GLP-1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA

Dec 1, 2020Molecular psychiatry

GLP-1 signals in a brain area controlling motivation reduce cocaine seeking by activating inhibitory circuits linked to the reward system

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Abstract

Administration of the GLP-1R agonist exendin-4 (Ex-4) into the LDTg significantly reduced cocaine seeking behavior without affecting other behaviors.

Targeting GLP-1 receptors may offer a new treatment approach for cocaine use disorder.
The laterodorsal tegmental nucleus (LDTg) connects key brain areas involved in cocaine-seeking behavior.
Activating circuits from the nucleus tractus solitarius (NTS) to the LDTg can reduce cocaine seeking through a GLP-1R-dependent mechanism.
GLP-1 receptors are primarily found on GABAergic neurons in the LDTg.
The effectiveness of Ex-4 in diminishing cocaine seeking is partly reliant on the activation of GABAergic projections from the LDTg to the ventral tegmental area (VTA).

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An emerging preclinical literature suggests that targeting central glucagon-like peptide-1 receptors (GLP-1Rs) may represent a novel approach to treating cocaine use disorder. However, the exact neural circuits and cell types that mediate the suppressive effects of GLP-1R agonists on cocaine-seeking behavior are largely unknown. The laterodorsal tegmental nucleus (LDTg) expresses GLP-1Rs and functions as a neuroanatomical hub connecting the nucleus tractus solitarius (NTS), the primary source of central GLP-1, with midbrain and forebrain nuclei known to regulate cocaine-seeking behavior. The goal of this study was to characterize the role of LDTg GLP-1R-expressing neurons and their projections to the ventral tegmental area (VTA) in the reinstatement of cocaine-seeking behavior, an animal model of relapse. Here, we showed that administration of the GLP-1R agonist exendin-4 (Ex-4) directly into the LDTg significantly attenuated cocaine seeking at a dose that did not affect sucrose seeking, ad libitum food intake, or body weight. In addition, our studies revealed that selectively activating NTS-to-LDTg circuits attenuated cocaine seeking via a GLP-1R-dependent mechanism. We also demonstrated, for the first time, that GLP-1Rs are expressed primarily on GABAergic neurons in the LDTg and that the efficacy of Ex-4 to reduce cocaine seeking depends, in part, on activation of LDTg-to-VTA GABAergic projections. Taken together, these studies identify a central mechanism by which Ex-4 attenuates cocaine seeking and highlight GABAergic GLP-1R-expressing circuits in the midbrain as important anti-craving pathways in regulating cocaine craving-induced relapse.

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GLP-1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA

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