Modified swim test as a model of enhanced contextual conditioning during depression: expression of GSK3 beta and effects of antidepressant treatment

Impaired brain plasticity is a well-established pathophysiologic feature of depression, but little is known about an enhancement of depression-associated cognitive processing. We studied a novel paradigm that potentially models the augmented acquisition of adverse memories during the development of a depressive-like state in mice. We used a modification of the classic two-day protocol of a mouse Porsolt’s test with an additional session on Day 5 following the initial swim session. On the last day of testing, floating behavior, a parameter of helplessness, was increased in naïve mice that was accompanied by a reduction in the pGSK3b/GSK3b ratio and increased levels of brain GSK3b mRNA. The increase in GSK3b mRNA in prefrontal cortex during delayed testing session correlated with increases in floating behavior, which is not observed in the classic Porsolt’s paradigm. Replacement of the last swim session with exposure to the context of testing resulted in increased GSK3b mRNA level similar to the effect of swimming, while exclusion of the last swim session prevented these changes. The behavioral changes and the alterations in GSK3b gene and protein levels were prevented by 2-week treatment with a low dose of classical antidepressant tricyclic imipramine (7.5 mg/kg/day), or vitamin B1 (thiamine) (200 mg/kg/day), or with the highly bioavailable thiamine precursor benfotiamine (200 mg/kg/day). Our study also demonstrated, for the first time, the antidepressant-like properties of vitamin B1 and its pre-cursor, in a pre-clinical model of depression. Thus, the new forced swim test paradigm models the enhanced contextual conditioning of adverse memories so the individual animals with distinct susceptibility to this syndrome to be differentiated.