As legalized gambling activities are rapidly expanding in our society so do gambling-related public health problems 
. The overall lifetime prevalence of problem and/or pathological gambling (PG) in the general adult population is about 5% 
and its annual cost to the American society as a result of crime, decreased productivity and bankruptcies approximates $54 billion 
. These figures likely underestimate the problems associated with PG because this is a more ‘silent’ addiction without characteristic symptoms of intoxication, needles' marks, or overdose, and therefore may only become apparent relatively late in the addiction process with the emergence of devastating and irreversible consequences, including attempted suicide in up to 24% of untreated individuals 
. Hence, to improve diagnosis and treatment of PG it is important to identify its objective markers and their underlying neurobiology.
There is evidence that PG is associated with heightened stress responses. For example, gambling-related activities or exposure to gambling-related cues increases physiological stress responses like heart rate, skin conductance and norepinephrine concentrations in plasma and in cerebrospinal fluid 
. There is also evidence that stress exposure causes gambling urges that may precipitate “relapse” to gambling 
. Thus, like in drug addiction 
, stress can precipitate and exacerbate the maladaptive addictive behavior (gambling) and engagement in the addictive behavior or exposure to cues associated with maladaptive behavior (e.g., a slot machine) can lead to exaggerated or sensitized activation of the brain stress systems 
We have previously evaluated psychosocial stress levels in individuals with PG and found heightened scores across all measures; additionally, greater perceived severity and amount of daily stressors was associated with more urges to gamble 
. Here, we further evaluated whether PG is associated with enhanced stress response by using yohimbine in conjunction with blood-oxygen-level dependent (BOLD) pharmacological magnetic resonance imaging (phMRI).
Yohimbine is an FDA-approved medication (oral formulation) for the treatment of male erectile dysfunction. It is a prototypical alpha-2 adrenoceptor antagonist that has been used in numerous studies to induce stress- and anxiety-like states in both humans and laboratory animals 
. In addition to its actions on the alpha-2 adrenergic systems, yohimbine also affects D2, alpha-1, 5HT1a, and benzodiazepine receptors 
. However, termination of yohimbine's effects by alpha-2 agonists, clonidine and lofexidine, and replication of these effects by the selective alpha-2 adrenoceptor antagonist, RS-79948-197, renders non alpha-2 receptors'-related effects an unlikely mechanisms of yohimbine's stressogenic action 
Due to the complexity of the brain and of the interactions among its various structures, it is possible on a theoretical basis to construct a lengthy list of brain regions, engaged by yohimbine-induced stress, activity in which could be altered in PG. In this study the amygdala was given a priori
emphasis because blockade of presynaptic alpha-2 adrenoceptor leads to subjective stress responses 
resulting from norepinephrine releases within the amygdala 
, which is also engaged by gambling cues reactivity 
and by drug craving 
in respective subjects with PG and with drug dependence. With these considerations in mind, it was hypothesized that, in comparison in healthy subjects, PG individuals would display amygdala hyperresponsivity to yohimbine.