Possible Anti-Depressant Effect of the Selective Cox-2 Inhibitor Meloxicam, Its Relationship With the Dopaminergic Brain System

Abstract

Inflammation is now believed to play an important role in the development of depression, and it is suggested that inflammation may be a promising target for the treatment and prevention of mood disorders. It is not surprising that various non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2), are being tested for their antidepressant properties. At the same time, it is known that inhibition of COX-2 has a certain effect on the dopaminergic (DA) system. However, in the literature, there are also opposite opinions on this matter, for example, that the neuroprotective effect of NSAIDs is associated not with COX-2, but with the PI3K/Akt signaling pathway, and inhibition of COX-2 does not have a neuroprotective effect, and even negatively affects the central nervous system up to until the pathophysiology of depression aggravates. Therefore, the question of the antidepressant properties of COX-2 inhibitors remains open for further research. In addition, because of the dynamic nature of depression, it is important to ascertain whether NSAIDs may be prophylactic in the early stages of depression. Accordingly, the aim of this study was to determine the presence or absence of antidepressant potential in the selective COX-2 inhibitor meloxicam (21 days, 1 mg/kg), its possible relationship with the DA system, by tracing these effects over time. The combined use of meloxicam and haloperidol (24 days, 2.5 mg kg) in the first 7 days of the experiment did not significantly affect the level of immobility of rats in the «Forced swim test», but on days 8, 12–19, and 21 of the experiment, the level of immobility in this the group was significantly higher than in the haloperidol group. The administration of meloxicam also failed to reverse the negative effects of stress: on days 1–5, 7–12 and 15–19, there were no differences between the groups in the level of immobility, and on days 6, 13–14 and 20-21, meloxicam even increased immobility by compared with the stress group. Another evidence in favor of the depressant effect of meloxicam is the fact that it increases the level of immobility in intact rats, while the MAO inhibitor selegiline (24 days, 3 mg/kg), on the contrary, does not affect the level of immobility – the data are indistinguishable from control. Meloxicam also failed to increase locomotor activity in rats in the «Actimeter», suppressed by the combined use of haloperidol and stress. The positive effect of meloxicam was manifested only in the improvement of the task performance on the Rotarod against the background of D2-receptor blockade. Inhibition of COX-2 by meloxicam did not have the expected antidepressant effect in the «Forced swim test» and «Actimeter», but, on the contrary, led to a worsens emotional state of the animals. At the behavioral level, we were unable to obtain convincing evidence of a direct connection between the effects of meloxicam and the functioning of the DA system, although its activating effect on animal locomotion in the Rotarod test after blockade of D2-receptors with haloperidol was established.