• Appetite and feeding are regulated by hormones that affect the brain.
• These hormones signal the present energy state of the body.
• These hormones can regulate reward and motivational processes.
• Ghrelin is an orexigenic gut hormone that activates reward circuitry.
• Ghrelin increase the consumption of food, but also drugs of addiction.
• Glucagon-like peptide-1 (GLP-1) is an anorexigenic hormone.
• GLP-1 reduces the consumption of food and drugs of addiction.
• Treatments that regulate appetite hormones and their receptors are viable targets for preventing relapse in addiction disorders.
Throughout this volume we have discussed evidence that addiction is characterized by the compulsion to seek and take a substance, the loss of control in limiting substance intake, and the emergence of a negative emotional state (e.g. dysphoria, anxiety) when intake is prevented (see Chapter 4). Importantly, this addiction trajectory is a reflection of functional disturbances to brain networks involved in controlling necessary motivational and cognitive processes (see Chapter 4—key neural substrates). Intriguingly, many of these same behavioural and brain disturbances are also seen in patients with obesity and binge-eating disorder (BED), suggesting that there are shared neural substrates between substance addiction and compulsive food consumption. Therefore, addiction and atypical eating behaviours (as seen in obesity and BED) may share some of their aetiology due to the effects of certain appetite hormones on the neural circuitry that supports reward, motivation, and cognition.
Food intake and appetite are regulated by numerous circulating hormones and neuropeptides, which signal the present energy state of the body. These signals are received by the brain, particularly the hypothalamus, eliciting the appropriate physiological responses to feed and restore energy. Several of these hormones, however, have also been shown to target brain areas implicated in reward processing, and significantly, addiction. Therefore, the possibility that endocrine signals from the gut traditionally known to regulate food intake, energy, and body weight homeostasis may also play a role in the regulation of reward and motivational processes should now be considered, in light of emerging evidence for their modulating effects on other types of behaviours.
Ghrelin is a 28 amino acid stomach-derived peptide hormone that activates hypothalamic orexigenic neurons, and inhibits anorectic (appetite-suppressing) neurons, to induce hunger and stimulate feeding. Ghrelin is an endogenous ligand at the growth hormone secretagogue receptor (GHS-R1a). GHS-R1a receptors are highly co-expressed with dopamine (DA) receptors in the midbrain, suggesting a modulatory role in reward processing. Specifically, it is thought that ghrelin activates cholinergic projections from the lateral dorsal tegmental nucleus (LDTg) in the brainstem, and these neurons project to release acetylcholine (ACh) onto nicotinic receptors (α3β2, β3, and α6) on DA neurons of the VTA. Ghrelin administration in humans has been shown to provoke neural responses associated with reward. Malik and colleagues (2008), for example, showed that ghrelin administered intravenously to healthy volunteers during fMRI increased neural responses to food pictures in a number of brain regions, including the amygdala, orbitofrontal cortex (OFC), anterior insula cortex, and striatum—brain regions that are implicated in encoding the incentive value of food cues (see Figure 12.1). These effects of ghrelin in the amygdala and OFC were also found to be correlated with self-rated hunger scores, suggesting that ghrelin enhances hedonic responses to food-related cues. Similar effects have also been reported by Goldstone and colleagues (2014) in the hippocampus and OFC. Therefore, there is strong evidence that ghrelin activates corticolimbic DA circuitry in the presence of food cues, suggesting that it may also play a modulating role in other types of rewards.
In preclinical studies, ghrelin (and food restriction) have indeed been shown to increase consumptive and reward behaviours to nicotine, alcohol, cocaine, and other drugs of abuse, as well as food. Preliminary studies in humans show differences in endogenous blood ghrelin levels in actively drinking and abstinent alcoholics. For example, Leggio and colleagues (2012) found significant differences in blood ghrelin between non-abstinent and abstinent alcoholics that were significantly and positively correlated with alcohol craving (see Figure 12.2). Other studies also indicate a significant positive correlation between ghrelin levels and alcohol craving, suggesting that this hormone may mediate the urge to drink alcohol due to its effects on mesolimbic DA circuitry. Leggio and colleagues (2012) administered intravenous ghrelin (1mcg/kg, 3 mcg/kg, or 0 mcg/kg placebo) to alcoholics, followed by a cue reactivity procedure—participants were exposed to neutral (juice) and alcohol cues. This study showed that during ghrelin (3 mcg/kg vs placebo) craving was significantly increased for alcohol (but not juice), providing strong preliminary evidence that ghrelin directly mediates alcohol craving (see Figure 12.3). Taken together, the effects of the ghrelin system in response to food and drug cues suggest that this orexigenic gut hormone is a powerful mediator of reward. Despite the scarcity of research, the few studies that have been conducted appear to demonstrate that the ghrelin system may be a viable target for ameliorating behaviours related to compulsive consumption, including drug and alcohol addiction.
The orexin (or hypocretin) system is made up of two neuropeptides, which include orexin-A and orexin-B. Orexin is produced from prepro-orexin in the lateral hypothalamus. Orexin-A is a 33 amino-acid neuropeptide and is an agonist at both Ox1 and Ox2 receptors. Orexin-B is a 28 amino-acid neuropeptide, which only activates Ox2 receptors. Orexin neurons project widely throughout the central nervous system, with their receptors expressed in the cerebral cortex, the striatum, and VTA. The orexin system is involved in a variety of processes such as arousal, reward, energy homeostasis, and cognition. Evidence is now emerging, however, that the orexin system may also have a role to play in addiction.
The orexigenic neuropeptides (both types A and B) have recently been shown to promote alcohol intake, and also affect craving, withdrawal, and relapse to drugs of addiction. Intra-VTA application of the orexin-A peptide increases cocaine-seeking behaviour and enhances cocaine-evoked increases in DA transmission to ventral striatal targets. Blockade of orexin transmission appears to reduce the reinforcing effects of cocaine by attenuating DA transmission in the VTA, with OX1 receptor antagonists attenuating cued and stress-induced reinstatement of cocaine-seeking. Thus, orexin transmission appears to mediate aspects of the rewarding and reinforcing properties of addictive drugs through both receptor subtypes, with antagonists reducing these effects. Research in humans by Ziółkowski and colleagues (2016) have also shown that orexin blood concentrations are significantly higher in alcohol-dependent patients, and that after four weeks of treatment for relapse prevention, these levels decrease significantly to a similar value observed in a comparison control group (see Figure 12.4). This study also showed that those with a higher level of alcohol dependence had the highest orexin blood concentrations at the beginning of treatment which after four weeks diminished to the same level as those seen in patients with less severe dependence. Therefore, given the role orexin appears to play in the motivation for drug rewards, it (or its receptor) may represent a potential target for relapse prevention treatment in alcohol and cocaine addiction.
Glucagon-like peptide-1 (GLP-1) is an anorexigenic peptide hormone released from intestinal L-cells after feeding. GLP-1 increases insulin secretion in a glucose-dependent manner, improves insulin sensitivity, and increases satiety by delaying gastric emptying. The effects of GLP-1 in the brain are believed to be through its hypothalamic–brainstem actions that reduce appetite and food intake. In preclinical studies GLP-1 agonists decrease both consumption and the rewarding value of food through its actions on mesolimbic DA pathways. Anorexigenic hormones, including GLP-1, also attenuate reward system responses to food in human fMRI studies. Gastric bypass surgery, known to increase GLP-1, has been shown to reduce brain responses to high calorie foods in obese subjects, particularly in the OFC, amygdala, striatum, and hippocampus (see Figure 12.5). This appears to lend credence to the supposition that augmenting GLP-1 reduces the incentive value of food reward.
Research by van Bloemendaal and colleagues (2014) showed that the GLP-1 receptor agonist exenatide (currently used for the treatment of type 2 diabetes to stimulate satiety) reduced activation in appetite- and reward-related brain regions when viewing food pictures. The effects of GLP-1 receptor activation, it has been suggested, are to decrease the prediction of food reward, but increase the hedonic response to food, which may reduce craving and prevent overeating respectively. Indeed, van Bloemendaal and colleagues (2015) have also shown that exenatide, compared to placebo, decreases neural responses to the anticipation of a high calorie reward (chocolate milk), but increases neural responses to the receipt of the reward (see Figures 12.6 and 12.7 respectively). These neural responses were also paralleled by reductions in food intake. Therefore, GLP-1 agonists, such as exenatide, may reduce the hedonic threshold during food consumption, which means there is a greater and more rapid satiation during eating. This effect then prevents overeating to compensate for the original blunted hedonic response. This may also suggest that the GLP-1 system is another viable target for remediating behaviours related to the compulsive consumption of drugs. Indeed, recent preclinical studies using GLP-1 agonists in animal models have been reported to reduce alcohol, nicotine, cocaine and stimulant reward (e.g. conditioned place preference), drug-induced accumbal DA release, and drug consumption.
The role of appetite hormones in reward and motivation has potential therapeutic implications for the future management of addiction. Given that GLP-1 analogues, such as exenatide, are now approved for type 2 diabetes, GLP-1 analogues could conceivably be used in the treatment of drug dependence. Presently, however, these treatments are not licensed for addiction disorders, but there are ongoing trials in human addiction populations which are aiming to elucidate the potential efficacy of exenatide in addiction disorders. Likewise, there are ongoing studies in human addiction investigating the potential efficacy of ghrelin receptor antagonism, given some of the preclinical evidence that this may also be a viable target for treating disorders of compulsive consumption, particularly alcoholism. There are also ongoing studies investigating the efficacy of orexin antagonists for addiction disorders. Suvorexant, for example, which is a dual orexin receptor antagonist (and FDA-approved to treat insomnia), has recently been shown to reduce cocaine administration and attenuate cocaine-induced elevations in ventral striatal DA in animals (see Gentile et al. 2017). While only preliminary, these types of research findings using a medication approved for use in humans bestow some optimism for the value of exploring brain endocrine pathways in the treatment of addiction disorders.
There is now evidence in animals that some appetite hormones influence the consumption of and desire for food, and also the intake of drugs of addiction. The two best examples, given some of the preclinical findings, are GLP1 and ghrelin, but there are other candidate systems (orexins) that are emerging as viable targets. The influence of these hormones is exerted through brain systems involved in the core behavioural components of addiction: reward sensitivity, stress, impulsivity and compulsivity. These behavioural components are also seen in obesity and BED. It is unknown whether these hormones directly influence the core behavioural components of addiction in humans, particularly during abstinence, but new research is attempting to address this. Therefore, there is an emerging shift into a new field of testing drugs that affect appetite hormones and their receptors, and their use in regulating the brain mechanisms that lead to relapse in addiction disorders.
References and Further Reading
Engel JA and Jerlhag E (2014). Role of appetite-regulating peptides in the pathophysiology of addiction: implications for pharmacotherapy. CNS Drugs, 28(10), 875–6.Find this resource:
Gentile TA, Simmons SJ, Barker DJ, et al. (2017). Suvorexant, an orexin/hypocretin receptor antagonist, attenuates motivational and hedonic properties of cocaine. Addiction Biology. doi:10.1111/adb.12507.Find this resource:
Goldstone AP, Prechtl CG, Scholtz S, et al. (2014). Ghrelin mimics fasting to enhance human hedonic, orbitofrontal cortex, and hippocampal responses to food. American Journal of Clinical Nutrition, 99(6), 1319–30.Find this resource:
Leggio L, Ferrulli A, Cardone S, et al. (2012). Ghrelin system in alcohol-dependent subjects: role of plasma ghrelin levels in alcohol drinking and craving. Addiction Biology, 17(2), 452–64. doi:10.1111/j.1369–1600.2010.00308.x.Find this resource:
Malik S, McGlone F, Bedrossian D, et al. (2008). Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metabolism, 7(5), 400–9.Find this resource:
Scholtz S, Miras AD, Chhina N, et al. (2014). Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding. Gut, 63(6), 891–902.Find this resource:
van Bloemendaal L, Ijzerman RG, Ten Kulve JS, et al. (2014). GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes, 63(12), 4186–96.Find this resource:
van Bloemendaal L, Veltman DJ, Ten Kulve JS, et al. (2015). Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans, Diabetes, Obesity and Metabolism, 17(9), 878–86.Find this resource:
Ziółkowski M, Czarnecki D, Budzynski J, et al. (2016). Orexin in patients with alcohol dependence treated for relapse prevention: a pilot study. Alcohol and Alcoholism, 51(4), 416–21. doi:10.1093/alcalc/agv129.Find this resource: