TRP canonical 4 and/or 5 channel inhibition reduces aversion- and increases reward-responding in chronically stressed mice

Background and purpose: Pharmacological inhibition of TRPC4 and/or TRPC5 channels reduces Pavlovian aversion memory in stressed mice and reduces amygdala reactivity to aversion in humans with depression. The aims of this mouse study were to improve understanding of these anxiolytic processes, determine whether there are corrective effects on reward processes, and provide further translational evidence for TRPC4/C5 channel brain and neuron distribution. Experimental approach: Mouse models of chronic social stress (CSS), with increased aversion and decreased reward responding, were applied to investigate the effects of a TRPC4/TRPC5 channel inhibitor. RT-qPCR and FISH were used to determine regional and neuronal gene expression. Key results: Male mice underwent CSS, or were controls, and a TRPC4/TRPC5 inhibitor or vehicle was administered prior to Pavlovian aversion learning: stressed-vehicle mice displayed excessive Pavlovian learning, measured as high freezing to tone and context, and this was reduced by a TRPC4/TRPC5 inhibitor. Different stressed and control mice were tested on discriminative reward learning: there was no TRPC4/TRPC5 inhibitor effect on learning, but it did increase reward responding and effortful reward motivation in stressed mice. In naive male and female mice, Trpc4 and Trpc5 gene levels were moderate and high in glutamate principal neurons in basolateral amygdala and ventral hippocampus, respectively; co-expression with the CCKB receptor was substantial. TRPC4 and TRPC5 were expressed by glutamate neurons in human amygdala and hippocampus. Conclusions and implications: This study furthers understanding of the therapeutic potential of TRPC4/TRPC5 channel inhibition for excessive aversion processing and impaired reward processing.