Abstract
Background: A large body of data suggests that inflammation may play a role in the pathophysiology and treatment of mood disorders. Consistently, anti-inflammatory drugs have been shown to exert mood-stabilizing effects in randomized clinical trials in humans, as well as in animal models of depression and mania. Particularly, selective cyclooxygenase-2 (COX-2) inhibitors such as celecoxib were found to reduce mood symptoms in patients with major depression and bipolar disorder.
Objectives: This study was undertaken to examine the effects of four mechanistically different anti-inflammatory drugs on mania-like behaviors in rats. The drugs that were tested are: 1) nimesulide (NMS), a selective COX-2 inhibitor; 2) dexamethasone (DXM), a potent anti-inflammatory corticosteroid; 3) pentoxifylline (PTF), a tumor necrosis factor (TNF)-a inhibitor; and, 4) montelukast (MTK), a leukotrienes receptors antagonist.
Methods: Part 1 - Rats were treated with NMS (5 mg/kg), DXM (1 mg/kg), PTF (10 mg/kg) and MTK (20 mg/kg) for 2 weeks through a daily intraperitoneal injection. At the end of drug treatment animals were subjected to an amphetamine (0.5 mg/kg)-induced hyperactivity test in which total distance travelled, mean velocity and the time spent in the center of an open field arena were measured. Part 2 – Rats were subjected to an aggression-inducing protocol (the resident-intruder aggression test, RIAT) for 4 weeks, at the last 2 weeks of which they were treated with NMS, DXM, PTF and MTK as described above. Then, aggressive behavior was evaluated by counting the number of attacks by “resident” (aggressive) rats against “intruder” (subject to aggression) rats.
Results and Discussion: Part 1- The administration of amphetamine prominently increased total distance travelled, mean velocity and time spent in center of the arena. NMS significantly and PTF non-significantly decreased all 3 tested measures. In contrast, DXM and MTK did not significantly alter the 3 tested measures (MTK increased time spent at center). Part 2 - PTF significantly attenuated aggressive behavior (number of attacks) among resident rats, while NMS, DXM and MTK did not have a significant effect. These results suggest that anti-inflammatory drugs do not exhibit potent anti-manic-like effects.