Administering glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) into the laterodorsal tegmental nucleus (LDTg) reduces cocaine-seeking behavior in individuals with cocaine use disorder, a new study found.

The study, published in Molecular Psychiatry, also reported for the first time that GLP-1Rs are expressed primarily on GABAergic neurons in the LDTg. The efficacy of Ex-4 on cocaine seeking depends, in part, the researchers found, on activation of LDTg-to-VTA GABAergic projections. These findings bring to light “important anti-craving pathways” to help prevent craving-induced relapse.

The researchers conducted behavioral testing on male Sprague–Dawley rats and transgenic rats. The researchers conducted 5 different experiments, including the effects of activating NTS-to-LDTg projections on cocaine seeking and the effects of LDTg GABA neuron-specific GLP-1R KD on cocaine taking and seeking.


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Among other conclusions, the researchers found activation of GLP-1Rs in the LDTg “decreases drug seeking and does not affect food intake or body weight in cocaine-experienced rats.” The drug crosses the blood-brain barrier and decreases cocaine-seeking without adverse effects.

They also found that activating NTS-to-LDTg circuits curbs drug seeking and does not affect food intake or body weight in cocaine-experienced rats. The activation works through a GLP-1-dependent mechanism. The drug Ex-4 reduces cocaine seeking by activating GLP-1Rs on inhibitory LDTg GABA neurons that project to the ventral tegmental area (VTA).

“Our findings highlight GLP-1R-expressing anti-craving circuits in the brain that could serve as potential targets to reduce cocaine craving-induced relapse,” the researchers concluded.

Reference

Hernandez NS, Weir VR, Ragnini K, et al. GLP-1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA. Mol Psychiatry. Published online November 30, 2020. doi:10.1038/s41380-020-00957-3