Journal
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
Volume 40, Issue 10, Pages 2247-2252Publisher
WILEY-BLACKWELL
DOI: 10.1111/acer.13199
Keywords
Alcohol; Intravenous Self-Administration; Exendin-4; Glucagon-Like Peptide 1; Mouse
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Funding
- NIDA NIH HHS [K99 DA027825, R43 DA041173, R44 DA041173, R00 DA027825] Funding Source: Medline
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BackgroundGlucagon-like peptide 1 (GLP-1) receptor agonists have been shown to decrease ethanol (EtOH) drinking in rodent assays. The GLP-1 system also powerfully modulates food and fluid intake, gastrointestinal functions, and metabolism. To begin to understand the neurobiological mechanisms by which GLP-1 receptor ligands may be able to control EtOH intake, it is important to ascertain whether they can modulate the direct reinforcing effects of EtOH, without the confound of effects on ingestive behaviors generally. MethodsWe trained experimentally naive, free-fed C57BL/6J mice to self-administer EtOH intravenously. Once stable EtOH intake was acquired, we tested the effect of acute pretreatment with the GLP-1 receptor agonist Exendin-4. Effect of Exendin-4 on operant behavior reinforced by a palatable liquid food was similarly evaluated as a control. ResultsIntravenous EtOH functioned as a positive reinforcer in over half the mice tested. In mice that acquired self-administration, EtOH intake was high, indeed, reaching toxic doses; 3.2g/kg Exendin-4 decreased intravenous EtOH intake by at least 70%, but had no significant effect on food-maintained operant responding. ConclusionsThis experiment produced 2 main conclusions. First, although technically challenging and yielding only moderate throughput, the intravenous self-administration procedure in mice is feasible, and sensitive to pharmacological manipulations. Second, GLP-1 receptor agonists can powerfully attenuate voluntary EtOH intake by directly modulating the reinforcing effects of EtOH. These findings support the potential usefulness of GLP-1 receptor ligands in the treatment of alcohol use disorder.
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