Dopamine D2/3 receptor antagonism reduces activity-based anorexia.

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-HT(2A/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.

Cholecystokinin and estradiol synergistically potentiate satiety in rats.

The ability of octapeptide cholecystokinin (CCK), in interaction with ovarian steroid conditions, to decrease 1-h feeding was studied in 5-h food-deprived Sprague-Dawley rats. In Experiment 1, intact, unilaterally ovariectomized, and bilaterally ovariectomized females and intact males were given IP injections of 0, 0.25, 0.50, and 1.0 microgram/kg b.wt. CCK and were assessed for food ingestion at 1, 3, and 19 h. Food intake at 1 h was suppressed in animals receiving CCK compared to saline (0 dose); the threshold dosage was 1 microgram/kg b.wt. (p < 0.01) in this paradigm. No significant sex difference was observed between the four groups; however, animals with decreased ovarian steroids (intact males and bilaterally ovariectomized females) suppressed ingestion less than animals with greater ovarian steroid levels (intact and unilaterally ovariectomized females) at both the 0.25 and 1.0 microgram/kg b.wt. dosages (p < 0.01). Therefore, in a second experiment, sensitivity to CCK was compared in females in early metestrus, when estrogen levels are decreased, and during late diestrus, when estrogen levels are high, using dosages of 0, 0.25, 1, and 2.5 micrograms/kg b.wt. A statistically significant difference was found between sensitivity at early metestrus and late diestrus at the 2.5 micrograms/kg b.wt. dose only, with food ingestion more reliably depressed during periods of increased estrogen (p < 0.05). These results suggest that estradiol and CCK can have a synergistic effect on satiety.