title: Enhanced Functional Activity of the Cannabinoid Type-1 Receptor Mediates Adolescent Behavior.
abstract: Adolescence is characterized by drastic behavioral adaptations and comprises a particularly vulnerable period for the emergence of various psychiatric disorders. Growing evidence reveals that the pathophysiology of these disorders might derive from aberrations of normal neurodevelopmental changes in the adolescent brain. Understanding the molecular underpinnings of adolescent behavior is therefore critical for understanding the origin of psychopathology, but the molecular mechanisms that trigger adolescent behavior are unknown. Here, we hypothesize that the cannabinoid type-1 receptor (CB1R) may play a critical role in mediating adolescent behavior because enhanced endocannabinoid (eCB) signaling has been suggested to occur transiently during adolescence. To study enhanced CB1R signaling, we introduced a missense mutation (F238L) into the rat Cnr1 gene that encodes for the CB1R. According to our hypothesis, rats with the F238L mutation (Cnr1(F238L)) should sustain features of adolescent behavior into adulthood. Gain of function of the mutated receptor was demonstrated by in silico modeling and was verified functionally in a series of biochemical and electrophysiological experiments. Mutant rats exhibit an adolescent-like phenotype during adulthood compared with wild-type littermates, with typical high risk/novelty seeking, increased peer interaction, enhanced impulsivity, and augmented reward sensitivity for drug and nondrug reward. Partial inhibition of CB1R activity in Cnr1(F238L) mutant rats normalized behavior and led to a wild-type phenotype. We conclude that the activity state and functionality of the CB1R is critical for mediating adolescent behavior. These findings implicate the eCB system as an important research target for the neuropathology of adolescent-onset mental health disorders.
  
  
  CONCLUSIONS
  We present the first rodent model with a gain-of-function mutation in the cannabinoid type-1 receptor (CB1R). Adult mutant rats exhibit an adolescent-like phenotype with typical high risk seeking, impulsivity, and augmented drug and nondrug reward sensitivity. Adolescence is a critical period for suboptimal behavioral choices and the emergence of neuropsychiatric disorders. Understanding the basis of these disorders therefore requires a comprehensive knowledge of how adolescent neurodevelopment triggers behavioral reactions. Our behavioral observations in adult mutant rats, together with reports on enhanced adolescent CB1R signaling, suggest a pivotal role for the CB1R in an adolescent brain as an important molecular mediator of adolescent behavior. These findings implicate the endocannabinoid system as a notable research target for adolescent-onset mental health disorders.
authors.affiliation: Institute of Psychopharmacology and Research Group Developmental Neuropsychopharmacology, Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany, miriam.schneider@zi-mannheim.de.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schneider
authors.affiliation: INSERM, Neurocentre Magendie, and University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Fernando
authors.initials: F
authors.lastname: Kasanetz
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina 27402.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Lynch
authors.affiliation: Research Group Developmental Neuropsychopharmacology, Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
authors.forename: Chris M
authors.identifier: http://orcid.org/0000-0002-0537-0970
authors.initials: CM
authors.lastname: Friemel
authors.affiliation: INSERM, U901, Marseille 13009, France, Université de la Méditerranée, UMR S901 Aix-Marseille 2, France, INMED, Marseille 13009, France.
authors.forename: Olivier
authors.identifier: http://orcid.org/0000-0002-8523-1988
authors.initials: O
authors.lastname: Lassalle
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina 27402.
authors.forename: Dow P
authors.initials: DP
authors.lastname: Hurst
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Steindel
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
authors.forename: Krisztina
authors.identifier: http://orcid.org/0000-0002-1548-7718
authors.initials: K
authors.lastname: Monory
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany, Department of Psychiatry and Psychotherapy, University of Cologne, 50924 Cologne, Germany, and.
authors.forename: Carola
authors.initials: C
authors.lastname: Schäfer
authors.affiliation: Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Miederer
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
authors.forename: F Markus
authors.identifier: http://orcid.org/0000-0002-8163-195X
authors.initials: FM
authors.lastname: Leweke
authors.affiliation: Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Schreckenberger
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina 27402.
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Reggio
authors.affiliation: INSERM, U901, Marseille 13009, France, Université de la Méditerranée, UMR S901 Aix-Marseille 2, France, INMED, Marseille 13009, France.
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Manzoni
authors.affiliation: Institute of Psychopharmacology and.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
mesh_terms: D000293:Adolescent; D000294:Adolescent Behavior / Q000502:physiology*; D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000254:growth & development; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage; D003342:Corpus Striatum / Q000166:cytology; D063388:Endocannabinoids / Q000378:metabolism / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D011877:Radionuclide Imaging; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D012309:Risk-Taking; D012919:Social Behavior; D013460:Sulfur Isotopes / Q000493:pharmacokinetics
chemical_list: C578453:CNR1 protein, mouse; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D013460:Sulfur Isotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D003042:Cocaine
keywords: CB1 receptor; ENU mutagenesis; adolescence; endocannabinoids; reward processing; risk seeking