The Gut-brain Axis in Food Reward and Alcohol Consumption

Similarities in striatocortical pathway dysfunction have been noted for alcoholism and
obesity. In prior studies we have demonstrated an inverse relationship between body mass
index and response in the dorsal striatum (DS) during consumption of a palatable
milkshake[1]. We have also shown that the magnitude of the reduced response predicts weight
gain, especially in individuals who carry a copy of the A1 allele of the taq1A
polymorphism[1]. Since the A1 allele is associated with reduced striatal D2 receptors [2-7],
this finding implicates the dopamine system in the reduced blood oxygen level dependent
(BOLD) response. Our results also indicate that this reduced response is a consequence,
rather than a cause of obesity, since gaining weight [8], but not risk for obesity [9] (by
virtue of parental obesity), is associated with reduced DS response to palatable food. Taken
together the results indicate that increased adiposity is associated with blunted DS
response to palatable food that may reflect altered dopamine signaling. More recently we
determined that reduced DS responses in overweight and obese subjects are associated with
increased impulsivity measured with the BIS-11 and a go no/no-go task [10]. Heavy drinkers
are also more likely to be impulsive [11]. In preliminary analyses of data on over 300
individuals assessed with the clinical core battery in the Center for the Translational
Neuroscience of Alcoholism (CTNA), we found that higher scores on the BIS-11 and other
measures of impulsivity were associated with greater alcohol consumption.

Related to these findings in humans, preliminary work in rodents shows that exogenous
administration of N-Acylethanolamines, such as oleoylethanolamine (OEA) can normalize
high-fat diet induced dopamine decreases in DS. Human testing of OEA supplementation is
possible based on the availability of a dietary supplement containing the OEA precursor
NOPE-EGCG ((PhosphoLEANtm, 85mg NOPE+50mg EGCG per capsule). PhosphoLEAN has been shown to
enhance adherence to dietary advice in overweight healthy subjects [12-14]. We therefore
propose a pilot study to test whether PhosphoLEAN will improve performance on impulsivity,
go/no-go tasks and negative outcome learning. Specifically, we will recruit heavy drinkers
because they are more likely to be impulsive [11]. Phospholean may improve negative
reinforcement learning in this population. This may lead to reductions in drinking as well.
We will also explore whether the supplement leads to reductions in alcohol consumption and
preference for high fat foods.

Inclusion Criteria:

- Subjects meeting NIAAA heavy drinking criteria (for men defined as consuming 5 or
more standard drinks on a drinking day and for women as consuming 4 or more standard
drinks on a drinking day at least once per week for the prior 30 days, with an upper
limit of 40 standard drinks per week). Half will be women. Right handed, English
speaking, be a non-smoker (never smoked more than 2 cigarettes per month). Subjects
will have a BMI between 18.5 and 35.

Exclusion Criteria:

- a) serious or unstable medical illness (e.g., cancer); b) past or current history of
alcoholism or consistent drug use; c) current major psychiatric illness as defined by
the DSM-IV criteria including eating disorders d) medications that affect alertness
(e.g., barbiturates, benzodiazepines, chloral hydrate, haloperidol, lithium,
carbamazepine, phenytoin, etc.); e) history of major head trauma with loss of
consciousness; f) ongoing pregnancy; g) known taste or smell dysfunction; h) a
diagnosis of diabetes; i) any known food allergy, certain food sensitivities
(lactose); j) pregnant or nursing women. Daily drinkers and individuals meeting
criteria for alcohol dependence will be excluded.