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The Journal of Neuroscience, June 21, 2006, 26(25):6677-6686; doi:10.1523/JNEUROSCI.0153-06.2006

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Behavioral/Systems/Cognitive
Cannabinoid CB1 Receptor Mediates Fear Extinction via Habituation-Like Processes

Kornelia Kamprath,¹ Giovanni Marsicano,^2,4 Jianrong Tang,¹ Krisztina Monory,^2,4 Tiziana Bisogno,³ Vincenzo Di Marzo,³ Beat Lutz,^2,4 and Carsten T. Wotjak¹

¹Neuronal Plasticity/Mouse Behavior Group and ²Molecular Genetics of Behavior Group, Max Planck Institute of Psychiatry, D-80804 Munich, Germany, ³Endocannabinoid Research Group, Institute Biomolecular Chemistry, 80078 Pozzuoli/Naples, Italy, and ⁴Department of Physiological Chemistry, Johannes Gutenberg University, 51099 Mainz, Germany

Correspondence should be addressed to Dr. Carsten T. Wotjak at the above address. Email: wotjak{at}mpipsykl.mpg.de

The interplay between fear expression and fear extinction provides an important prerequisite for adequate coping with aversive encounters. Current models propose that extinction of conditioned fear is mediated by associative safety learning. Here, we demonstrate that the cannabinoid CB1 receptor, which is crucially involved in fear extinction, is dispensable for associative safety learning. In fact, our results indicate that CB1 mediates fear extinction primarily via habituation-like processes. CB1 null-mutant mice were severely impaired not only in extinction of the fear response to a tone after fear conditioning but also in habituation of the fear response to a tone after sensitization with an inescapable footshock. Surprisingly, long-term habituation was generally affected even in situations with proper short-term adaptation, suggesting the existence of two separated CB1-dependent effector systems for short- and long-term fear adaptation. Our findings underscore the importance of habituation as a determinant of fear extinction in mice and characterize the cannabinoid CB1 receptor as an essential molecular correlate of this process.

Key words: sensitization; fear conditioning; anxiety; memory; endocannabinoids; stress

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Received Jan. 13, 2006; revised April 5, 2006; accepted April 25, 2006.

Correspondence should be addressed to Dr. Carsten T. Wotjak at the above address. Email: wotjak{at}mpipsykl.mpg.de

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