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Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype.
Biol Psychiatry 2017; 82(7):500-510BP

Abstract

BACKGROUND

Corticotropin-releasing factor (CRF) mediates anxiogenic responses by activating CRF type 1 (CRF1) receptors in limbic brain regions. Anxiety is further modulated by the endogenous cannabinoid (eCB) system that attenuates the synaptic effects of stress. In the amygdala, acute stress activates the enzymatic clearance of the eCB N-arachidonoylethanolamine via fatty acid amide hydrolase (FAAH), although it is unclear whether chronic dysregulation of CRF systems induces maladaptive changes in amygdalar eCB signaling. Here, we used genetically selected Marchigian Sardinian P (msP) rats carrying an innate overexpression of CRF1 receptors to study the role of constitutive upregulation in CRF systems on amygdalar eCB function and persistent anxiety-like effects.

METHODS

We applied behavioral, pharmacological, and biochemical methods to broadly characterize anxiety-like behaviors and amygdalar eCB clearance enzymes in msP versus nonselected Wistar rats. Subsequent studies examined the influence of dysregulated CRF and FAAH systems in altering excitatory transmission in the central amygdala (CeA).

RESULTS

msPs display an anxious phenotype accompanied by elevations in amygdalar FAAH activity and reduced dialysate N-arachidonoylethanolamine levels in the CeA. Elevations in CRF-CRF1 signaling dysregulate FAAH activity, and this genotypic difference is normalized with pharmacological blockade of CRF1 receptors. msPs also exhibit elevated baseline glutamatergic transmission in the CeA, and dysregulated CRF-FAAH facilitates stress-induced increases in glutamatergic activity. Treatment with an FAAH inhibitor relieves sensitized glutamatergic responses in msPs and attenuates the anxiety-like phenotype.

CONCLUSIONS

Pathological anxiety and stress hypersensitivity are driven by constitutive increases in CRF1 signaling that dysregulate N-arachidonoylethanolamine signaling mechanisms and reduce neuronal inhibitory control of CeA glutamatergic synapses.

Authors+Show Affiliations

Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California; Virginia Tech School of Neuroscience, Virginia Tech, Blacksburg, Virginia.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California.School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California. Electronic address: mroberto@scripps.edu.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28209423

Citation

Natividad, Luis A., et al. "Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype." Biological Psychiatry, vol. 82, no. 7, 2017, pp. 500-510.
Natividad LA, Buczynski MW, Herman MA, et al. Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype. Biol Psychiatry. 2017;82(7):500-510.
Natividad, L. A., Buczynski, M. W., Herman, M. A., Kirson, D., Oleata, C. S., Irimia, C., ... Parsons, L. H. (2017). Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype. Biological Psychiatry, 82(7), pp. 500-510. doi:10.1016/j.biopsych.2017.01.005.
Natividad LA, et al. Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype. Biol Psychiatry. 2017 Oct 1;82(7):500-510. PubMed PMID: 28209423.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype. AU - Natividad,Luis A, AU - Buczynski,Matthew W, AU - Herman,Melissa A, AU - Kirson,Dean, AU - Oleata,Christopher S, AU - Irimia,Cristina, AU - Polis,Ilham, AU - Ciccocioppo,Roberto, AU - Roberto,Marisa, AU - Parsons,Loren H, Y1 - 2017/01/13/ PY - 2016/09/20/received PY - 2016/12/21/revised PY - 2017/01/04/accepted PY - 2017/2/18/pubmed PY - 2018/5/9/medline PY - 2017/2/18/entrez KW - Anxiety KW - CRF1 KW - Central amygdala (CeA) KW - Endocannabinoid KW - Excitatory KW - Glutamate SP - 500 EP - 510 JF - Biological psychiatry JO - Biol. Psychiatry VL - 82 IS - 7 N2 - BACKGROUND: Corticotropin-releasing factor (CRF) mediates anxiogenic responses by activating CRF type 1 (CRF1) receptors in limbic brain regions. Anxiety is further modulated by the endogenous cannabinoid (eCB) system that attenuates the synaptic effects of stress. In the amygdala, acute stress activates the enzymatic clearance of the eCB N-arachidonoylethanolamine via fatty acid amide hydrolase (FAAH), although it is unclear whether chronic dysregulation of CRF systems induces maladaptive changes in amygdalar eCB signaling. Here, we used genetically selected Marchigian Sardinian P (msP) rats carrying an innate overexpression of CRF1 receptors to study the role of constitutive upregulation in CRF systems on amygdalar eCB function and persistent anxiety-like effects. METHODS: We applied behavioral, pharmacological, and biochemical methods to broadly characterize anxiety-like behaviors and amygdalar eCB clearance enzymes in msP versus nonselected Wistar rats. Subsequent studies examined the influence of dysregulated CRF and FAAH systems in altering excitatory transmission in the central amygdala (CeA). RESULTS: msPs display an anxious phenotype accompanied by elevations in amygdalar FAAH activity and reduced dialysate N-arachidonoylethanolamine levels in the CeA. Elevations in CRF-CRF1 signaling dysregulate FAAH activity, and this genotypic difference is normalized with pharmacological blockade of CRF1 receptors. msPs also exhibit elevated baseline glutamatergic transmission in the CeA, and dysregulated CRF-FAAH facilitates stress-induced increases in glutamatergic activity. Treatment with an FAAH inhibitor relieves sensitized glutamatergic responses in msPs and attenuates the anxiety-like phenotype. CONCLUSIONS: Pathological anxiety and stress hypersensitivity are driven by constitutive increases in CRF1 signaling that dysregulate N-arachidonoylethanolamine signaling mechanisms and reduce neuronal inhibitory control of CeA glutamatergic synapses. SN - 1873-2402 UR - https://www.unboundmedicine.com/medline/citation/28209423/Constitutive_Increases_in_Amygdalar_Corticotropin_Releasing_Factor_and_Fatty_Acid_Amide_Hydrolase_Drive_an_Anxious_Phenotype_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-3223(17)30037-9 DB - PRIME DP - Unbound Medicine ER -