NMDA receptor antagonists traxoprodil and lanicemine improve hippocampal-prefrontal coupling and reward-related networks in rats
The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine is known to have not only a rapid antidepressant effect but also dissociative side effects. Traxoprodil and lanicemine, also NMDA antagonists, are candidate antidepressant drugs with fewer side effects.
In order to understand their mechanism of action, we investigated the acute effects of traxoprodil and lanicemine on brain connectivity using resting-state functional magnetic resonance imaging (rs-fMRI).
Functional connectivity (FC) alterations were examined using interregional correlation networks. Graph theoretical methods were used for whole brain network analysis. As interest in NMDAR antagonists as potential antidepressants was triggered by the antidepressant effect of ketamine, results were compared to previous findings from our ketamine studies.
Similar to ketamine but to a smaller extent, traxoprodil increased hippocampal-prefrontal (Hc-PFC) coupling. Unlike ketamine, traxoprodil decreased connectivity within the PFC. Lanicemine had no effect on these properties. The improvement of Hc-PFC coupling corresponds well to clinical result, showing ketamine to have a greater antidepressant effect than traxoprodil, while lanicemine has a weak and transient effect. Connectivity changes overlapping between the drugs as well as alterations of local network properties occurred mostly in reward-related regions.
The antidepressant effect of NMDA antagonists appears to be associated with enhanced Hc-PFC coupling. The effects on local network properties and regional connectivity suggest that improvement of reward processing might also be important for understanding the mechanisms underlying the antidepressant effects of these drugs.
KeywordsNMDA antagonists fMRI Networks Hippocampal-prefrontal coupling
We thank Claudia Falfan-Melgoza and Felix Hörner for excellent technical assistance.
This study was supported by an unrestricted grant of Boehringer Ingelheim Pharma, Ingelheim, Germany.
It was partially supported by grants from the German Research Foundation (Deutsche Forschungsgemeinschaft): DFG GA 2109/2-1 to N.G. and DFG SA 1869/11-2 and SA 1869/14–1 to A.S.
Compliance with ethical standards
Conflict of interest
LK, BS, SS, DS, and CDC are employees of Boehringer Ingelheim Pharma, Ingelheim, Germany. All other authors state no conflict of interest.
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