Yohimbine-Induced Amygdala Activation in Pathological Gamblers: A Pilot Study

et al. (2012) Yohimbine-Induced Amygdala Activation in Pathological Gamblers: A Pilot Study. PLoS ONE 7(2): e31118. doi:10.1371/journal.pone.0031118 Yohimbine-Induced Amygdala Activation in Pathological Gamblers: A Pilot Study Igor Elman 0 Lino Becerra 0 Evelyne Tschibelu 0 Rinah Yamamoto 0 Edward George 0 David Borsook 0 Bernard Le Foll, Centre for Addiction and Mental Health, Canada 0 1 Bedford Veterans Administration Medical Center and Department of Psychiatry, Cambridge Health Alliance, Harvard Medical School , Somerville , Massachusetts, United States of America, 2 P.A.I.N Group, McLean Hospital and Harvard Medical School , Belmont , Massachusetts, United States of America, 3 Clinical Psychopathology Laboratory, McLean Hospital and Harvard Medical School , Belmont, Massachusetts , United States of America Rationale and Objectives: There is evidence that drug addiction is associated with increased physiological and psychological responses to stress. In this pilot functional magnetic resonance imaging (fMRI) study we assessed whether a prototype behavioral addiction, pathological gambling (PG), is likewise associated with an enhanced response to stress. Methods: We induced stress by injecting yohimbine (0.2-0.3 mg/kg, IV), an alpha-2 adrenoceptor antagonist that elicits stress-like physiological and psychological effects in humans and in laboratory animals, to four subjects with PG and to five non-gamblers mentally healthy control subjects. Their fMRI brain responses were assessed along with subjective stress and gambling urges ratings. Results: Voxelwise analyses of data sets from individual subjects, utilizing generalized linear model approach, revealed significant left amygdala activation in response to yohimbine across all PG subjects. This amygdala effect was not observed in the five control individuals. Yohimbine elicited subjective stress ratings in both groups with greater (albeit not statically significantly) average response in the PG subjects. On the other hand, yohimbine did not induce urges to gamble. Conclusions: The present data support the hypothesis of brain sensitization to pharmacologically-induced stress in PG. - Funding: This work was supported by the Grant DA017959 from the National Institute on Drug Abuse, awarded to Dr. Igor Elman. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. As legalized gambling activities are rapidly expanding in our society so do gambling-related public health problems [1]. The overall lifetime prevalence of problem and/or pathological gambling (PG) in the general adult population is about 5% [2,3] and its annual cost to the American society as a result of crime, decreased productivity and bankruptcies approximates $54 billion [4]. 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 [46]. 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 [716]. There is also evidence that stress exposure causes gambling urges that may precipitate relapse to gambling [1720]. Thus, like in drug addiction [2123], 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 [20]. 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 [20]. 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 [24,25]. In addition to its actions on the alpha-2 adrenergic systems, yohimbine also affects D2, alpha-1, 5HT1a, and benzodiazepine receptors [2628]. However, termination of yohimbines effects by alpha-2 agonists, clonidine and lofexidine, and replication of these effects by the selective alpha-2 adrenoceptor antagonist, RS79948-197, renders non alpha-2 receptors-related effects an unlikely mechanisms of yohimbines stressogenic action [27,28]. 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 yohimbineinduced 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 [29] resulting from norepinephrine releases within the amygdala [3032], which is also engaged by gambling cues reactivity [33] and by drug craving [34] 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. Subjects Participants of this pilot proof of concept/feasibility study comprised of four subjects [mean age (standard deviation, SD): 40.6 (13.0) years; 2 males and 2 females; 3 Caucasian and 1 African-American; weight: 80.4 (9.8) kg] meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR [35]) criteria for PG and for no other Axis I DSM-IV-TR diagnosis. The control subjects were five mentally healthy individuals [age: 31.0 (9.3) years; 4 males and 1 female, 3 Caucasian and 2 African-American; weight: 74.5 (9.3) kg] who were free from any type of gambling problems. There were no significant group differences in age (t = 1.06; df = 7; p = 0.32), in weight (t = 0.93; df = 7; p = 0.32) and in gender distribution (p = 0.52; two-tailed Fishers exact test). The subjects were diagnosed using a best estima (...truncated)