Elsevier

Physiology & Behavior

Volume 106, Issue 4, 25 June 2012, Pages 574-578
Physiology & Behavior

Brief communication
Exendin-4 decreases amphetamine-induced locomotor activity

https://doi.org/10.1016/j.physbeh.2012.03.014Get rights and content

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.

Introduction

Glucagon-like peptide-1 (GLP-1) is an endogenous peptide secreted from the gastrointestinal tract in response to nutrient ingestion and is a physiological regulator of glucose homeostasis and food intake [1], [2]. The effects of GLP-1 are best understood in the pancreas where it enhances glucose-dependent insulin secretion. GLP-1 receptor (GLP-1R) agonists are currently in clinical use for the treatment of type II diabetes [3]. The first GLP-1 analog to be approved for human clinical use was exenatide, a synthetic form of the naturally occurring Gila monster (Heloderma suspectum) peptide exendin-4 (Ex-4). This peptide exhibits about 50% amino acid identity with human GLP-1 and is a potent agonist of human and rodent GLP-1Rs [4], [5]. While GLP-1 is rapidly inactivated in circulation by cleavage by the proteolytic enzyme dipeptidyl peptidase IV [6], Ex-4 is resistant to this cleavage. Thus Ex-4 has a significantly longer half-life and pharmacokinetic efficacy in vivo than GLP-1. Furthermore, systemically administered Ex-4 readily crosses the blood-brain barrier [7], [8], [9]. In this study, we used Ex-4 to investigate the effect of GLP-1R signaling on both basal locomotion and locomotor activation by AMPH. We also evaluated the behavioral effects of Ex-4 by using a conditioned place assay. This is a standard behavioral test for assessing the positive (“preference”) or negative (“aversion”) state that an animal associates with administration of a drug.

GLP-1Rs are broadly distributed throughout the central nervous system [10], [11]. In addition to release from the gut into circulation, GLP-1 is also produced in the brain by neurons in the nucleus tractus solitarius (NTS). NTS GLP-1 neurons project widely to brain regions including the ventral tegmental area (VTA) and the nucleus accumbens (NAc) [12], [13], [14], [15], [16], [17]. GLP-1R signaling in the brain is known to regulate food intake as well as other behaviors [16], [18], [19], [20].

There are well established links between regulation of food intake and responses to drugs of abuse [21], [22]. Several neuropeptides regulating food intake have also been demonstrated to modulate the behavioral responses to drugs of abuse including psychostimulants [23], [24], [25]. It has also been shown that GLP-1R signaling in brain regulates ambulatory activity [20], [26]. However, whether GLP-1R signaling can modulate the locomotor behavioral response to the abused psychostimulant amphetamine (AMPH) is unknown. We hypothesized that GLP-1R activation may regulate the locomotor activating properties of AMPH. Here, we demonstrate that in rats a single acute administration of the GLP-1R agonist Ex-4 blunts the locomotor activating response to AMPH, implicating GLP-1R signaling as a novel modulator of psychostimulant induced behavior.

Section snippets

Animals

Male Sprague–Dawley rats (275–300 g, Charles River) were housed in a facility kept on a 12-hour light cycle. Subjects were acclimated for one week and housed two per cage. After the week of acclimation, rats were handled and given an intraperitoneal (i.p.) saline injection (1 mL/kg) once a day for 3 days. All behavior tests were performed at the Vanderbilt Murine Neurobehavioral Lab core facility. Rats had continuous access to standard chow and water ad libitum in their home cages including on the

Ex-4 decreases basal and AMPH-induced locomotion

In Experiment 1, Ex-4 was used to investigate the effect of GLP-1R signaling on both basal locomotion and locomotor activation by AMPH. The schematic of the protocol is illustrated in Fig. 1A. Locomotor activity was monitored in 5 minute intervals and analyzed across all drug treatment groups over time by 2 way ANOVA followed by Bonferroni post hoc tests. Rats were placed in a locomotor activity chamber for 30 min and then given an i.p. injection of either Ex-4 or saline (Fig. 1B, white arrow).

Ex-4 regulates AMPH-induced locomotion

The major conclusion of this study is that systemic administration of the GLP1-R agonist Ex-4 decreases both basal and AMPH-induced locomotor activity (Fig. 1B). This observation may be specific to the drug dosage and timing of our protocol. Future studies characterizing the full dosage and time dependence of both Ex-4 and AMPH may be important in elucidating details of this effect. GLP-1 has previously been reported to decrease basal locomotor activity when injected (i.c.v.) directly into the

Funding source

NIH K99DA025716 (KE); NARSAD Young Investigator (KE); NIH R01DK085712 (AG).

Acknowledgments

We thank Nicole Bibus Christianson for excellent technical support and Lotte Bjerre Knudsen for constructive comments on the manuscript.

References (66)

  • C.T. Peters et al.

    A glucagon-like peptide-1 receptor agonist and an antagonist modify macronutrient selection by rats

    J Nutr

    (2001)
  • C.L. Meachum et al.

    Behavioral conditioned responses to contextual and odor stimuli paired with LiCl administration

    Physiol Behav

    (1992)
  • C.M. Tenk et al.

    Dose response effects of lithium chloride on conditioned place aversions and locomotor activity in rats

    Eur J Pharmacol

    (2005)
  • J.C. Halford et al.

    Behavioral satiety sequence (BSS) for the diagnosis of drug action on food intake

    Pharmacol Biochem Behav

    (1998)
  • D. Treit et al.

    Thigmotaxis as a test for anxiolytic activity in rats

    Pharmacol Biochem Behav

    (1988)
  • C.L. Heusner et al.

    Viral restoration of dopamine to the nucleus accumbens is sufficient to induce a locomotor response to amphetamine

    Brain Res

    (2003)
  • F. Rodriquez de Fonseca et al.

    Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats

    Metabolism

    (2000)
  • M. Tauchi et al.

    Role of central glucagon-like peptide-1 in hypothalamo–pituitary–adrenocortical facilitation following chronic stress

    Exp Neurol

    (2008)
  • J.R. Strawn et al.

    Failure of glucagon-like peptide-1 to induce panic attacks or anxiety in patients with panic disorder

    J Psychiatr Res

    (2008)
  • P. Grant et al.

    Psychological and quality of life changes in patients using GLP-1 analogues

    J Diabetes Complications

    (2011)
  • J.J. Holst

    The physiology of glucagon-like peptide 1

    Physiol Rev

    (2007)
  • T.J. Kieffer et al.

    Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV

    Endocrinology

    (1995)
  • A.J. Kastin et al.

    Entry of exendin-4 into brain is rapid but may be limited at high doses

    Int J Obes Relat Metab Disord

    (2003)
  • A.J. Kastin et al.

    Interactions of glucagon-like peptide-1 (GLP-1) with the blood–brain barrier

    J Mol Neurosci

    (2002)
  • S.E. Kanoski et al.

    Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4

    Endocrinology

    (2011)
  • E. Alvarez et al.

    Expression of the glucagon-like peptide-1 receptor gene in rat brain

    J Neurochem

    (1996)
  • I. Merchenthaler et al.

    Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system

    J Comp Neurol

    (1999)
  • S.L. Jin et al.

    Distribution of glucagonlike peptide I (GLP-I), glucagon, and glicentin in the rat brain: an immunocytochemical study

    J Comp Neurol

    (1988)
  • A.M. Dossat et al.

    Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake

    J Neurosci

    (2011)
  • A.L. Alhadeff et al.

    GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake

    Endocrinology

    (2012)
  • M.J. During et al.

    Glucagon-like peptide-1 receptor is involved in learning and neuroprotection

    Nat Med

    (2003)
  • M.D. Turton et al.

    A role for glucagon-like peptide-1 in the central regulation of feeding

    Nature

    (1996)
  • Volkow ND, Wang GJ, Fowler JS, Tomasi D, Baler R. Food and drug reward: overlapping circuits in human obesity and...
  • Cited by (68)

    • Gut-brain axis

      2022, Neurocircuitry of Addiction
    • The therapeutic potential of GLP-1 analogues for stress-related eating and role of GLP-1 in stress, emotion and mood: a review

      2021, Progress in Neuro-Psychopharmacology and Biological Psychiatry
      Citation Excerpt :

      The notion that GLP-1 potentially impacts mood states other than stress (such as anxiety, depression) stems from an understanding of its neuroprotective and neurogenerative effects (Muscogiuri et al., 2017; McIntyre et al., 2013), the expression of GLP-1R mRNA in limbic areas of the brain such as the amygdala and hippocampus, and studies assessing anxiety-like and depressive-like behavior using animal models, are summarised in Table 4. Using validated behavioral tests [Elevated Plus Maze (EPM), Vogel Conflict Test (VCT), Open Field Test (OFT), and Light/Dark Box (LDB)], acute GLP-1 and GLP-1R agonist administration (liraglutide, exenatide) has shown to both increase anxiety-like behavior (Möller et al., 2002; Kinzig et al., 2003; Gulec et al., 2010; Anderberg et al., 2016; Kamble et al., 2016; López-Ferreras et al., 2020), not change (Möller et al., 2002; Gulec et al., 2010; Krass et al., 2012, 2015; Erreger et al., 2012; Terrill et al., 2016; Décarie-Spain et al., 2019), and decrease anxiety-like behavior (Sharma et al., 2015a), compared to saline in rats and mice. Studies that found an anxiogenic effect as a result of acute GLP-1R activation support the aforementioned studies which found increased levels of corticosterone and ACTH as a result of acute GLP-1 exposure.

    View all citing articles on Scopus
    1

    These authors contributed equally to this work.

    View full text