohol use disorder (AUD) is a chronic and fatal disease. The main impediment of the AUD therapy is a high probability of relapse to alcohol abuse even after prolonged abstinence. The molecular mechanisms of cue-induced relapse are not well established, despite the fact that they may offer new targets for the treatment of AUD. Using a comprehensive animal model of AUD, virally-mediated and amygdala-targeted genetic manipulations by CRISPR/Cas9 technology and ex vivo electrophysiology, we identify a mechanism that selectively controls cue-induced alcohol relapse and AUD symptom severity. This mechanism is based on activity-regulated cytoskeleton-associated protein (Arc)/ARG3.1-dependent plasticity of the amygdala synapses. In humans, we identified single nucleotide polymorphisms in the ARC gene and their methylation predicting not only amygdala size, but also frequency of alcohol use, even at the onset of regular consumption. Targeting Arc during alcohol cue exposure may thus be a selective new mechanism for relapse prevention. Alcohol use disorder (AUD) is a chronic and fatal disease. The main impediment of AUD therapy is a high probability of relapse to alcohol abuse even after prolonged abstinence. The molecular mechanisms of cue-induced relapse are not well established, despite the fact that they may offer new targets for the treatment of AUD. Using a comprehensive animal model of AUD, virally-mediated and amygdala-targeted genetic manipulations by CRISPR/Cas9 technology and ex vivo electrophysiology, we identify a mechanism that selectively controls cue-induced alcohol relapse and AUD symptom severity. This mechanism is based on activity-regulated cytoskeleton-associated protein (arc)/Arg3.1-dependent plasticity of the amygdala synapses. In humans, we identified single nucleotide polymorphisms in the ARC gene and their methylation predicting not only amygdala size, but also frequency of alcohol use, even at the onset of regular consumption. Targeting Arc during alcohol exposure may thus be a selective new mechanism for relapse prevention. اضطراب تعاطي الكحول (AUD) هو مرض مزمن ومميت. العائق الرئيسي لعلاج AUD هو احتمال كبير للانتكاس إلى تعاطي الكحول حتى بعد الامتناع عن ممارسة الجنس لفترات طويلة. الآليات الجزيئية للانتكاس الناجم عن الإشارة ليست راسخة، على الرغم من حقيقة أنها قد تقدم أهدافًا جديدة لعلاج AUD. باستخدام نموذج حيواني شامل من AUD، والتلاعب الجيني بوساطة فيروسية واستهداف اللوزة بواسطة تقنية CRISPR/Cas9 والفسيولوجيا الكهربية خارج الجسم الحي، نحدد آلية تتحكم بشكل انتقائي في انتكاس الكحول الناجم عن الإشارة وشدة أعراض AUD. تعتمد هذه الآلية على البروتين المرتبط بالهياكل الخلوية المنظم للنشاط (ARC )/ اللدونة المعتمدة على Arg3.1 في مشابك اللوزة الدماغية. في البشر، حددنا تعدد أشكال النيوكليوتيدات المفردة في جين القوس وتنبأت مثيلتها ليس فقط بحجم اللوزة، ولكن أيضًا بتكرار تعاطي الكحول، حتى في بداية الاستهلاك المنتظم. وبالتالي، قد يكون استهداف القوس أثناء التعرض للكحول آلية جديدة انتقائية للوقاية من الانتكاس.

Le trouble de la consommation d'alcool (AUD) est une maladie chronique et mortelle. Le principal obstacle au traitement par AUD est une forte probabilité de rechute à l'abus d'alcool, même après une abstinence prolongée. Les mécanismes moléculaires de la rechute induite par les signaux ne sont pas bien établis, malgré le fait qu'ils peuvent offrir de nouvelles cibles pour le traitement de l'AUD. En utilisant un modèle animal complet d'AUD, des manipulations génétiques à médiation virale et ciblées sur l'amygdale par la technologie CRISPR/Cas9 et l'électrophysiologie ex vivo, nous identifions un mécanisme qui contrôle sélectivement la rechute d'alcool induite par les signaux et la gravité des symptômes d'AUD. Ce mécanisme est basé sur l'activité régulée de la protéine associée au cytosquelette (ARC)/plasticité dépendante de l'Arg3.1 des synapses de l'amygdale. Chez l'homme, nous avons identifié des polymorphismes mononucléotidiques dans le gène ARC et leur méthylation prédisant non seulement la taille de l'amygdale, mais aussi la fréquence de la consommation d'alcool, même au début de la consommation régulière. Cibler l'arc pendant l'exposition à l'alcool peut donc être un nouveau mécanisme sélectif pour la prévention des rechutes. El trastorno por consumo de alcohol (TCA) es una enfermedad crónica y mortal. El principal impedimento de la terapia AUD es una alta probabilidad de recaída en el abuso de alcohol incluso después de una abstinencia prolongada. Los mecanismos moleculares de la recaída inducida por señales no están bien establecidos, a pesar de que pueden ofrecer nuevas dianas para el tratamiento de la AUD. Utilizando un modelo animal integral de AUD, manipulaciones genéticas mediadas por virus y dirigidas a la amígdala mediante tecnología CRISPR/Cas9 y electrofisiología ex vivo, identificamos un mecanismo que controla selectivamente la recaída de alcohol inducida por señales y la gravedad de los síntomas de AUD. Este mecanismo se basa en la actividad regulada de la proteína asociada al citoesqueleto (ARC)/plasticidad dependiente de Arg3.1 de las sinapsis de la amígdala. En humanos, identificamos polimorfismos de un solo nucleótido en el gen ARC y su metilación prediciendo no solo el tamaño de la amígdala, sino también la frecuencia del consumo de alcohol, incluso al inicio del consumo regular. Dirigirse a Arc durante la exposición al alcohol puede ser, por lo tanto, un nuevo mecanismo selectivo para la prevención de recaídas. Alcohol use disorder (AUD) is a chronic and fatal disease. The main impediment of the AUD therapy is a high probability of relapse to alcohol abuse even after prolonged abstinence. The molecular mechanisms of cue-induced relapse are not well established, despite the fact that they may offer new targets for the treatment of AUD. Using a comprehensive animal model of AUD, virally-mediated and amygdala-targeted genetic manipulations by CRISPR/Cas9 technology and ex vivo electrophysiology, we identify a mechanism that selectively controls cue-induced alcohol relapse and AUD symptom severity. This mechanism is based on activity-regulated cytoskeleton-associated protein (Arc)/ARG3.1-dependent plasticity of the amygdala synapses. In humans, we identified single nucleotide polymorphisms in the ARC gene and their methylation predicting not only amygdala size, but also frequency of alcohol use, even at the onset of regular consumption. Targeting Arc during alcohol cue exposure may thus be a selective new mechanism for relapse prevention. Alcohol use disorder (AUD) is a chronic and fatal disease. The main impediment of AUD therapy is a high probability of relapse to alcohol abuse even after prolonged abstinence. The molecular mechanisms of cue-induced relapse are not well established, despite the fact that they may offer new targets for the treatment of AUD. Using a comprehensive animal model of AUD, virally-mediated and amygdala-targeted genetic manipulations by CRISPR/Cas9 technology and ex vivo electrophysiology, we identify a mechanism that selectively controls cue-induced alcohol relapse and AUD symptom severity. This mechanism is based on activity-regulated cytoskeleton-associated protein (arc)/Arg3.1-dependent plasticity of the amygdala synapses. In humans, we identified single nucleotide polymorphisms in the ARC gene and their methylation predicting not only amygdala size, but also frequency of alcohol use, even at the onset of regular consumption. Targeting Arc during alcohol exposure may thus be a selective new mechanism for relapse prevention. اضطراب تعاطي الكحول (AUD) هو مرض مزمن ومميت. العائق الرئيسي لعلاج AUD هو احتمال كبير للانتكاس إلى تعاطي الكحول حتى بعد الامتناع عن ممارسة الجنس لفترات طويلة. الآليات الجزيئية للانتكاس الناجم عن الإشارة ليست راسخة، على الرغم من حقيقة أنها قد تقدم أهدافًا جديدة لعلاج AUD. باستخدام نموذج حيواني شامل من AUD، والتلاعب الجيني بوساطة فيروسية واستهداف اللوزة بواسطة تقنية CRISPR/Cas9 والفسيولوجيا الكهربية خارج الجسم الحي، نحدد آلية تتحكم بشكل انتقائي في انتكاس الكحول الناجم عن الإشارة وشدة أعراض AUD. تعتمد هذه الآلية على البروتين المرتبط بالهياكل الخلوية المنظم للنشاط (ARC )/ اللدونة المعتمدة على Arg3.1 في مشابك اللوزة الدماغية. في البشر، حددنا تعدد أشكال النيوكليوتيدات المفردة في جين القوس وتنبأت مثيلتها ليس فقط بحجم اللوزة، ولكن أيضًا بتكرار تعاطي الكحول، حتى في بداية الاستهلاك المنتظم. وبالتالي، قد يكون استهداف القوس أثناء التعرض للكحول آلية جديدة انتقائية للوقاية من الانتكاس.

A 48-year-old intoxicated man was admitted to a hospital with an acute subarachnoid hemorrhage from a blow to the head following a drinking session. Lidocaine jelly was used to facilitate intubation during cardiopulmonary resuscitation. While his heart resumed beating, he was classified as brain dead and his heart stopped 114 h after admission. His brain was soft and weighed 1.7 kg at autopsy. A small rupture (0.5 by 0.3 cm) of the left vertebral artery and diffuse subarachnoid hemorrhage were observed. Ethanol was detected only in the cerebrum, cerebellum and clotted blood in the superior sagittal sinus at 0.29, 0.15 and 0.12 mg/g, respectively. Lidocaine was also found in these areas at levels of 28, 24 and 7 ng/g, respectively. Significant amounts of ethanol were present in his brain because blood flow stopped after the injury. Smaller amounts of intubation-related lidocaine were probably distributed to the brain by limited cerebral circulation and remained there after circulation ceased. Toxicological analysis of the brain after death was useful for evaluating his state during treatment.

A 48-year-old intoxicated man was admitted to a hospital with an acute subarachnoid hemorrhage from a blow to the head following a drinking session. Lidocaine jelly was used to facilitate intubation during cardiopulmonary resuscitation. While his heart resumed beating, he was classified as brain dead and his heart stopped 114 h after admission. His brain was soft and weighed 1.7 kg at autopsy. A small rupture (0.5 by 0.3 cm) of the left vertebral artery and diffuse subarachnoid hemorrhage were observed. Ethanol was detected only in the cerebrum, cerebellum and clotted blood in the superior sagittal sinus at 0.29, 0.15 and 0.12 mg/g, respectively. Lidocaine was also found in these areas at levels of 28, 24 and 7 ng/g, respectively. Significant amounts of ethanol were present in his brain because blood flow stopped after the injury. Smaller amounts of intubation-related lidocaine were probably distributed to the brain by limited cerebral circulation and remained there after circulation ceased. Toxicological analysis of the brain after death was useful for evaluating his state during treatment.

The present study was designed to investigate: (1) the involvement of dopamine D(1) and D(2) receptors, and (2) the roles of these receptors and endogenous opioid systems (endorphinergic and enkephalinergic systems) in the ethanol-induced place preference in rats exposed to conditioned fear stress using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) induced a significant place preference. The selective D(1) receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H3-benzazepine)hydrochloride (SCH23390; 0.01 and 0.03 mg/kg, s.c.) and the selective D(2) receptor antagonist S(-)-5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2- methoxybenzamide (sulpiride; 20 and 40 mg/kg, s.c.) significantly attenuated the ethanol-induced place preference. The administration of ethanol (75 mg/kg, i.p.) tended to produce a place preference, but this effect was not significant. SCH23390 (0.03 mg/kg, s.c.) and sulpiride (40 mg/kg, s.c.) significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.). In addition, SCH23390 (0.03 mg/kg, s.c.) also significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12aalpha-octahydroquinolino[2,3,3,-g]isoquinoline (TAN-67; 20 mg/kg, s.c.). On the other hand, sulpiride (40 mg/kg) had no significant effect on the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by TAN-67. These results suggest that D(1) and D(2) receptors may be involved in the rewarding mechanism of ethanol under psychological stress. In addition, D(1) receptors may participate in the rewarding effect of ethanol modulated by the activation of mu- and delta-opioid receptors, whereas D(2) receptors may participate in the rewarding effect of ethanol modulated by the activation of mu-opioid receptors, but not in that modulated by the activation of delta-opioid receptors.

The present study was designed to investigate: (1) the involvement of dopamine D(1) and D(2) receptors, and (2) the roles of these receptors and endogenous opioid systems (endorphinergic and enkephalinergic systems) in the ethanol-induced place preference in rats exposed to conditioned fear stress using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) induced a significant place preference. The selective D(1) receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H3-benzazepine)hydrochloride (SCH23390; 0.01 and 0.03 mg/kg, s.c.) and the selective D(2) receptor antagonist S(-)-5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2- methoxybenzamide (sulpiride; 20 and 40 mg/kg, s.c.) significantly attenuated the ethanol-induced place preference. The administration of ethanol (75 mg/kg, i.p.) tended to produce a place preference, but this effect was not significant. SCH23390 (0.03 mg/kg, s.c.) and sulpiride (40 mg/kg, s.c.) significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.). In addition, SCH23390 (0.03 mg/kg, s.c.) also significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12aalpha-octahydroquinolino[2,3,3,-g]isoquinoline (TAN-67; 20 mg/kg, s.c.). On the other hand, sulpiride (40 mg/kg) had no significant effect on the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by TAN-67. These results suggest that D(1) and D(2) receptors may be involved in the rewarding mechanism of ethanol under psychological stress. In addition, D(1) receptors may participate in the rewarding effect of ethanol modulated by the activation of mu- and delta-opioid receptors, whereas D(2) receptors may participate in the rewarding effect of ethanol modulated by the activation of mu-opioid receptors, but not in that modulated by the activation of delta-opioid receptors.