Universität zu Köln

Schneider, Miriam, Kasanetz, Fernando ORCID: 0000-0003-4585-2314, Lynch, Diane L., Friemel, Chris M., Lassalle, Olivier ORCID: 0000-0002-8523-1988, Hurst, Dow P., Steindel, Frauke, Monory, Krisztina, Schaefer, Carola, Miederer, Isabelle, Leweke, F. Markus ORCID: 0000-0002-8163-195X, Schreckenberger, Mathias, Lutz, Beat, Reggio, Patricia H., Manzoni, Olivier J. and Spanagel, Rainer (2015). Enhanced Functional Activity of the Cannabinoid Type-1 Receptor Mediates Adolescent Behavior. J. Neurosci., 35 (41). S. 13975 - 13989. WASHINGTON: SOC NEUROSCIENCE. ISSN 0270-6474

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schneider, Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED Kasanetz, Fernando UNSPECIFIED orcid.org/0000-0003-4585-2314 UNSPECIFIED Lynch, Diane L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Friemel, Chris M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lassalle, Olivier UNSPECIFIED orcid.org/0000-0002-8523-1988 UNSPECIFIED Hurst, Dow P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Steindel, Frauke UNSPECIFIED UNSPECIFIED UNSPECIFIED Monory, Krisztina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaefer, Carola UNSPECIFIED UNSPECIFIED UNSPECIFIED Miederer, Isabelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Leweke, F. Markus UNSPECIFIED orcid.org/0000-0002-8163-195X UNSPECIFIED Schreckenberger, Mathias UNSPECIFIED UNSPECIFIED UNSPECIFIED Lutz, Beat UNSPECIFIED UNSPECIFIED UNSPECIFIED Reggio, Patricia H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Manzoni, Olivier J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Spanagel, Rainer UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-389800
DOI:	10.1523/JNEUROSCI.1937-15.2015
Journal or Publication Title:	J. Neurosci.
Volume:	35
Number:	41
Page Range:	S. 13975 - 13989
Date:	2015
Publisher:	SOC NEUROSCIENCE
Place of Publication:	WASHINGTON
ISSN:	0270-6474
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SYNAPTIC-TRANSMISSION; MOLECULAR-DYNAMICS; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; DOPAMINE NEURONS; KNOCKOUT MICE; RATS; REWARD; ADULT; BRAIN Multiple languages Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38980