Abstract
Ketamine exerts rapid, long-lasting antidepressant effects after a single administration and, thus, overcomes the limitations of classic drugs but also induces psychotic effects. It is, therefore, essential to pinpoint the biomarkers of each effect to develop new fast-acting antidepressants.
With this purpose, we examined, in male mice, the temporal evolution of the antidepressant and psychotic-like effects of 5 and 30 mg/kg of ketamine, and the electrical activity and the expression of the plasticity-related molecules in both the ventromedial prefrontal cortex and dorsal hippocampus were analyzed.
Ketamine induced immediate psychotic-like effects. They were milder and shorter at the 5 mg/kg dose, with an equivalent antidepressant-like effect of both doses, at 2 and 24 h. Both doses evoked a short-lasting electrical pattern that was dose-dependent, characterized mainly by increased synchronized gamma, excitatory/inhibitory balance, synchronized theta, phase-amplitude coupling, and decreased mutual information in slow (SW), beta, and theta waves. The higher dose led to longer-lasting changes. The most significant were decreased SW and beta and increased gamma and communication in theta and beta. Both doses altered sleep architecture at 24 h and the expression of AKT, pAKT, pAKT/AKT, pERK/ER, and pmTOR/mTOR at 2 and 24 h.
Given their temporal association, the decreased SW and beta mutual information, changes in hyperexcitability and gamma and theta activity may be biomarkers of ketamine’s psychotic effect. However, changes in sleep architecture and in the expression of plasticity proteins, together with delayed increased raw information, gamma and excitability, among others, are likely associated with its antidepressant effect.