Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain

This placebo-controlled animal study (n=135) investigated the possibility of synergistic interactions between the antidepressant imipramine (10-20mg/kg) with ketamine (5-10mg/kg). The results indicate that co-administration of imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone.

Abstract of Ketamine plus imipramine treatment induces antidepressant-like behaviour… in rat brain

“A growing body of evidence has pointed to the N-methyl-d-aspartate (NMDA) receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study investigated the possibility of synergistic interactions between antidepressant imipramine with the uncompetitive NMDA receptor antagonist ketamine. Wistar rats were acutely treated with ketamine (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) and then subjected to forced swimming tests. The cAMP response element bindig (CREB) and brain-derived neurotrophic factor (BDNF) protein levels and protein kinase C (PKC) and protein kinase A (PKA) phosphorylation were assessed in the prefrontal cortex, hippocampus and amygdala by imunoblot. Imipramine at the dose of 10 mg/kg and ketamine at the dose of 5 mg/kg did not have effect on the immobility time; however, the effect of imipramine (10 and 20 mg/kg) was enhanced by both doses of ketamine. Ketamine and imipramine alone or in combination at all doses tested did not modify locomotor activity. Combined treatment with ketamine and imipramine produced stronger increases of CREB and BDNF protein levels in the prefrontal cortex, hippocampus and amygdala, and PKA phosphorylation in the hippocampus and amygdala and PKC phosphorylation in prefrontal cortex. The results described indicate that co-administration of antidepressant imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whilst limiting side effects.”

Authors: Gislaine Z. Réus, Roberto B. Stringari, Karine F. Ribeiro, Ana K. Ferraro, Marcelo F. Vitto, Patrícia Cesconetto, Claúdio T. Souza & João Quevedo

Summary of Ketamine plus imipramine treatment induces antidepressant-like behaviour… in rat brain

Several studies have shown that NMDA receptor antagonists have antidepressant effect in animal models and humans, as well as changes in NMDA receptor subunits.

Several studies have pointed to the role of brain-derived-neurotrophic factor (BDNF) in major depression. BDNF levels are decreased in animal models of depression and humans with depression, and BDNF levels are increased by antidepressant drugs and brain infusion of BDNF produces antidepressant-like actions in rats.

CREB is a transcription activator that is activated by a number of signal transduction cascades, including cAMP protein kinase A (PKA), and is implicated in both stress and antidepressant-induced transcriptional regulation. PKA is also reduced in post mortem brain tissue from people with a history of major depression.

In the present study, rats were given a combination of imipramine and ketamine intraperitoneally 60 min before the test session, to test if ketamine and imipramine would produce synergistic antidepressive-like effects in the forced swim test, BDNF and CREB protein levels and PKA and PKC phosphorylation in rat brain.

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Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain

https://doi.org/10.1016/j.bbr.2011.02.024

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Cite this paper (APA)

Réus, G. Z., Stringari, R. B., Ribeiro, K. F., Ferraro, A. K., Vitto, M. F., Cesconetto, P., ... & Quevedo, J. (2011). Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behavioural brain research221(1), 166-171.

Study details

Compounds studied
Ketamine

Topics studied
Depression

Study characteristics
Animal Study

Participants
135 Rodents

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