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Functional interactions between endocannabinoid and CCK neurotransmitter systems may be critical for extinction learning.
Neuropsychopharmacology. 2009 Jan; 34(2):509-21.N

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.

Authors+Show Affiliations

Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

18580872

Citation

Chhatwal, Jasmeer P., et al. "Functional Interactions Between Endocannabinoid and CCK Neurotransmitter Systems May Be Critical for Extinction Learning." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 34, no. 2, 2009, pp. 509-21.
Chhatwal JP, Gutman AR, Maguschak KA, et al. Functional interactions between endocannabinoid and CCK neurotransmitter systems may be critical for extinction learning. Neuropsychopharmacology. 2009;34(2):509-21.
Chhatwal, J. P., Gutman, A. R., Maguschak, K. A., Bowser, M. E., Yang, Y., Davis, M., & Ressler, K. J. (2009). Functional interactions between endocannabinoid and CCK neurotransmitter systems may be critical for extinction learning. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 34(2), 509-21. https://doi.org/10.1038/npp.2008.97
Chhatwal JP, et al. Functional Interactions Between Endocannabinoid and CCK Neurotransmitter Systems May Be Critical for Extinction Learning. Neuropsychopharmacology. 2009;34(2):509-21. PubMed PMID: 18580872.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional interactions between endocannabinoid and CCK neurotransmitter systems may be critical for extinction learning. AU - Chhatwal,Jasmeer P, AU - Gutman,Alisa R, AU - Maguschak,Kimberly A, AU - Bowser,Michael E, AU - Yang,Yong, AU - Davis,Michael, AU - Ressler,Kerry J, Y1 - 2008/06/25/ PY - 2008/6/27/pubmed PY - 2009/2/24/medline PY - 2008/6/27/entrez SP - 509 EP - 21 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 34 IS - 2 N2 - 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. SN - 1740-634X UR - https://www.unboundmedicine.com/medline/citation/18580872/Functional_interactions_between_endocannabinoid_and_CCK_neurotransmitter_systems_may_be_critical_for_extinction_learning_ L2 - http://dx.doi.org/10.1038/npp.2008.97 DB - PRIME DP - Unbound Medicine ER -