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. 2012 Jun 25;106(4):574-8.
doi: 10.1016/j.physbeh.2012.03.014. Epub 2012 Mar 19.

Exendin-4 decreases amphetamine-induced locomotor activity

Kevin Erreger  1 , Adeola R Davis, Amanda M Poe, Nigel H Greig, Gregg D Stanwood, Aurelio Galli
Affiliations

Exendin-4 decreases amphetamine-induced locomotor activity

Kevin Erreger et al. Physiol Behav. .

Abstract

Glucagon-like peptide-1 (GLP-1) is released in response to nutrient ingestion and is a regulator of energy metabolism and consummatory behaviors through both peripheral and central mechanisms. The GLP-1 receptor (GLP-1R) is widely distributed in the central nervous system, however little is known about how GLP-1Rs regulate ambulatory behavior. The abused psychostimulant amphetamine (AMPH) promotes behavioral locomotor activity primarily by inducing the release of the neurotransmitter dopamine. Here, we identify the GLP-1R agonist exendin-4 (Ex-4) as a modulator of behavioral activation by AMPH. We report that in rats a single acute administration of Ex-4 decreases both basal locomotor activity as well as AMPH-induced locomotor activity. Ex-4 did not induce behavioral responses reflecting anxiety or aversion. Our findings implicate GLP-1R signaling as a novel modulator of psychostimulant-induced behavior and therefore a potential therapeutic target for psychostimulant abuse.

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Figures

Figure 1
Figure 1. Ex-4 decreases basal and AMPH-induced locomotor activity
A) The diagram depicts the timeline for the experimental protocol. Injection times are indicated by arrows. B) Locomotor activity is plotted in 5 min blocks for saline/AMPH (open black circles), Ex-4/AMPH (closed black squares), saline/saline (open gray circles), and Ex-4/saline (closed gray squares). Drugs were administered i.p. at the following doses: Ex-4 (30 μg/kg), AMPH (2.78 mg/kg). Statistical analysis across all 4 groups was performed by a 2 way ANOVA followed by Bonferroni post hoc tests. Stars indicate significant difference between saline/AMPH (open black circles) and EX-4/AMPH (closed black squares) groups (*p<0.05). C) Center distance was quantified throughout the locomotor experiment as an index of anxiety-like behavior. The relative distance traveled in the center of the chamber is expressed as a percentage of total distance. There was no significant difference between saline/AMPH (open black circles) and EX-4/AMPH (closed black squares) groups (2 way ANOVA p>0.05).
Figure 2
Figure 2. Ex-4 does not induce conditioned place aversion
A) Ex-4 (30 μg/kg, i.p.) decreases locomotor activity in the chamber during the training session compared with control saline treated animals. (***p<0.001; Student’s t-test). B) The difference score quantifies the change in the amount of time (s) spent on the drug associated side of the chamber induced by the drug exposure training. Ex-4 did not significantly alter the difference score compared to saline controls and was therefore not aversive. (p>0.05; Student’s t-test). Inset: As a positive control for the CPA assay, LiCl (127 mg/kg i.p.) treated rats displayed a significantly altered difference score compared to saline controls. (*p<0.01; Student’s t-test). The negative difference score indicates that rats spent less time on the chamber side associated with LiCl, reflecting CPA to LiCl administration.
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