Brain Site-Specific Inhibitory Effects of the GLP-1 Analogue Exendin-4 on Alcohol Intake and Operant Responding for Palatable Food

Abstract

Approximately 14.4 million Americans are experiencing alcohol use disorder (AUD) and about two-thirds of people who experience drug addiction will relapse, highlighting the need to develop novel and effective treatments. Glucagon-like peptide-1 (GLP-1) is a peptide hormone implicated in the mesocorticolimbic reward system and has become a peptide of interest with respect to its putative inhibitory effects on drug reward. In order to further develop treatments for those diagnosed with AUD, the interplay between GLP-1 receptor signaling and ethanol consumption must be elucidated. In the present study, we investigated the ability of the GLP-1 analogue, exendin-4 (Ex-4), to alter alcohol intake and operant responding for sucrose pellets in order to further understand the role of this compound in mediating reward. We selected multiple sites throughout the prosencephalic and mesencephalic regions of the brain, where we directly administered various doses of Ex-4 to male Sprague Dawley rats. In alcohol investigations, we utilized a two-bottle choice intermittent access protocol. In separate groups of rats, we adopted an operant paradigm in order to examine the effect of Ex-4 on motivated responding for palatable food. Results indicated that GLP-1 receptor signaling effectively suppressed voluntary alcohol intake when injected into the ventral tegmental area (VTA), the accumbens core (NAcC) and shell (NAcS), the dorsomedial hippocampus (DMHipp), and the lateral hypothalamus (LH), which are all structures linked to brain reward mechanisms. The arcuate nucleus (ARcN) and the paraventricular nucleus (PVN) of the hypothalamus were unresponsive, as was the basolateral amygdala (BLA). However, Ex-4 treatment into the ArcN and PVN suppressed operant responding for sucrose pellets. In fact, the VTA, NAcC, NAcS, LH, and the DMHipp all showed comparable suppression of sucrose responding. Overall, our findings suggest that these central structures are implicated in brain reward circuitry, including alcohol and appetitive motivation, which may be mediated by GLP-1 receptor mechanisms. GLP-1, therefore, may play a critical role in modifying addictive behaviors via activation of multiple GLP-1 systems throughout the brain.

A Functional Inhibitory Role of Habenular Glucagon-Like Peptide-1 (GLP-1) in Forebrain Reward Signaling

“…For example, direct hypothalamic injection into the PVN nucleus has been shown to reduce food intake and alter energy substrate oxidation [40]. Interestingly, lateral hypothalamic injection of GLP-1 is reported to decrease operant responding for sucrose pellets and alcohol intake in a two-bottle choice paradigm [5]. In contrast, no effect of GLP-1 was found on alcohol intake when Ex-4 was administered into the ArcN or PVN [5].…”

“…Interestingly, lateral hypothalamic injection of GLP-1 is reported to decrease operant responding for sucrose pellets and alcohol intake in a two-bottle choice paradigm [5]. In contrast, no effect of GLP-1 was found on alcohol intake when Ex-4 was administered into the ArcN or PVN [5]. It is known that a majority of GLP-1 receptor-expressing neurons in the LH project directly to the VTA [24].…”

“…Operant training and alcohol administration were performed as described previously [5]. Rats were injected with either Ex-4 or saline vehicle in a 0.2 μl volume.…”

“…GLP-1 receptor (GLP-1R) expression has been identified in regions throughout the central nervous system (CNS), including hypothalamic nuclei as well as mesolimbic and other forebrain structures [1] [2]. While studies investigating the effects of exogenous GLP-1 may be difficult to interpret given the short half life of the peptide [3], other work has shown that ventricular or hypothalamic injection of the GLP-1 agonist, exendin-4 (Ex-4), reduces food intake in freely feeding rats [4] [5] [6] [7]. Ventricular administration of Ex-4 results in elevated expression of interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus and hindbrain as well as reduced food intake.…”

An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side

“…Three pharmacological approaches also converged on excluding a peripheral site of action: GPR119 agonists stimulate the production of GLP-1 in the gut, a DPP-4 inhibitor slows down its breakdown in the blood, and systemically injected Ex-9 primarily targets peripheral GLP-1R, neither of these manipulations affected alcohol intake in male rats (Marty et al, 2020 ). Within the brain, the region with the most solid data showing an effect of Ex-4 on alcohol intake is NAc shell—this has been shown by two studies in male (Vallof et al, 2019a ; Colvin et al, 2020 ) and one study in female rats (Abtahi et al, 2018 ). NAc core was also shown to be involved in male rats (Colvin et al, 2020 ); however, in females, the same dose of Ex-4 failed to affect alcohol intake via NAc core (Abtahi et al, 2018 ).…”