Mehdi Farokhnia

Exogenous ghrelin administration increases alcohol self-administration and modulates brain functional activity in heavy-drinking alcohol-dependent individuals

Preclinical evidence suggests that ghrelin, a peptide synthesized by endocrine cells of the stomach and a key component of the gut–brain axis, is involved in alcohol seeking as it modulates both central reward and stress pathways. However, whether and how ghrelin administration may impact alcohol intake in humans is not clear. For, we believe, the first time, this was investigated in the present randomized, crossover, double-blind, placebo-controlled, human laboratory study. Participants were non-treatment-seeking alcohol-dependent heavy-drinking individuals. A 10-min loading dose of intravenous ghrelin/placebo (3 mcg kg−1) followed by a continuous ghrelin/placebo infusion (16.9 ng/kg/min) was administered. During a progressive-ratio alcohol self-administration experiment, participants could press a button to receive intravenous alcohol using the Computerized Alcohol Infusion System. In another experiment, brain functional magnetic resonance imaging was conducted while participants performed a task to gain points for alcohol, food or no reward. Results showed that intravenous ghrelin, compared to placebo, significantly increased the number of alcohol infusions self-administered (percent change: 24.97±10.65, P=0.04, Cohen’s d=0.74). Participants were also significantly faster to initiate alcohol self-administration when they received ghrelin, compared to placebo (P=0.03). The relationships between breath alcohol concentration and subjective effects of alcohol were also moderated by ghrelin administration. Neuroimaging data showed that ghrelin increased the alcohol-related signal in the amygdala (P=0.01) and modulated the food-related signal in the medial orbitofrontal cortex (P=0.01) and nucleus accumbens (P=0.08). These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder.

The Microbiota, the Gut and the Brain in Eating and Alcohol Use Disorders: A ‘Ménage à Trois’?

Aims Accumulating evidence for the influence of the gut microbiota on the bidirectional communication along the gut-brain axis suggests a role of the gut microbiota in eating disorders (EDs) and alcohol and substance use disorders. The potential influence of altered gut microbiota (dysbiosis) on behaviors associated with such disorders may have implications for developing therapeutic interventions. Methods A systematic review of preclinical and clinical studies evaluating the gut microbiota, EDs and alcohol and substance use disorders was conducted using MEDLINE, Embase and Web of Science databases with the objective being to examine the role of the gut microbiota in behavioral correlates of these disorders. Original papers focused on the gut microbiota and potential behavioral implications were deemed eligible for consideration. Results The resulting 12 publications were limited to gut microbiota studies related to EDs and alcohol and substance use disorders. Some studies suggest that dysbiosis and gut microbial byproducts may influence the pathophysiology of EDs via direct and indirect interference with peptide hormone signaling. Additionally, dysbiosis was shown to be correlated with alcohol use disorder-related symptoms, i.e. craving, depression and anxiety. Finally, a mouse study suggests that manipulations in the gut microbiota may affect cocaine-related behaviors. Conclusions Promising, albeit preliminary, findings suggest a potential role of the gut microbiota in behavioral correlates of EDs and alcohol and substance use disorders. Short summary Preliminary evidence exists supporting the role of the gut microbiota in eating disorders and alcohol and substance use disorders, although additional investigation is needed to determine what is causative versus epiphenomenological.

The Role of the Ghrelin System in Drug Addiction

In the past years, a significant volume of research has implicated the appetitive hormone ghrelin in the mechanisms underlying drug use and addiction. From a neuroscientific standpoint, ghrelin modulates both reward and stress pathways, two key drivers of substance use behaviors. Previous investigations support a connection between the ghrelin system and alcohol, stimulants, and tobacco use in both animals and humans, while the research on opioids and cannabis is scarce. In general, upregulation of the ghrelin system seems to enhance craving for drugs as well as substances use. On the other hand, acute and chronic exposure to drugs of abuse influences the ghrelin system at different levels. This chapter summarizes the literature on the relationship between the ghrelin system and substance-related behaviors. We also review recent work investigating the ghrelin system as a potential pharmacological target for treating substance use disorders and discuss the need for additional research.

T76. Baclofen as a Pharmacotherapy for the Treatment of Concurrent Alcohol and Nicotine Dependence: A Double-blind, Placebo-Controlled, Randomized Trial

T76. Baclofen as a Pharmacotherapy for the Treatment of Concurrent Alcohol and Nicotine Dependence: A Double-blind, Placebo-Controlled, Randomized Trial

Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment

&NA; Gamma‐aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system, plays an important role in biobehavioral processes that regulate alcohol seeking, food intake, and stress response. The metabotropic GABA‐B receptor has been investigated as a potential therapeutic target for alcohol use disorder, by using orthosteric agonists (e.g., baclofen) and positive allosteric modulators. Whether and how pharmacological manipulation of the GABA‐B receptor, in combination with alcohol intake, may affect feeding‐ and stress‐related neuroendocrine pathways remains unknown. In the present randomized, double‐blind, placebo‐controlled study, thirty‐four alcohol‐dependent individuals received baclofen (30 mg/day) or placebo in a naturalistic outpatient setting for one week, and then performed a controlled laboratory experiment which included alcohol cue‐reactivity, fixed‐dose priming, and self‐administration procedures. Blood samples were collected, and the following neuroendocrine markers were measured: ghrelin, leptin, amylin, glucagon‐like peptide‐1 (GLP‐1), insulin, prolactin, thyroid‐stimulating hormone, growth hormone, cortisol, and adrenocorticotropic hormone (ACTH). During the outpatient phase, baclofen significantly increased blood concentrations of acyl‐ghrelin (p = 0.01), leptin (p = 0.01), amylin (p = 0.004), and GLP‐1 (p = 0.02). Significant drug × time‐point interaction effects for amylin (p = 0.001) and insulin (p = 0.03), and trend‐level interaction effects for GLP‐1 (p = 0.06) and ACTH (p = 0.10) were found during the laboratory experiment. Baclofen, compared to placebo, had no effect on alcohol drinking in this study (ps ≥ 0.05). Together with previous studies, these findings shed light on the role of the GABAergic system and GABA‐B receptors in the shared neurobiology of alcohol‐, feeding‐, and stress‐related behaviors. HighlightsBaclofen administration in an outpatient setting increased blood ghrelin, leptin, amylin, and GLP‐1 concentrations.Baclofen altered the pattern of change in blood amylin, insulin, GLP‐1, and ACTH concentrations during a human lab experiment.GABA‐B receptors mediate the neuroendocrine correlates of alcohol‐, feeding‐, and stress‐related behaviors.

The Validity of the Montgomery-Asberg Depression Rating Scale in an Inpatient Sample with Alcohol Dependence

BACKGROUND The Montgomery-Asberg Depression Rating Scale (MADRS) is commonly used to examine depressive symptoms in clinical settings, including facilities treating patients for alcohol addiction. No studies have examined the validity of the MADRS compared to an established clinical diagnostic tool of depression in this population. This study aimed to examine the following: (i) the validity of the MADRS compared to a clinical diagnosis of a depressive disorder (using the Structured Clinical Interview for DSM-IV-TR [SCID-IV-TR]) in patients seeking treatment for alcohol dependence (AD); (ii) whether the validity of the MADRS differs by type of SCID-IV-TR-based diagnosis of depression; and (iii) which items contribute to the optimal predictive model of the MADRS compared to a SCID-IV-TR diagnosis of a depressive disorder. METHODS Individuals seeking treatment for AD and admitted to an inpatient unit were administered the MADRS at day 2 of their detoxification program. Clinical diagnoses of AD and depression were made via the SCID-IV-TR at the beginning of treatment. RESULTS In total, 803 participants were included in the study. The MADRS demonstrated low overall accuracy relative to the clinical diagnosis of depression with an area under the receiver operating characteristic curve of 0.68. The optimal threshold for balancing sensitivity and specificity identified by the Euclidean distance was >14. This cut-point demonstrated a sensitivity of 66%, a specificity of 60%, a positive predictive value of 50%, and a negative predictive value of 75%. The MADRS performed slightly better for major depressive disorders compared to alcohol-induced depression. Items related to lassitude, concentration, and appetite slightly decreased the accuracy of the MADRS. CONCLUSIONS The MADRS does not appear to be an appropriate substitute for a diagnostic tool among alcohol-dependent patients. The MADRS may, however, still be a useful screening tool assuming careful consideration of cut-points.

Oxytocin receptor mRNA expression in dorsolateral prefrontal cortex in major psychiatric disorders: A human post-mortem study

There is growing interest in oxytocin as a putative treatment for various psychiatric disorders including major depressive disorder, bipolar disorder and schizophrenia/schizoaffective disorder. However, potential alterations in the endogenous brain oxytocin system in these disorders are poorly characterized. Brain expression of oxytocin and its receptor genes in patients with these psychiatric disorders has not been well studied outside the hypothalamus. We measured expression of mRNA for oxytocin and its receptor in the dorsolateral prefrontal cortex of postmortem brains using quantitative polymerase chain reaction in a total of 581 individuals. These individuals either were diagnosed with major depressive disorder (n = 135), bipolar disorder (n = 57), schizophrenia/schizoaffective disorder (n = 169), or were control subjects, defined as individuals with no lifetime history of any of these disorders (n = 220). Diagnoses of major depressive disorder and bipolar disorder were associated with significantly increased oxytocin receptor mRNA levels in the dorsolateral prefrontal cortex. This finding is discussed in light of the extant literature on the dysregulation of oxytocin signaling in individuals with major psychiatric disorders.

Pharmacological manipulation of the ghrelin system and alcohol hangover symptoms in heavy drinking individuals: Is there a link?

ABSTRACT Ghrelin, an orexigenic peptide synthesized in the stomach, is a key player in the gut‐brain axis. In addition to its role in regulating food intake and energy homeostasis, ghrelin has been shown to modulate alcohol‐related behaviors. Alcohol consumption frequently results in hangover, an underexplored phenomenon with considerable medical, psychological, and socioeconomic consequences. While the pathophysiology of hangover is not clear, contributions of mechanisms such as alcohol‐induced metabolic/endocrine changes, inflammatory/immune response, oxidative stress, and gut dysbiosis have been reported. Interestingly, these mechanisms considerably overlap with ghrelins physiological functions. Here, we investigated whether pharmacological manipulation of the ghrelin system may affect alcohol hangover symptoms. Data were obtained from two placebo‐controlled laboratory studies. The first study tested the effects of intravenous (IV) ghrelin and consisted of two experiments: a progressive‐ratio IV alcohol self‐administration (IV‐ASA) and a fixed‐dose IV alcohol clamp. The second study tested the effects of an oral ghrelin receptor inverse agonist (PF‐5190457) and included a fixed‐dose oral alcohol administration experiment. Alcohol hangover data were collected the morning after each alcohol administration experiment using the Acute Hangover Scale (AHS). IV ghrelin, compared to placebo, significantly reduced alcohol hangover after IV‐ASA (p = 0.04) and alcohol clamp (p = 0.04); PF‐5190457 had no significant effect on AHS scores. Females reported significantly higher hangover symptoms than males following the IV‐ASA experiment (p = 0.04), but no gender × drug condition (ghrelin vs. placebo) effect was found. AHS total scores were positively correlated with peak subjective responses, including ‘stimulation’ (p = 0.08), ‘sedation’ (p = 0.009), ‘feel high’ (p = 0.05), and ‘feel intoxicated’ (p = 0.03) during the IV‐ASA. IV ghrelin blunted the positive association between alcohol sedation and hangover as shown by trend‐level drug × sedation effect (p = 0.08). This is the first study showing that exogenous ghrelin administration, but not ghrelin receptor inverse agonism, affects hangover symptoms. Future research should investigate the potential mechanism(s) underlying this effect. HighlightsGhrelin, an orexigenic peptide primarily synthesized in the stomach, modulates alcohol‐related behaviors.There is considerable overlap between the pathways underlying both ghrelins function and alcohol hangover pathophysiology.Ghrelin administration significantly reduced the severity of alcohol hangover following intravenous alcohol administration.Ghrelin receptor inverse agonism had no effect on the severity of alcohol hangover following oral alcohol administration.Ghrelins effect on alcohol hangover may be mediated through oxidative, inflammatory, metabolic, and/or endocrine pathways.

Identifying and Characterizing Subpopulations of Heavy Alcohol Drinkers Via a Sucrose Preference Test: A Sweet Road to a Better Phenotypic Characterization?

Aims Sweet preference in individuals with alcohol use disorder (AUD) has been associated with family history of AUD and personality traits. Therefore, testing sweet preference may help identify subpopulations of AUD individuals. Short summary Sweet preference has been associated with family history of AUD and personality traits. We compared heavy drinkers based on their sweet liker status and using two cutoffs. Our findings support the role of sweet preference in heavy drinkers and point to the importance of how sweet likers are defined. Methods This study aimed at describing and comparing heavy drinkers based on their sweet liker status, through demographic, neuroendocrine, inflammatory, behavioral and drinking characteristics. Participants rated the pleasantness and intensity of sucrose solutions (0.05, 0.10, 0.21, 0.42 and 0.83 M). Two cutoffs were used to identify likers versus dislikers: Grouping A likers preferred 0.83 M and Grouping B likers preferred 0.83 or 0.42 M; the rest were dislikers. Results Sweet likers were 36% (n = 20) using Grouping A and 58.2% (n = 32) using Grouping B. Grouping B, but not Grouping A, sweet likers had higher BMI (P = 0.01). In Grouping B, sweet likers had higher plasma leptin and insulin concentrations and higher insulin resistance (Ps < 0.05). C-reactive protein concentrations were higher in sweet likers in Grouping A (P = 0.0015) and at a trend level in Grouping B (P = 0.07). Grouping A sweet likers had higher alcohol craving (P = 0.0004). Sweet likers preferred spirits compared to nonspirits (wine and beer) across both grouping (Ps < 0.05). Conclusions These results provide further support for the role of sweet liking phenotype in identifying subpopulations of AUD individuals. These findings also point to the importance of how sweet likers are defined, therefore highlighting the need for further research.