The Effect of Selective Serotonin Releasing Agents in the Chronic Mild Stress Model of Depression in Rats

Chronic exposure to mild unpredictable stress has been found to depress the consumption of, and preference for, highly palatable sucrose solution in rats. Stress-induced behavioral deficits may be maintained for a long time, however chronic administration of clinically effective antidepressants can restore normal behavior. This is the first report showing that Sprague-Dawley rats can be used in this model. A preference deficit in this strain of rats took at least 7 weeks to develop; about twice the time required when hooded Lister or Wistar rats are used in this model. Water consumption was not effected by chronic exposure to the mild stress regime and/or by chronic administration of the selective serotonin (5-HT) releasing agent MMAI (5-methoxy-6-methyl-2-aminoindan). The stress-induced deficit in sucrose intake was completely reversed by chronic treatment with MMAI (5 mg/kg, 2 x day) over 3 weeks in the two-bottle tests. In single-bottle tests, chronic treatment with the selective 5-HT releasers, MMAI (5 mg/kg, 2 x day) or MTA (p-methylthioamphetamine; 5 mg/kg, 2 x day), reversed the deficit in rewarded behavior (anhedonia) measured as a decrease in the consumption of 1% sucrose solution in the chronic mild stress model of depression in rats. With the experimental procedure employed, and at a dose of 10 mg/kg/day of 5-HT releasers, the magnitude and onset of this effect were greater than observed following similar administration of the selective 5-HT reuptake inhibitor (SSRI) sertraline (10 mg/kg/day), used as a standard anti-depressant drug.