ERK-MAPK Pathway activation and inhibition of Proteasome 26S may contribute to OCD

Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling.

Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. … Our hypothesis that TrkB/ERK-MAPK pathway overactivation contributes to OCD was confirmed by artificial pathway downregulation using selumetinib, which restored normal behavior in SPRED2 KO mice. With this study, we discovered a link between SPRED2 deficiency, TrkB/ERK signaling, thalamo-amygdala malfunction, and psychiatric conditions like OCD. (R1)

Glucocorticoids inhibit MAPK

A completely different mechanism by which GR might exert its anti‐inflammatory effects is the inhibition of signaling pathways that regulate inflammatory processes, in particular the mitogen‐activated protein (MAP) kinases pathways.

For example, GR‐mediated inhibition of c‐Jun N‐terminal kinase (JNK) activity, leading to inhibition of c‐Jun phosphorylation, is proposed as an alternative mode of action of GR for the repression of AP‐1 activity.

The MAP kinase p38 is also a target for negative regulation by glucocorticoids, and its inhibition is involved in the destabilization of cyclooxygenase‐2 mRNA by GR. (R2)