Interaction between serotonin transporter and dopamine D2/D3 receptor radioligand measures is associated with harm avoidant symptoms in anorexia and bulimia nervosa

Bailer, Ursula F.; Frank, Guido; Price, Julie C.; Meltzer, Carolyn C.; Becker, Carl; Mathis, Chester A.; Wagner, Angela; Barbarich-Marsteller, Nicole C.; Bloss, Cinnamon S.; Putnam, Karen; Schork, Nicholas J.; Gamst, Anthony; Kaye, Walter H.

doi:10.1016/j.pscychresns.2012.06.010

Cited by 74 publications

(75 citation statements)

References 85 publications

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“…That is, AN patients are more sensitive to negative feedback than control participants (Harrison et al, 2010; Harrison, Treasure, & Smillie, 2011; Jappe et al, 2011) and this sensitivity to punishment has been linked with abnormal eating behaviors in non-clinical samples (Loxton & Dawe, 2006). As for those parameters thought to be sensitive to the integrity of dopamine levels (γ and λ), these were selected given previous studies showing increased dopamine binding using PET imaging (indicative of decreased dopamine levels) in the ventral striatumin weight restored AN patients (Bailer et al, 2013; Frank et al, 2005). Taken together, the simulation results are very promising in terms of helping to better pinpoint the nature of set shifting performance in AN-WR individuals and to help support the hypothesis that alterations in striatal dopamine may be the underlying neurobiological substrate for set shifting deficits in these patients.…”

Section: Discussionmentioning

confidence: 99%

Simulating category learning and set shifting deficits in patients weight-restored from anorexia nervosa.

et al. 2014

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Objective To examine set shifting in a group of women previously diagnosed with anorexia nervosa who are now weight-restored (AN-WR) and then apply a biologically-based computational model (Competition between Verbal and Implicit Systems; COVIS) to simulate the pattern of category learning and set shifting performances observed. Method Nineteen AN-WR women and 35 control women (CW) were administered an explicit category learning task that required rule acquisition and then a set shift following a rule change. COVIS was first fit to the behavioral results of the controls and then parameters of the model theoretically relevant to AN were altered to mimic the behavioral results. Results Relative to CW, the AN-WR group displayed steeper learning curves (i.e., hyper learning) prior to the rule shift, but greater difficulty in learning the new categories after the rule shift (i.e., a deficit in set shifting).Hyper learning and set shifting deficits in the AN-WR group were not associated and differentially correlated with clinical measures. Hyper learning in the AN-WR group was simulated by increasing the model parameter that represents sensitivity to negative feedback (δ parameter), whereas the deficit in set shifting was simulated by altering the parameters that represent changes in rule selection and flexibility (λ and γ parameters, respectively). Conclusions These simulations suggest that multiple factors can impact category learning and set shifting in AN-WR individuals (e.g., alterations in sensitivity to negative feedback, rule selection deficits, and inflexibility) and provide an important starting point to further investigate this pervasive deficit in adult AN.

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Section: Discussionmentioning

confidence: 99%

Simulating category learning and set shifting deficits in patients weight-restored from anorexia nervosa.

et al. 2014

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“…Centrally, SERT interactions with other G protein-coupled receptors, such as the A3 adenosine receptors in mouse midbrain serotonergic neurons and heterologous expression systems (Zhu et al, 2011), where SERT physically complexes with and functionally regulates the receptor. In humans, the interaction of SERT and striatal D2/D3 dopamine receptors has recently be hypothesized to contribute to the mechanism of harm avoidance in eating disorders (Bailer et al, 2013). In the future, therefore, it will be interesting to see whether central, direct SERT and 5-HT receptors interact not only physiologically, but also pathophysiologically as in models of diabetes or insulin signaling impairment.…”

Section: Discussionmentioning

confidence: 99%

Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function

Saunders

Siuta

Robertson

et al. 2014

Neurochemistry International

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The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. Here, we examined whether phosphorylation of Akt, a key regulator of the insulin signaling pathway, controls serotonin (5-HT) signaling. To explore how impairment in Akt function regulates 5-HT homeostasis, we used a brain-specific rictor knockout (KO) mouse model of impaired neuronal phosphorylation of Akt at Ser473. Cortical 5-HT1A and 5-HT2A receptor binding was significantly elevated in rictor KO mice. Concomitant with this elevated receptor expression, the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) led to an increased hypothermic response in rictor KO mice. The increased cortical 5-HT1A receptor density was associated with higher 5-HT1A receptor levels on the cortical cell surface. In contrast, rictor KO mice displayed significantly reduced head-twitch response (HTR) to the 5-HT2A/C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), with evidence of impaired 5-HT2A/C receptor signaling. In vitro, pharmacological inhibition of Akt significantly increased 5-HT1A receptor expression and attenuated DOI-induced 5-HT2A receptor signaling, thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation. These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors, demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function.

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“…For instance, a PET study of a mixed group of subjects with recovered ED showed a significant positive correlation between 5-HTT and DA D2/D3 binding for the dorsal caudate, anteroventral striatum, medial caudate, ventral putamen and dorsal putamen. 47 A linear regression analysis showed that the interaction between 5-HTT and DA D2/D3 binding potential in the dorsal putamen significantly predicted HA, while there was a trend towards significance in the dorsal caudate.…”

Section: Competition Between Da and 5-htmentioning

confidence: 94%

Nothing Tastes as Good as Skinny Feels: the Neurobiology of Anorexia Nervosa

Kaye¹,

Wierenga²,

Bailer³

et al. 2014

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Individuals with anorexia nervosa (AN) engage in relentless, restrictive eating and often become severely emaciated. Because there are no proven treatments, AN has high rates of relapse, chronicity, and death. Those with AN tend to have childhood temperament and personality traits, such as anxiety, obsessions, and perfectionism, which may reflect neurobiological risk factors for developing AN. Restricted eating may be a means of reducing negative mood caused by skewed interactions between serotonin aversive or inhibitory and dopamine reward systems. Brain imaging studies suggest altered eating is a consequence of dysregulated reward, and/or awareness of homeostatic needs, perhaps related to enhanced executive ability to inhibit incentive motivational drives. Understanding the neurobiology of this disorder is likely to be important for developing more effective treatments.

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Interaction between serotonin transporter and dopamine D2/D3 receptor radioligand measures is associated with harm avoidant symptoms in anorexia and bulimia nervosa

Cited by 74 publications

References 85 publications

Simulating category learning and set shifting deficits in patients weight-restored from anorexia nervosa.

Simulating category learning and set shifting deficits in patients weight-restored from anorexia nervosa.

Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function

Nothing Tastes as Good as Skinny Feels: the Neurobiology of Anorexia Nervosa

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