Association between Repeated Unpredictable Chronic Mild Stress (UCMS) Procedures with a High Fat Diet: A Model of Fluoxetine Resistance in Mice

Major depressive disorder is a debilitating disease. Unfortunately, treatment with antidepressants (ADs) has limited therapeutic efficacy since resistance to AD is common. Research in this field is hampered by the lack of a reliable natural animal model of AD resistance. Depression resistance is related to various factors, including the attendance of cardiovascular risk factors and past depressive episodes. We aimed to design a rodent model of depression resistance to ADs, associating cardiovascular risk factors with repeated unpredicted chronic mild stress (UCMS). Male BALB/c mice were given either a regular (4% fat) or a high fat diet (45% fat) and subjected to two 7-week periods of UCMS separated by 6 weeks. From the second week of each UCMS procedure, vehicle or fluoxetine (10 mg/kg, i.p.) was administrated daily. The effects of the UCMS and fluoxetine in both diet conditions were assessed using physical (coat state and body weight) and behavioural tests (the reward maze test and the splash test). The results demonstrate that during the second procedure, UCMS induced behavioural changes, including coat state degradation, disturbances in self-care behaviour (splash test) and anhedonia (reward maze test) and these were reversed by fluoxetine in the regular diet condition. In contrast, the high-fat diet regimen prevented the AD fluoxetine from abolishing the UCMS-induced changes. In conclusion, by associating UCMS—an already validated animal model of depression—with high-fat diet regimen, we designed a naturalistic animal model of AD resistance related to a sub-nosographic clinical entity of depression

Total grooming time in the splash test as an index of motivational and self-care behaviour.

<p>The grooming time (Mean +/− SEM) is presented for the control and the unpredictable chronic mild stress (UCMS) groups treated or not with fluoxetine (10 mg/kg, administrated daily during the last 5 weeks of each UCMS procedure) in the regular and high fat diet conditions. A) Before (S1) and after (S2) the first UCMS procedure. *p<.05: comparison between S1 and S2 for each group. B) Before (S3) and after (S4) the second UCMS procedure. *p<.05: comparison between S3 and S4 for each group.</p

Latency to chew a cookie in the reward maze test as an index of anhedonia.

<p>The latency to chew the chocolate cookie (Mean +/− SEM) is given for the session performed at the end of the second unpredictable chronic mild stress (UCMS) procedure (R2). The results are presented for the Control and UCMS mice under a regular or a high fat diet regimen who receive during the last 5 weeks of each UCMS procedure daily injection of either NaCl (9%) or Fluoxetine (10 mg/kg). *p<.05: Comparison to the control/NaCl group in the regular diet condition. #p<.05: Comparison between UCMS/NaCl and UCMS/fluoxetine groups in the same diet condition.</p

General procedure and experimental groups.

<p>In each regular diet and high fat diet condition, half of the mice were submitted to two 7-week periods of unpredictable chronic mild stress (UCMS) procedures separated by 6 weeks. Control mice were kept in standard laboratory conditions. After two weeks of UCMS, mice received either fluoxetine treatment (10 mg/kg, i.p.) or vehicle treatment (NaCl, 0.9%, i.p.). Treatments were administered daily during the last 5 weeks of the UCMS protocol and the same treatment procedure was performed during the second UCMS phase. Coat state and body weight were evaluated weekly and behaviour was assessed using the reward maze test and the splash test. One session of the reward maze test was performed at the end of the first UCMS procedure (Session R1) and one session at the end of the second UCMS procedure (Session R2). The splash test was performed at the beginning (session S1 for the first UCMS procedure and session S3 for the second UCMS procedure) and the end (session S2 for the first UCMS procedure and session S4 for the second UCMS procedure) of each UCMS procedure.</p

Coat state changes.

<p>The coat state scores (Mean +/− SEM) at the end of the two unpredictable chronic mild stress (UCMS) procedures are presented for both the regular diet (left) and the high fat diet (right) conditions for Control and UCMS groups treated or not with fluoxetine (10 mg/kg, administrated daily during the last 5 weeks of each UCMS procedure). *p<.05: comparison between the control and UCMS groups, from the same diet and treatment conditions. #p<.05: comparison between NaCl and fluoxetine-treated groups, from the same UCMS condition.</p