4.7 Article

Enhanced Functional Activity of the Cannabinoid Type-1 Receptor Mediates Adolescent Behavior

Journal

JOURNAL OF NEUROSCIENCE
Volume 35, Issue 41, Pages 13975-13988

Publisher

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1937-15.2015

Keywords

adolescence; CB1 receptor; endocannabinoids; ENU mutagenesis; reward processing; risk seeking

Categories

Funding

  1. Bundesministerium fur Bildung und Forschung [01ZX1311A 36]
  2. Deutsche Forschungsgemeinschaft [SCHN 958/3-1, FOR926 SCHN 958/4-1 SP9, KFO256, GRK1044]
  3. MWK in Baden-Wurttemberg
  4. Focus Program Translational Neuroscience of the Johannes Gutenberg University Mainz
  5. National Institutes of Health [RO1 DA003934, KO5 DA021358]
  6. INSERM
  7. ANR Samenta Cannado

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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.

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