Abstract
The endocannabinoid system and the cannabinoid type 1 receptor (CB1R) are required for the extinction of conditioned fear. CB1 antagonists have been shown to prevent extinction when delivered both systemically and within the amygdala. Anatomical studies suggest that CB1Rs in the basolateral amygdala (BLA) are expressed on GABAergic interneurons expressing the anxiogenic peptide cholecystokinin (CCK). Pre-synaptic CB1Rs inhibit neurotransmitter release, suggesting that CB1R activation during extinction may decrease CCK peptide release as well as GABA release. Thus, we examined whether extinction involves the CB1R modulation of CCK2 receptor activation. We found that intracerebroventricular administration of the CCK2 agonist pentagastrin dose-dependently impaired extinction of conditioned fear. Systemic administration of a CB1 antagonist, rimonabant (SR141716), also potently inhibited extinction learning. This effect was ameliorated with systemic administration of a CCK2 antagonist, CR2945. Furthermore, the extinction blockade by systemic SR141716 was reversed with intra-BLA, but not intrastriatal, infusion of CR2945. Lastly, as extinction usually leads to an increase in Akt phosphorylation, a biochemical effect antagonized by systemic CB1 antagonist treatment, we examined whether CR2945 co-administration would increase extinction-induced p-Akt levels. We observed that extinction-trained animals showed increased Akt phosphorylation following extinction, CB1 antagonist-treated animals showed p-Akt levels similar to those of non-extinction trained animals, and co-administration of CR2945 with SR141716 led to levels of p-Akt similar to those of vehicle-treated, extinction-trained controls. Together, these data suggest that interactions between the endocannabinoid and CCKergic transmitter systems may underlie the process of extinction of conditioned fear.
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Acknowledgements
This work was supported by NIH (DA019624, MH074097, MH069884, MH070218, MH47840, MH067314), NARSAD, the Center for Behavioral Neuroscience (NSF agreement IBN-987675), The Woodruff Foundation, and by an NIH/NCRR base grant (P51RR000165) to Yerkes National Primate Research Center. JPC is supported by an NIH MD/PhD predoctoral fellowship (NRSA). We thank George Toth, Michael Bowser, and Kevin Hertzberg for excellent technical support in performing these studies, and Karyn Myers for helpful comments.
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KJR, MD, and JPC have filed a provisional patent application for the use of enhancers of eCB transmission to augment extinction in clinical settings. Notably, no drugs of this type were used in these studies. KJR has received research support from Lundbeck Pharmaceuticals, LLC. KJR has received consultation fees from Tikvah Pharmaceuticals, LLC.
Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)
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Chhatwal, J., Gutman, A., Maguschak, K. et al. Functional Interactions between Endocannabinoid and CCK Neurotransmitter Systems May Be Critical for Extinction Learning. Neuropsychopharmacol 34, 509–521 (2009). https://doi.org/10.1038/npp.2008.97
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DOI: https://doi.org/10.1038/npp.2008.97