Dopamine D2/3 receptor antagonism reduces activity-based anorexia

Abstract

Anorexia nervosa (AN) is an eating disorder characterized by severe hypophagia and weight loss, and an intense fear of weight gain. Activity-based anorexia (ABA) refers to the weight loss, hypophagia and paradoxical hyperactivity that develops in rodents exposed to running wheels and restricted food access, and provides a model for aspects of AN. The atypical antipsychotic olanzapine was recently shown to reduce both AN symptoms and ABA. We examined which component of the complex pharmacological profile of olanzapine reduces ABA. Mice received 5-HT2A/2C, 5-HT3, dopamine D1-like, D2, D3 or D2/3 antagonist treatment, and were assessed for food intake, body weight, wheel running and survival in ABA. D2/3 receptor antagonists eticlopride and amisulpride reduced weight loss and hypophagia, and increased survival during ABA. Furthermore, amisulpride produced larger reductions in weight loss and hypophagia than olanzapine. Treatment with either D3 receptor antagonist SB277011A or D2 receptor antagonist L-741,626 also increased survival. All the other treatments either had no effect or worsened ABA. Overall, selective antagonism of D2 and/or D3 receptors robustly reduces ABA. Studies investigating the mechanisms by which D2 and/or D3 receptors regulate ABA, and the efficacy for D2/3 and/or D3 antagonists to treat AN, are warranted.

A focus on reward in anorexia nervosa through the lens of the activity‐based anorexia rodent model

“…Indeed, mice treated with the SSRI fluoxetine during the ABA paradigm showed increased food intake and reduced FAA; however, survival of the ABA paradigm was not increased compared to vehicle‐treated mice . Furthermore, treatment with d‐fenfluramine, a drug that stimulates 5‐HT release and blocks its reuptake, primarily through the 5‐HT 2C receptor, either did not impact the ABA phenotype or accelerated the associated weight loss and selective 5‐HT receptor antagonism promoted weight loss in ABA . Conversely, decreasing 5‐HT signalling by treatment with the 5‐HT antagonist 8‐OHDPAT was shown to prevent starvation‐induced hyperactivity in ABA without changing food intake .…”

“…It may be that the behavioural responses to global DA antagonism differ in the altered reward context of the ABA paradigm. Selective antagonism of DA2/3 receptors is shown to ameliorate ABA by increasing food intake to a greater extent than olanzapine administration, which is an antagonist to 5‐HT2 and DA receptors D1‐5, suggesting that the effects of D2/3 may underlie the mechanism of action of olanzapine in reducing ABA symptoms . Because dopamine is integral to mesolimbic reward processing, it follows logically that central reward dysfunction in AN and ABA is associated with the DA disturbances described above, specifically within the mesolimbic reward circuit.…”

“…69 Furthermore, treatment with d-fenfluramine, a drug that stimulates 5-HT release and blocks its reuptake, primarily through the 5-HT 2C receptor, either did not impact the ABA phenotype 70 or accelerated the associated weight loss 71 and selective 5-HT receptor antagonism promoted weight loss in ABA. 72 Conversely, decreasing 5-HT signalling by treatment with the 5-HT antagonist 8-OHDPAT was shown to prevent starvationinduced hyperactivity in ABA without changing food intake. 73 Despite these unconvincing findings, it is important to note that the 5-HT system is particularly complex, with 14 (or more) receptor subtypes and many other components that modulate regionally-specific effects.…”

Effects of 17<i>β</i>-Estradiol on Dopamine D2 Receptors in Thiamine-Deficient Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

“…Weight gain has been associated with increases in fasting glucose and lipids [57]. Selective anatgonism of D2 receptors with amisulpiride reduced largely severe weight loss and hypophagia in anorexia nervosa patients [58]. To explain the mechanisms of sulpiride-induced overweight, Parada et al [59] reported that intrahypothalamic injections of sulpiride elicited feeding, even in satiated rats.…”

The Role of Psychotropic Medications in the Management of Anorexia Nervosa: Rationale, Evidence and Future Prospects

“…Brain reward learning is altered in AN, behavior that has been associated with brain dopamine function suggesting that dopaminergic agents could ameliorate this dysfunction [132]. One study that tested serotonin 2A/2C, serotonin 3, dopamine D1-like, D2, D3 and D2/3 receptor antagonists indicated that the dopamine D2 and D3 receptor antagonists increased survival, while the other agents did not [133]. This is an interesting result, as the clinical studies using antipsychotics with dopamine D2/D3 antagonism have not shown benefits (see above).…”