Brief communicationExendin-4 decreases amphetamine-induced locomotor activity
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)
- et al.
Biology of incretins: GLP-1 and GIP
Gastroenterology
(2007) - et al.
Glucagon-like peptide-1, glucose homeostasis and diabetes
Trends Mol Med
(2008) - et al.
Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas
J Biol Chem
(1992) - et al.
Exendin-4 is a high potency agonist and truncated exendin-(9–39)-amide an antagonist at the glucagon-like peptide 1-(7–36)-amide receptor of insulin-secreting beta-cells
J Biol Chem
(1993) - et al.
Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem
Neuroscience
(1997) - et al.
Preproglucagon neurons project widely to autonomic control areas in the mouse brain
Neuroscience
(2011) Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure
Brain Res.
(2010)- et al.
The gut hormones PYY(3–36) and GLP-1(7–36 amide) reduce food intake and modulate brain activity in appetite centers in humans
Cell Metab
(2011) - et al.
Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine
Neuron
(2006) - et al.
Modulation of the mesolimbic dopamine system by leptin
Brain Res
(2010)
A glucagon-like peptide-1 receptor agonist and an antagonist modify macronutrient selection by rats
J Nutr
Behavioral conditioned responses to contextual and odor stimuli paired with LiCl administration
Physiol Behav
Dose response effects of lithium chloride on conditioned place aversions and locomotor activity in rats
Eur J Pharmacol
Behavioral satiety sequence (BSS) for the diagnosis of drug action on food intake
Pharmacol Biochem Behav
Thigmotaxis as a test for anxiolytic activity in rats
Pharmacol Biochem Behav
Viral restoration of dopamine to the nucleus accumbens is sufficient to induce a locomotor response to amphetamine
Brain Res
Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats
Metabolism
Role of central glucagon-like peptide-1 in hypothalamo–pituitary–adrenocortical facilitation following chronic stress
Exp Neurol
Failure of glucagon-like peptide-1 to induce panic attacks or anxiety in patients with panic disorder
J Psychiatr Res
Psychological and quality of life changes in patients using GLP-1 analogues
J Diabetes Complications
The physiology of glucagon-like peptide 1
Physiol Rev
Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV
Endocrinology
Entry of exendin-4 into brain is rapid but may be limited at high doses
Int J Obes Relat Metab Disord
Interactions of glucagon-like peptide-1 (GLP-1) with the blood–brain barrier
J Mol Neurosci
Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4
Endocrinology
Expression of the glucagon-like peptide-1 receptor gene in rat brain
J Neurochem
Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system
J Comp Neurol
Distribution of glucagonlike peptide I (GLP-I), glucagon, and glicentin in the rat brain: an immunocytochemical study
J Comp Neurol
Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake
J Neurosci
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
Glucagon-like peptide-1 receptor is involved in learning and neuroprotection
Nat Med
A role for glucagon-like peptide-1 in the central regulation of feeding
Nature
Cited by (68)
Gut-brain axis
2022, Neurocircuitry of AddictionLong-term functional alterations following prenatal GLP-1R activation
2021, Neurotoxicology and TeratologyThe 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 PsychiatryCitation 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.
- 1
These authors contributed equally to this work.