Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism

被引：57

作者：

Meinhardt, Marcus W. ^{[1
]}

Pfarr, Simone ^{[1
]}

Fouquet, Gregory ^{[2
]}

Rohleder, Cathrin ^{[3
,4
,5
,6
,7
]}

Meinhardt, Manuela L. ^{[1
]}

Barroso-Flores, Janet ^{[1
]}

Hoffmann, Rebecca ^{[1
]}

Jeanblanc, Jerome ^{[2
]}

Paul, Elisabeth ^{[1
]}

Wagner, Konstantin ^{[1
]}

Hansson, Anita C. ^{[1
]}

Koehr, Georg ^{[1
,8
]}

Meier, Nils ^{[9
]}

Halbach, Oliver von Bohlen und ^{[9
]}

Bell, Richard L. ^{[10
]}

Endepols, Heike ^{[4
,5
,6
,11
,12
]}

Neumaier, Bernd ^{[4
,5
,9
]}

Schoenig, Kai ^{[13
]}

Bartsch, Dusan ^{[13
]}

Naassila, Mickael ^{[2
]}

Spanagel, Rainer ^{[1
]}

Sommer, Wolfgang H. ^{[1
,14
]}

机构：

[1] Heidelberg Univ, Med Fac Mannheim, Inst Psychopharmacol, Cent Inst Mental Hlth, D-68159 Mannheim, Germany

[2] Univ Picardie Jules Verne, INSERM UMRS 1247, Amiens, France

[3] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany

[4] Univ Cologne, Fac Med, Inst Radiochem & Expt Mol Imaging, Cologne, Germany

[5] Univ Cologne, Univ Hosp Cologne, Cologne, Germany

[6] Max Planck Inst Neurol Res, Dept Multimodal Imaging, Cologne, Germany

[7] Univ Sydney, Brain & Mind Ctr, Sydney, NSW, Australia

[8] Heidelberg Univ, Med Fac Mannheim, Dept Neurophysiol, Mannheim, Germany

[9] Univ Med Greifswald, Inst Anat & Cell Biol, Greifswald, Germany

[10] Indiana Univ Sch Med, Stark Neurosci Res Inst, Dept Psychiat, Indianapolis, IN 46202 USA

[11] Univ Cologne, Fac Med, Dept Nucl Med, Cologne, Germany

[12] Forschungszentrum Julich, Nucl Chem INM 5, Inst Neurosci & Med, Julich, Germany

[13] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Mol Biol, Mannheim, Germany

[14] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Addict Med, Mannheim, Germany

来源：

SCIENCE ADVANCES | 2021年 / 7卷 / 47期

关键词：

METABOTROPIC GLUTAMATE RECEPTORS; POSITIVE ALLOSTERIC MODULATOR; HALLUCINOGENIC DRUG; AGONIST LY379268; ANIMAL-MODELS; RATS; REINSTATEMENT; FLEXIBILITY; SENSITIVITY; PHYSIOLOGY;

D O I：

10.1126/sciadv.abh2399

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood, and new effective pharmacological treatments are desired. Here, using a bidirectional neuromodulation approach, we demonstrate a causal link between reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. A neuron-specific prefrontal mGluR2 knockdown in rats generated a phenotype of reduced cognitive flexibility and excessive alcohol seeking. Conversely, virally restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. In the search for a pharmacological intervention with high translational potential, psilocybin was capable of restoring mGluR2 expression and reducing relapse behavior. Last, we propose a FDG-PET biomarker strategy to identify mGluR2 treatment-responsive individuals. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving and provided a personalized mGluR2 mechanism-based intervention strategy for medication development for alcoholism.

引用

页数：13

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