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Activation of glucagon‐like peptide‐1 receptors in the nucleus accumbens attenuates cocaine seeking in rats
Author(s) -
Hernandez Nicole S.,
O'Donovan Bernadette,
Ortinski Pavel I.,
Schmidt Heath D.
Publication year - 2019
Publication title -
addiction biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.445
H-Index - 78
eISSN - 1369-1600
pISSN - 1355-6215
DOI - 10.1111/adb.12583
Subject(s) - nucleus accumbens , medium spiny neuron , excitatory postsynaptic potential , agonist , postsynaptic potential , receptor , conditioned place preference , dopamine , pharmacology , chemistry , neuroscience , endocrinology , medicine , psychology , striatum
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.