Mechanisms contributing to the development and maintenance of obesity remain to be elucidated especially regarding the interaction between appetite regulating hormones and mesolimbic reward circuits. Leptin was recently suggested to attenuate dopamine release in mesolimbic reward pathways. We now test the functional relevance assessing whether leptin plasma concentration affects the BOLD-response following the presentation of food cues.

21 obese and 23 normal weight subjects were investigated. Visual food cues and neutral stimuli were presented in a block design during fMRI. Blood-samples were collected immediately prior to the scan to assess plasma leptin concentration. Using linear regression analyses, the association between BOLD response to food cues and the body mass index (BMI) as well as plasma leptin concentration was examined.

Food-cues elicited activation of large cortical and subcortical networks, whereas only in obese patients food cues activated the left ventral and right dorsal striatum. Mean plasma concentration of leptin was significantly increased in obese subjects compared to normal weight controls. We found a significant positive correlation between the food cue-induced BOLD signal change in the ventral striatum and leptin plasma concentration. Furthermore, ventral and dorsal striatum BOLD response to food cues was significantly positive associated with the body mass index (BMI).

These findings suggest a physiological role of the satiety factor leptin in modulating responsivity of reward pathways towards food cues. Altered homeostatic feedback regulation of the mesolimbic brain reward circuit might explain the inability of obese patients to adapt their food intake according to physiologically needs.

The orexins (hypocretins) are neuropeptides recently identified as neurotransmitters in lateral hypothalamus neurons. Although the majority of studies associated the function of orexin neurons with arousal and sleep, these neurons also project to reward-associated brain regions, including the nucleus accumbens and ventral tegmental area. This indicates a possible role for orexins in reward function and motivation and thus in addictive diseases. Additionally, there is growing evidence from preclinical studies for an involvement of orexins in the regulation of stress, affectivity and drug seeking behavior.

We investigated orexin plasma concentrations and psychological symptoms in a sample of 34 alcohol dependent subjects on day 1 and day 14 of detoxification. For this purpose we used the Brief Symptom Inventory (BSI) as well as the Obsessive-Compulsive Drinking Scale to identify self-reported clinically relevant psychological symptoms including alcohol craving.

As a main result a significant positive correlation between orexin plasma concentration and depression as well as global distress indicies of the BSI was detected during early withdrawal (day 1), which is not shown after detoxification on day 14. No association with subjective craving for alcohol was found.

Our data indicate that orexins may be directly involved in affective dysregulation in alcohol dependent patients; moreover the effects of orexins on reinstatement of drug seeking behaviors might be mediated by impaired brain stress systems.

Ghrelin plays an orexigenic role in regulating appetite and energy balance. Preclinical studies also provided support for an important role of ghrelin in the neurobiology of addiction-related reward pathways. In contrast, clinical data have failed to support an association between ghrelin and alcohol craving, possibly due to analysing the pharmacologically inactive, preprohormone ghrelin instead of ghrelin in its active, acetylated form.

In a sample of 61 alcohol-dependent male inpatients we assessed plasma concentrations of both active and total ghrelin, using blood samples taken at the onset of withdrawal and then again after 14 days of controlled abstinence. During this time, we also assessed the patients' alcohol cravings (applying the obsessive compulsive drinking scale, OCDS), symptoms of depression (Beck Depression Inventory; BDI) and anxiety (State Trait Anxiety Inventory; STAI). The severity of alcohol dependence was assessed using the alcohol dependence scale (ADS).

We found a significant positive correlation between the plasma concentration of active ghrelin and alcohol craving in both blood samples. In a linear regression model, the plasma concentration of active ghrelin on day one, the scores of the ADS, and the BDI explained 36% of the variance in OCDS sum score (p < 0.0001). By day 14, these same factors accounted for 54% (p < 0.0001). We did not detect any association between the plasma concentration of total ghrelin and patients' alcohol cravings.

Our results suggest that biologically active, acetylated ghrelin is involved in reward-associated craving during alcohol withdrawal and early abstinence in alcohol-dependent patients.