Activation of glucagon-like peptide-1 receptors in the nucleus accumbens attenuates cocaine seeking in rats

Addict Biol. 2019 Mar;24(2):170-181. doi: 10.1111/adb.12583. Epub 2017 Dec 11.

Abstract

Recent evidence indicates that activation of glucagon-like peptide-1 (GLP-1) receptors reduces cocaine-mediated behaviors and cocaine-evoked dopamine release in the nucleus accumbens (NAc). However, no studies have examined the role of NAc GLP-1 receptors in the reinstatement of cocaine-seeking behavior, an animal model of relapse. Here, we show that systemic infusion of a behaviorally relevant dose of the GLP-1 receptor agonist exendin-4 penetrated the brain and localized with neurons and astrocytes in the NAc. Administration of exendin-4 directly into the NAc core and shell subregions significantly attenuated cocaine priming-induced reinstatement of drug-seeking behavior. These effects were not due to deficits in operant responding or suppression of locomotor activity as intra-accumbal exendin-4 administration had no effect on sucrose-seeking behavior. To determine the effects of GLP-1 receptor activation on neuronal excitability, exendin-4 was bath applied to ex vivo NAc slices from cocaine-experienced and saline-experienced rats following extinction of cocaine-taking behavior. Exendin-4 increased the frequency of action potential firing of NAc core and shell medium spiny neurons in cocaine-experienced rats while no effect was observed in saline controls. In contrast, exendin-4 did not affect the frequency or amplitude of spontaneous excitatory postsynaptic currents or alter the paired-pulse ratios of evoked excitatory postsynaptic currents. These effects were not associated with altered expression of GLP-1 receptors in the NAc following cocaine self-administration. Taken together, these findings indicate that increased activation of GLP-1 receptors in the NAc during cocaine abstinence increases intrinsic, but not synaptic, excitability of medium spiny neurons and is sufficient to reduce cocaine-seeking behavior.

Keywords: glucagon-like peptide-1; nucleus accumbens; relapse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Conditioning, Operant / drug effects
  • Dopamine Uptake Inhibitors / pharmacology*
  • Drug-Seeking Behavior / drug effects*
  • Exenatide / pharmacology
  • Extinction, Psychological / drug effects
  • Glucagon-Like Peptide-1 Receptor / antagonists & inhibitors
  • Glucagon-Like Peptide-1 Receptor / physiology*
  • Male
  • Neurons / drug effects
  • Nucleus Accumbens / physiology*
  • Rats, Sprague-Dawley

Substances

  • Dopamine Uptake Inhibitors
  • Glucagon-Like Peptide-1 Receptor
  • Exenatide
  • Cocaine