Vesicular glutamate transporter 2-containing neurons of the centrally-projecting Edinger-Westphal nucleus regulate alcohol drinking and body temperature

• Published in: Neuropharmacology Vol. 200; p. 108795
• Main Authors: Zuniga, Alfredo, Smith, Monique L., Caruso, Maya, Ryabinin, Andrey E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2021
• Subjects: Alcohol; Alcohol Drinking - pathology; Animals; Body Temperature - drug effects; Body Temperature Regulation - drug effects; Centrally-projecting edinger westphal; Dependovirus; Designer Drugs - pharmacology; Designer receptors exclusively activated by designer drugs; Edinger-Westphal Nucleus - drug effects; Ethanol - pharmacology; Glutamate; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Thermoregulation; Urocortin; Urocortins - drug effects; Vesicular Glutamate Transport Protein 2 - drug effects; Thermoregulation; Urocortin; Alcohol; Glutamate; Designer receptors exclusively activated by designer drugs; Centrally-projecting edinger westphal
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2021.108795

Previous studies in rodents have repeatedly demonstrated that the centrally-projecting Edinger-Westphal nucleus (EWcp) is highly sensitive to alcohol and is also involved in regulating alcohol intake and body temperature. Historically, the EWcp has been known as the main site of Urocortin 1 (Ucn1) expression, a corticotropin-releasing factor-related peptide, in the brain. However, the EWcp also contains other populations of neurons, including neurons that express the vesicular glutamate transporter 2 (Vglut2). Here we transduced the EWcp with adeno-associated viruses (AAVs) encoding Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to test the role of the EWcp in alcohol drinking and in the regulation of body temperature. Activation of the EWcp with excitatory DREADDs inhibited alcohol intake in a 2-bottle choice procedure in male C57BL/6J mice, whereas inhibition of the EWcp with DREADDs had no effect. Surprisingly, analysis of DREADD expression indicated Ucn1-containing neurons of the EWcp did not express DREADDs. In contrast, AAVs transduced non-Ucn1-containing EWcp neurons. Subsequent experiments showed that the inhibitory effect of EWcp activation on alcohol intake was also present in male Ucn1 KO mice, suggesting that a Ucn1-devoid population of EWcp regulates alcohol intake. A final set of chemogenetic experiments showed that activation of Vglut2-expressing EWcp neurons inhibited alcohol intake and induced hypothermia in male and female mice. These studies expand on previous literature by indicating that a glutamatergic, Ucn1-devoid subpopulation of the EWcp regulates alcohol consumption and body temperature. •Activation, but not inhibition, of the EWcp using DREADDs decreased alcohol intake in mice.•AAVs did not lead to DREADD expression in Ucn1-containing neurons of the EWcp.•Activation of the EWcp using DREADDs decreased alcohol intake in Ucn1 knockout mice.•Activation of Vglut2 neurons of the EWcp using DREADDs inhibited alcohol intake.•Activation of Vglut2 neurons of the EWcp using DREADDs reduced body temperature.