Previous studies found that depression primarily results fro

Previous studies found that depression primarily results from impaired monoaminergic neurotransmission systems [1], [2]. The glutamatergic and GABAergic systems as well as several neuropeptide systems have also been the focus of pathophysiological studies on depression [1], [2]. Inflammatory cytokines and molecular intermediates are also suggested to be involved in depression, presumably by regulating neurotransmitter metabolism, neuroendocrine function, and synaptic function [4]. Among these molecules, cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin (PG) production, is suggested to play an important role in depression because COX-2 mRNA is increased in the peripheral blood cells of patients with depression [5]. Consistent with this, a specific COX-2 inhibitor, celecoxib, has a therapeutic effect on depression (for a review, see [6]). COX-2 was also demonstrated to be involved in animal depression models. In the forced-swim test (FST), a behavioral despair paradigm, chronic treatment with selective and non-selective COX-2 inhibitors shows antidepressant-like effect [7]. In a chronic unpredictable stress model, treatment with celecoxib blocks decreased sucrose preference, an indicator of a key symptom of depression [8]. The five primary PGs (PGD2, PGE2, PGF2α, PGI2, and thromboxane A2) are synthesized from arachidonic Cy5 TSA Fluorescence System Kit via sequential actions of COX subtypes and their respective synthases; these PGs exert their actions through their cognate G-protein-coupled receptors, including the chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) [9]. PGE2 signaling mediated through the E prostanoid receptor 1 (EP1) receptor is critical for susceptibility to repeated stress, a risk factor for depression [10]. Considering the major effect observed for COX-2 inhibitors in depression, the other PGs and their receptors are likely to be involved. However, the precise role of each PG and its receptor is largely unknown. CRTH2 and the D prostanoid receptor (DP1) function as receptors for PGD2[11]. In the central nervous system, DP1 but not CRTH2 is involved in PGE2-induced allodynia, the sleep–wake cycle, glutamate-induced neuronal toxicity, and food intake [12], [13], [14], [15], suggesting that DP1 and CRTH2 have distinct functions in the central nervous system. Recently, we found that central CRTH2 but not DP1 regulates emotional aspects of lipopolysaccharide (LPS)- and tumor-induced sickness behaviors [16]. Given that LPS-induced sickness behavior critically involves the COX-2-PG pathway [17], [18], [19], [20], [21], PGD2-CRTH2 is likely to modulate sickness behavior by regulating COX-2-mediated signaling in the brain [16]. Furthermore, several lines of evidence suggest that sickness behavior and depression share many of the same symptoms and common inflammatory pathways [22]. These findings led us to further investigate the possible involvement of central PGD2-CRTH2 in motivational impairments such as depression and sickness behavior.
Materials and methods
Results
Discussion Previous studies have found that the COX-dependent production of PG in the brain plays an important role in various animal models of depression [7], [8]; however, it is largely unknown which PG subtypes mediate the behavioral changes in these models. Using well-established depression-related models, we here demonstrated that both the genetic and acute pharmacological inhibition of CRTH2 abolished an increase in depression-related behaviors, such as decreased social interaction in the SIT and increased immobility in the FST. We also found that the mRNA expression of COX-2 and L-PGDS, both of which regulate PGD2 production, were increased by CORT treatment. Taken together, these results suggest that CRTH2-mediated signaling in the brain is likely a molecular player that mediates depression-related behaviors. Clinical studies revealed that non-steroidal anti-inflammatory drugs, which inhibit COX activity, have therapeutic effects in major depression [42], [43]. These studies suggested that PGs are involved in depression; however, the precise mechanisms underlying COX-mediated depression remain unclear. Our current studies strongly argue that central CRTH2-mediated signaling plays an important role in depression. Recently, Narumiya's group found that PGE2 together with its receptor EP1 are relevant in repeated social defeat stress, a mouse model of depression [10]. Furthermore, other PGE2 receptors, including EP2, EP3, and EP4, are likely to be involved in depression-related behavior (for a review, see [44]). In contrast to these receptors, DP1, another PGD2 receptor, is unlikely to be involved in depression [16]. Future studies using genetic and pharmacological interventions of PG-mediated pathways are needed to elucidate the precise functions of these pathways in depression. Specifically, it will be interesting to learn whether PGD2−CRTH2 and PGE2−EP1 pathways cooperatively or independently regulate depression.