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Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.

Title: Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.
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Name(s): Reddy, I A, author
Pino, J A, author
Weikop, P, author
Osses, N, author
Sørensen, G, author
Bering, T, author
Valle, C, author
Bluett, R J, author
Erreger, K, author
Wortwein, G, author
Reyes, J G, author
Graham, D, author
Stanwood, G D, author
Hackett, T A, author
Patel, S, author
Fink-Jensen, A, author
Torres, G E, author
Galli, A, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2016-05-17
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA.
Identifier: FSU_pmch_27187231 (IID), 10.1038/tp.2016.86 (DOI), PMC5070047 (PMCID), 27187231 (RID), 27187231 (EID), tp201686 (PII)
Grant Number: R01 DA035263, R01 DA038058, U54 HD083211
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070047.
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_27187231
Owner Institution: FSU
Is Part Of: Translational psychiatry.
2158-3188
Issue: vol. 6

Choose the citation style.
Reddy, I. A., Pino, J. A., Weikop, P., Osses, N., Sørensen, G., Bering, T., … Galli, A. (2016). Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels. Translational Psychiatry. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_27187231