The combination of a glucagon-like peptide-1 and amylin receptor agonists reduces alcohol consumption in both male and female rats.

Objective: Combining different pharmaceuticals may be beneficial when treating disorders with complex neurobiology, including alcohol use disorder (AUD). The gut-brain peptides amylin and GLP-1 may be of potential interest as they individually reduce alcohol intake in rodents. While the combination of amylin receptor (AMYR) and glucagon-like peptide-1 receptor (GLP-1R) agonists have been found to decrease feeding and body weight in obese male rats synergistically, their combined impact on alcohol intake is unknown.

Synergistic-like decreases in alcohol intake following combined pharmacotherapy with GLP-1 and amylin in male rats.

Background And Purpose: The limited effectiveness of current pharmacological treatments for alcohol use disorder (AUD) highlights the need for novel therapies. These may involve the glucagon-like peptide-1 receptor or the amylin receptor, as treatment with agonists targeting either of these receptors lowers alcohol intake. The complexity of the mechanisms underlying AUD indicates that combining agents could enhance treatment efficacy.

LEAP2, a ghrelin receptor inverse agonist, and its effect on alcohol-related responses in rodents.

The underlying neurobiology of alcohol use disorder (AUD) is complex and needs further unraveling, with one of the key mechanisms being the gut-brain peptide ghrelin and its receptor (GHSR). However, additional substrates of the ghrelin pathway, such as liver-expressed antimicrobial peptide 2 (LEAP2), an endogenous GHSR inverse agonist, may contribute to this neurobiological framework. While LEAP2 modulates feeding and reward through central mechanisms, its effects on alcohol responses are unknown.

The GLP-1 receptor agonist exendin-4 reduces taurine and glycine in nucleus accumbens of male rats, an effect tentatively involving the nucleus tractus solitarius.

The physiological effects of glucagon-like peptide-1 (GLP-1) are mainly centered on its ability to decrease blood glucose levels and facilitate satiety. Additional physiological functions have been identified by means of GLP-1 agonists such as exenatide (exendin-4; Ex4). In particular, Ex4 reduces the intake of natural and artificial rewards, effects that to some extent involve activation of GLP-1 receptors in the nucleus tractus solitarius (NTS).

Des-acyl ghrelin reduces alcohol intake and alcohol-induced reward in rodents.

The mechanisms contributing to alcohol use disorder (AUD) are complex and the orexigenic peptide ghrelin, which enhances alcohol reward, is implied as a crucial modulator. The major proportion of circulating ghrelin is however the non-octanoylated form of ghrelin, des-acyl ghrelin (DAG), whose role in reward processes is unknown. As recent studies show that DAG decreases food intake, we hypothesize that DAG attenuates alcohol-related responses in animal models.

Activation of glucagon-like peptide-1 receptors reduces the acquisition of aggression-like behaviors in male mice.

Aggression is a complex social behavior, which is provoked in the defense of limited resources including food and mates. Recent advances show that the gut-brain hormone ghrelin modulates aggressive behaviors. As the gut-brain hormone glucagon-like peptide-1 (GLP-1) reduces food intake and sexual behaviors its potential role in aggressive behaviors is likely.

Salmon Calcitonin Attenuates Some Behavioural Responses to Nicotine in Male Mice.

The behavioural responses to nicotine involve appetite-regulatory hormones; however, the effects of the anorexigenic hormone amylin on reward-related behaviours induced by nicotine remain to be established. Previous studies have shown that the amylinergic pathway regulates behavioural responses to alcohol, amphetamine and cocaine. Here, we evaluated the effects of salmon calcitonin (sCT), an amylin and calcitonin receptor (CTR) agonist, on nicotine-induced locomotor stimulation and sensitisation as well as dopamine release in the nucleus accumbens (NAc) shell.

A ghrelin receptor antagonist reduces the ability of ghrelin, alcohol or amphetamine to induce a dopamine release in the ventral tegmental area and in nucleus accumbens shell in rats.

The orexigenic peptide ghrelin increases the release of dopamine in the nucleus accumbens (NAc) shell via central ghrelin receptors, especially those located in the ventral tegmental area (VTA). The activity of the VTA dopamine neurons projecting to NAc shell, involves somatodendritic dopamine release within the VTA. However, the effects of ghrelin on the concomitant dopamine release in the VTA and NAc shell is unknown.

Activation of glucagon-like peptide-1 receptors and skilled reach foraging.

Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exendin-4 (Ex4), liraglutide and dulaglutide, regulate glucose homeostasis and are thus used to treat diabetes type II. GLP-1 also contributes towards a variety of additional physiological functions, including suppression of reward and improvement of learning. Acute activation of GLP-1R in the nucleus accumbens (NAc) shell, an area essential for motivation, reduces the motivation to consume sucrose or alcohol when assessed in a simple motor task.

The glucagon-like peptide-1 receptor agonist, exendin-4, reduces sexual interaction behaviors in a brain site-specific manner in sexually naïve male mice.

Besides reducing food intake and controlling energy balance, glucagon-like peptide-1 (GLP-1) suppresses the reinforcing properties of palatable foods and addictive drugs. This reduction in reward involves activation of GLP-1 receptors (GLP-1R) within areas processing natural and artificial rewards, including the laterodorsal tegmental area (LDTg), ventral tegmental area (VTA) and nucleus accumbens (NAc) shell. These areas are part of a neurocircuitry mediating reward from addictive drugs and natural rewards including sexual behaviors.

Glucagon-like peptide-1 receptors and sexual behaviors in male mice.

The gut-brain peptide glucagon-like peptide-1 (GLP-1) reduces reward from palatable food and drugs of abuse. Recent rodent studies show that activation of GLP-1 receptors (GLP-1R) within the nucleus of the solitary tract (NTS) not only suppresses the motivation and intake of palatable food, but also reduces alcohol-related behaviors. As reward induced by addictive drugs and sexual behaviors involve similar neurocircuits, we hypothesized that activation of GLP-1R suppresses sexual behavior in sexually naïve male mice.

Effects of a selective long-acting amylin receptor agonist on alcohol consumption, food intake and body weight in male and female rats.

Alcohol use disorder is a complex neuropsychiatric disorder affecting both males and females worldwide; however, the efficacy of current pharmacotherapies varies. Recent advances show that gut-brain peptides, like amylin, regulate alcohol behavioural responses by acting on brain areas involved in alcohol reward processes. Thus, the activation of amylin receptors (AMYRs) by salmon calcitonin (sCT) decreases alcohol behaviours in male rodents.

Neuromedin U induces self-grooming in socially-stimulated mice.

Emerging evidence suggest that appetite-regulating peptides modulate social behaviors. We here investigate whether the anorexigenic peptide neuromedin U (NMU) modulates sexual behavior in male mice. However, instead of modulating sexual behaviors, NMU administered into the third ventricle increased self-grooming behavior.

Ghrelin signalling within the rat nucleus accumbens and skilled reach foraging.

Motivation alters behaviour in a complex manner and nucleus accumbens (NAc) shell has been implied as a key structure regulating such behaviour. Recent studies show that acute ghrelin signalling enhances motivation when assessed in a simple motor task. The aim of the present study was to define the role of ghrelin signalling on motivation in a more complex motor behaviour.

Ghrelin and aggressive behaviours-Evidence from preclinical and human genetic studies.

Aggressive behaviour is of crucial importance in the defence for limited resources including food and mates and involves central serotonin as well as dopamine signalling. As ghrelin modulates food intake and sexual behaviour we initially investigated the hypothesis that central ghrelin signalling regulates aggressive behaviour in the resident intruder paradigm in male mice. Moreover, interaction between ghrelin signalling and serotonergic, noradrenergic as well as dopaminergic neurotransmission in aggression was investigated.

Glucagon-like peptide-1 receptors within the nucleus of the solitary tract regulate alcohol-mediated behaviors in rodents.

The ability of glucagon-like peptide-1 (GLP-1) to reduce food intake involves activation of GLP-1 receptors (GLP-1R) in the nucleus of the solitary tract (NTS). It has also been demonstrated that systemic administration of GLP-1R agonists attenuates alcohol-mediated behaviors via, to date, unknown mechanisms. Therefore, we evaluated the effects of NTS-GLP-1R activation by exendin-4 (Ex4) on alcohol-induced locomotor stimulation, accumbal dopamine release and memory of alcohol reward in the conditioned place preference (CPP) model in mice.

The Anorexigenic Peptide Neuromedin U (NMU) Attenuates Amphetamine-Induced Locomotor Stimulation, Accumbal Dopamine Release and Expression of Conditioned Place Preference in Mice.

Amphetamine dependence, besides its substantial economical consequence, is a serious cause of mortality and morbidity. By investigations of the neurochemical correlates through which addictive drugs, such as amphetamine, activate the mesoaccumbal dopamine system unique targets for treatment of drug addiction can be identified. This reward link consists of a dopamine projection from the ventral tegmental area to the nucleus accumbens (NAc) suggesting that these brain areas are important for reward.