Olanzapine, but Not Fluoxetine, Treatment Increases Survival in Activity-Based Anorexia in Mice

Abstract

Anorexia nervosa (AN) is an eating disorder characterized by extreme hypophagia, hyperactivity, and fear of weight gain. No approved pharmacological treatments exist for AN despite high mortality rates. The activity-based anorexia (ABA) phenomenon models aspects of AN in rodents, including progressive weight loss, reduced food intake, and hyperactivity. First, we optimized the ABA paradigm for mice. We compared mouse strains (Balb/cJ, A/J) for susceptibility with ABA, and evaluated the effects of different food access durations (2, 4, 6, 8, and 10 h) on ABA parameters. Balb/cJ mice exhibited significantly shorter survival time (days until 25% bodyweight loss) in the ABA paradigm compared with A/J mice. Furthermore, 6 h of food access reduced survival in mice housed with wheels without reducing survival in mice housed without wheels. We then evaluated the effects of chronic treatment with fluoxetine (4 weeks) or subchronic treatment with olanzapine (OLZ) (1 week) on ABA in BALB/cJ mice. OLZ (12 mg/kg/day) significantly increased survival and reduced food anticipatory activity (FAA). However, OLZ did not alter food intake or running wheel activity during ad-lib feeding (baseline) or restriction conditions, or in mice housed without wheels. Fluoxetine (18 mg/kg/day) increased food intake and reduced FAA, but did not alter survival. Here, we report for the first time that OLZ, but not fluoxetine, reduces ABA in mice. Our findings indicate further need for clinical investigations into the effects of OLZ, but not selective serotonin reuptake inhibitors, on core features of AN.

Activity-Based Anorexia Alters the Expression of BDNF Transcripts in the Mesocorticolimbic Reward Circuit

“…During the scheduled food access period (14 days), mice in the STV and ABA groups had access to food only 6 hours a day from 09:00–15:00, and were removed or “dropped” from the paradigm when they lost 25% of their baseline body weight. Based on results from previous studies [36], STV mice were not expected to lose 25% baseline body weight as rapidly as ABA mice. Therefore, to induce a dropout rate equivalent to ABA mice, STV mice received a daily-adjusted, limited amount of food during the 6 hours of food access [36].…”

“…Based on results from previous studies [36], STV mice were not expected to lose 25% baseline body weight as rapidly as ABA mice. Therefore, to induce a dropout rate equivalent to ABA mice, STV mice received a daily-adjusted, limited amount of food during the 6 hours of food access [36]. Since Ad Lib and RUN mice were also not expected to lose 25% of their baseline body weight, each Ad Lib mouse was yoked to a STV mouse, and each RUN mouse was yoked to an ABA mouse for removal from the study.…”

Anorexia Nervosa and Antipsychotics: How to Apply Research Findings to the Adolescent Population

“…Previous case studies of adolescents treated with SGAs have shown decreased obsessional thinking, agitation, and body image concerns (McKnight & Park, 2010;Trunko et al, 2011;Flament, et al, 2012;Dennis et al, 2006). In an activity-based anorexia model in mice, olanzapine was found to significantly decrease food-related anticipatory activity, indicating that olanzapine may help reduce anxious behaviors related to AN (Klenotich et al, 2012). With this goal in mind, there are further steps to take to ensure that future studies with SGAs are well constructed and thorough.…”

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

“…One study applied olanzapine to rats, which reduced hyperactivity on the running wheel suggesting that this drug could reduce excessive exercise drive in AN [117]. A study that compared olanzapine and the SSRI fluoxetine found that one-week treatment with olanzapine improved survival, but a four-week course of fluoxetine did not [118]; interestingly, olanzapine did not affect feeding or wheel-running. The dopamine D1,2 and 3 receptor antagonist cis-flupenthixol was given to ABA rats and improved feeding behavior and reduced weight loss [119].…”