The Neuropsychoendocrinology of Substance Use Disorders

Chapter Intro

Our understanding of the neurobiological basis of substance use disorders (SUD) is limited, so are available treatment options. Patterns of substance use intersect with stress, appetite, sleep, anxiety and sex. These physiologic drives are regulated predominantly by endocrine pathways. As such, it makes sense to examine whether hormonal systems play a role in the initiation or maintenance of substance use disorders. Exploring and exploiting these pathways confers the potential to better understand and target the neurophysiology of addictions. Hormones are circulating compounds that may be objectively measured and tracked. As such, with a growing body of knowledge about their role in addictions, hormones may be used as potential biomarkers to gauge SUD predisposition or prognosis. Similarly, these pathways can be investigated for the development of safe and novel therapeutic targets for SUD. This chapter will survey and review preclinical and clinical studies addressing the relationship between substance use disorders and hormones implicated in regulating stress, water volume, appetite, sleep, reproduction, and parturition.

Appetite Regulating Hormones

Appetite regulating hormones including ghrelin, leptin, glucagon-like peptide 1 (GLP-1) and insulin are known to govern the metabolism of ingested nutrients. In addition, research supports their role in modulating cognitive function, stress, and reward processing that affects hedonic drive. The involvement between appetite regulating hormones and substance use has been most extensively documented with alcohol. Indeed, alcohol is both a source of calories and a substance of abuse.

Ghrelin

Ghrelin is a 28-amino acid peptide hormone produced primarily by gastric endocrine cells. It is frequently labeled as the “hunger hormone” because of its primary role in increasing appetite and food intake. Ghrelin produces its effect by binding the growth hormone secretagogue receptor 1a (GHS-R1a), which is expressed in peripheral organs as well as in the brain. As such, ghrelin's actions are mediated by direct peripheral as well as central effects when it crosses the blood–brain barrier. The latter is postulated to modulate dopamine transmission in the reward processing for food and other reinforcers. Ghrelin also interacts with the hypothalamic–pituitary–adrenal (HPA) axis modulating stress responses and anxiety. It is thought that ghrelin's interactions with both the reward and stress pathways explain its role in addictive behaviors.

Ghrelin and Alcohol

Early data from rodent models shows that blood ghrelin concentration is lowered in rats exposed to alcohol, and this reduction is blunted in alcohol preferring rats. Conversely, ghrelin administration to rats is shown to increase alcohol consumption.

Molecular studies found that following exposure to alcohol, alcohol preferring rats show an upregulation of the ghrelin receptors in the parts of the brain regulating the reward pathway, namely, in the prefrontal cortex, the nucleus accumbens, hippocampus, amygdala, and ventral tegmental area. To test this finding, central ghrelin infusions directly in the ventral tegmental area, the laterodorsal tegmental nucleus, or cerebral ventricles led to increased alcohol drinking in rodents.

It is thought that ghrelin's central effects on the amygdala modulate GABA and serotonin pathways and this is responsible for its relationship with alcohol drinking behaviors. Peripheral ghrelin signaling, on the other hand, does not appear to play a role.

Human studies show similar findings. Indeed, alcohol consumption in adults without Alcohol Use Disorder (AUD) lowers plasma ghrelin levels. Similarly, early abstinence from alcohol in subjects with AUD is associated with increased circulating ghrelin levels. Observational studies are inconclusive as it has been suggested that individuals with AUD have higher ghrelin levels, while others demonstrated opposite findings.

Ghrelin was also found to affect craving for alcohol. A positive correlation has been identified in numerous studies between the urges to drink alcohol and ghrelin plasma concentration. In order to examine whether there is a cause and effect relationship between craving and ghrelin levels, Leggio et al. used a placebo-controlled double-blind design where participants were randomized to receive intravenous injections of ghrelin or placebo followed by measurements of craving for alcohol. They demonstrated that subjects who received ghrelin injections had higher measures of cravings for alcohol but not for neutral cues such as juice. In addition, craving measure scores correlated with plasma ghrelin concentration. Single-nucleotide polymorphism studies examining variability in the gene coding for the ghrelin receptor identified a gene missense polymorphism to be associated significantly with a diagnosis of AUD.

The research summarized above highlights a role for ghrelin and the ghrelin receptor as potential pharmacological targets for the treatment of AUD. Ghrelin antagonists have been developed and studied in rodent models of AUD. Early findings demonstrate a reduction in alcohol consumption and alcohol seeking behaviors associated with the systemic administration of these compounds. Similar results were seen in ghrelin receptor knockout mice. Human studies examining the effects of ghrelin receptor antagonists are currently underway.

Ghrelin and Stimulants

Not unlike the alcohol data, early evidence of ghrelin's role in stimulant use is derived from animal and translational studies. In rodent models, exposure to methamphetamine or MDMA was found to correlate with higher plasma ghrelin levels. Similarly, ghrelin levels were found to correlate with cocaine seeking behaviors following a period of extinction. Ghrelin injection in the ventral tegmental area in rats is associated with increased preference for cocaine. Similarly, exogenous ghrelin led to cocaine-induced hyperlocomotion when infused intraperitoneally or directly into the nucleus accumbens.

In one human gene polymorphism study, a single-nucleotide polymorphism (SNP) in the gene coding for ghrelin was found to be associated with the severity of stimulant use. Another SNP polymorphism in the gene coding for the ghrelin receptor correlated with the incidence of stimulant use disorder in a sample of amphetamine using adults.

These findings support the consideration of ghrelin receptor antagonists to reduce stimulant use. One such compound was tested prior to an injection of cocaine or methamphetamine in a rodent model. It led to reduction in dopamine release in the nucleus accumbens as well as decreased conditioned place preference for stimulants. In another study, the compound was associated with reduced stimulant-induced hyperlocomotion.

Ghrelin and Nicotine

Ghrelin potentiates dopamine release in rats' striatum in response to nicotine. Conversely, nicotine exposure leads to increased ghrelin levels in rats. In humans, there is some evidence of increased ghrelin levels immediately after smoking. Ghrelin levels in individuals with tobacco use disorders were found to correlate with the years of smoking and were predictive of relapse to tobacco use. In a rodent model of tobacco use disorder, the administration of a ghrelin receptor antagonist diminished nicotine associated behaviors and dopamine release.

Ghrelin and Opioids

The research examining the role of ghrelin in modulating opioid use is very limited. In a rat model of opioid use, the direct injection of ghrelin in the CSF led to increased heroin seeking and consumption. Conversely, the administration of ghrelin receptor antagonists is associated with increased levels of endogenous opioid levels in brain tissue as well as decreased opioid seeking behaviors and accumbal dopamine release. New data suggests these effects might be mediated by ghrelin's role in modulating the interaction between the opioid and endocannabinoid pathways.

Ghrelin and Cannabis

Cannabis administration in a rat model led to increased serum ghrelin levels as well as food consumption. Similarly, in a study, men who smoke cannabis to increase appetite in the context of HIV infection were found to have higher ghrelin levels. More research is necessary to better understand the role of ghrelin in cannabis use.

Leptin

Leptin is a peptide hormone produced by adipose tissue with appetite regulating function opposite to that of ghrelin. Leptin causes diminished appetite and reward associated with eating. Such opposing effects suggest a “cross-talk” between ghrelin and leptin in regulating appetite, and in turn, a role for leptin in addictive behaviors. Leptin receptors are expressed in the central reward processing pathway, namely, the ventral tegmental area, the substantia nigra, and the arcuate nucleus of the hypothalamus. Leptin was found to regulate the stress responses via the HPA axis, which is suggested as one mechanism explaining its role in addictive behaviors.

Leptin and Alcohol

Studies of individuals with AUD show a correlation between serum leptin levels and craving for alcohol. Conversely, treating persons with AUD with acamprosate or naltrexone leads to lower leptin levels, suggesting that leptin concentration can potentially play a role in prognostic determinations and treatment response (I, 13). In humans, leptin levels were found to be elevated with chronic alcohol use and correlated significantly with craving for alcohol. In a study of subjects with AUD, Haass-Koffler et al. demonstrated that a ghrelin infusion leads to lower leptin levels. The change in leptin levels correlated with craving for alcohol.

Leptin and Stimulants

Animal models are instrumental for understanding the role of leptin in stimulant use. In rodent models, exposure to methamphetamine or MDMA was found to correlate with lower plasma leptin levels. Similarly, leptin infusion causes the blunting of dopaminergic signaling in the nucleus accumbens and a reduction of the rewarding effects of cocaine in rats.

In humans with a stimulant use disorder, Martinotti et al. demonstrated a correlation between leptin levels and cocaine use and craving for cocaine in early abstinence.

Leptin and Nicotine

In a rat model of nicotine use, rodents exposed to nicotine were observed to eat less and had lower leptin plasma levels that normalized following nicotine abstinence. In a study of humans who have never smoked, nicotine administration was found to correlate with leptin levels in the mesocorticolimbic system and was associated with decreased appetite. Another study demonstrated increased plasma leptin levels in individuals who had stopped smoking for 2 months. Al’Absi et al. found that in smokers, circulating leptin levels correlated significantly with craving for nicotine and withdrawal symptoms.

Leptin and Opioids

Little is known on the effects of leptin on opioid use. One human study identified reduced circulating leptin levels in subjects with opioid use disorder maintained on methadone.

Leptin and Cannabis

Cannabis use was found to be associated with elevated leptin levels in adults with HIV. No other studies have examined this relationship.

Glucagon-like Peptide-1 (GLP-1)

GLP-1 is a neuropeptide hormone produced in the intestinal L-cells following food intake with central and peripheral effects leading to insulin release and reduced appetite. As such, GLP-1 receptor agonists have been developed and approved by the FDA for the treatment of diabetes. In the CNS, GLP-1 receptors are found in the nucleus accumbens, the globus pallidus, and the ventral tegmental area suggesting that it may play a role in the reward pathway.

GLP-1 and Alcohol

Significant data coming from animal models suggests that GLP-1 plays an important role in the regulation of alcohol drinking. GLP-1 receptor agonists were found to reduce dopamine release and diminish alcohol mediated rewards in mice leading to decreased spontaneous alcohol intake. In a model of alcohol preferring mice, alcohol deprivation is used as a paradigm to study the aversive effects of withdrawal as well as craving. GLP-1 agonist treatment in these mice prevented the expected increase in alcohol intake following re-exposure to alcohol. Similarly, rats with increased circulating levels of GLP-1 following a gastric bypass procedure reduced their alcohol intake. Conversely, GLP-1 receptor antagonists led to increased alcohol self-administration.

Human studies examining the role of GLP-1 in alcohol drinking behaviors are limited. Suchankova et al. tested SNP variability in the gene coding for the GLP-1 receptor in a large sample of individuals with AUD. They identified a functional mutation that is significantly associated with AUD. Individuals with the mutation were also more likely to seek intravenous alcohol self-administration and on fMRI to show a strong response mapping to the globus pallidus.