Behavioural Brain Research
October 1, 2021
A. Rafało-ulińska, A. Pałucha-poniewiera
46 citations
In a mouse model of chronic unpredictable mild stress, (R)-ketamine reduced anhedonia and apathy for up to seven days after a single dose, whereas (S)-ketamine's effects lasted only 24 hours to three days. (R)-ketamine's behavioral effects required activation of TrkB receptors, while (S)-ketamine's did not. (S)-ketamine activated mTOR and ERK pathways and increased GluA1 protein in the prefrontal cortex; (R)-ketamine increased mTOR expression without changing ERK phosphorylation. (S)-ketamine produced signs of possible side effects at the doses tested, while (R)-ketamine did not. These results suggest (R)-ketamine may be more effective, longer-lasting, and safer than (S)-ketamine.
Pharmaceuticals
February 1, 2023
A. Pałucha-poniewiera, B. Bobula, A. Rafało-ulińska
A combination of (R)-ketamine and an mGlu2/3 receptor antagonist (LY341495), called mixRL, produced rapid and sustained antidepressant effects in mice subjected to chronic unpredictable mild stress (CUMS), a model of depression. A single dose reversed CUMS-induced memory deficits and depression-like behaviors. Electrophysiological recordings showed that mixRL normalized increased field potential amplitudes and paired-pulse responses in the prefrontal cortex (PFC) of stressed mice and restored reduced long-term potentiation (LTP). The findings suggest that mixRL's antidepressant and cognitive-enhancing actions involve modulation of glutamatergic transmission and synaptic plasticity in the PFC, with a low risk of side effects.
Pharmacology, Biochemistry and Behavior
August 1, 2022
A. Pałucha-poniewiera
Combining a low, subeffective dose of ketamine or its enantiomer (R)-ketamine with an mGlu2/3 receptor antagonist produces antidepressant-like effects in animal models of depression without the undesirable side effects seen with higher doses of ketamine or (S)-ketamine, such as psychostimulatory effects. The antidepressant effect of ketamine appears linked to mGlu2 receptor activity and may be reduced by mGlu2 agonists. This strategy aims to enhance ketamine's therapeutic effect while lowering its dose to reduce side effects, which are particularly concerning in patients with treatment-resistant depression. Further research is needed to confirm effectiveness in humans.
Progress in Neuro-psychopharmacology and Biological Psychiatry
January 2, 2021
A. Pałucha-poniewiera, K. Podkowa, A. Rafało-ulińska
The mGlu2/3 receptor antagonist LY341495 produced a dose-dependent antidepressant-like effect in mice exposed to chronic unpredictable mild stress, after both a single dose and three daily doses. Combining a low, ineffective dose of LY341495 with a low, ineffective dose of ketamine reversed stress-induced behavioral deficits, suggesting the combination could lower ketamine's therapeutic dose. The combination activated the mTOR pathway and did not cause hyperactivity, memory impairment, or motor coordination problems that occur with a higher ketamine dose. The findings indicate mGlu2/3 receptor antagonists may safely reduce the effective dose of ketamine.
Behavioural Pharmacology
September 1, 2019
A. Pałucha-poniewiera, K. Podkowa, Andrzej Pilc
Ketamine produces rapid antidepressant effects in people with depression. In rats, a drug called LY341495, which blocks group II metabotropic glutamate receptors, also shows rapid and lasting antidepressant-like activity and can boost the effect of a low dose of ketamine without side effects. This study examined how AMPA receptors and TrkB receptors contribute to the antidepressant-like effects of ketamine (3 mg/kg) given together with LY341495 (0.1 mg/kg) in the forced swim test in rats, measured 40 minutes, 3 hours, and 24 hours after administration. Blocking AMPA receptors with NBQX (10 mg/kg) reversed the antidepressant effect at all time points, while blocking TrkB receptors with ANA-12 blocked the effect only at 3 hours.