Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core.
Drugs of abuse increase the frequency and magnitude of brief (1-3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release - possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse.
Graduate Program in Neuroscience, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA. Electronic address: sforti2@uic.edu.
Samantha M
SM
Fortin
Graduate Program in Neuroscience, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA; Department of Psychology, University of Illinois at Chicago, 1007 W Harrison St, Chicago, IL 60607, USA. Electronic address: mroitman@uic.edu.
Mitchell F
MF
Roitman
D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004572:Electrolysis / Q000379:methods; D000077270:Exenatide; D000067758:Glucagon-Like Peptide-2 Receptor / Q000819:agonists / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014688:Venoms / Q000494:pharmacology
D018765:Dopamine Uptake Inhibitors; D000067758:Glucagon-Like Peptide-2 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D003042:Cocaine; D004298:Dopamine
Cocaine; Dopamine; Drug addiction; Glucagon-like peptide-1; Nucleus accumbens; Reward