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The dopaminergic effects of esketamine are mediated by a dual mechanism involving glutamate and opioid receptors

Esketamine represents a new class of drugs for treating mood disorders. Unlike traditional monoaminergic-based therapies, esketamine primarily targets N-methyl-D-aspartate receptors (NMDAR). However, esketamine is a complex drug with low affinity for NMDAR and can also bind to other targets, such as opioid receptors. Its precise mechanism of action for its antidepressant properties remains debated, as does its potential for misuse. A key component at the intersection of mood and reward processing is the dopaminergic system. In this study, we evaluated the effects of esketamine in locomotion, anxiety tests and operant responding and we used in vivo fiber photometry to explore the neurochemical effects of esketamine in the nucleus accumbens of mice. Our findings demonstrated multifaceted effects of esketamine on neurotransmitter dynamics. In freely behaving mice, esketamine increased locomotion and increased extracellular dopamine tone -by impairing dopamine clearance rather than promoting dopamine release- while decreasing glutamatergic activity. However, it decreased dopamine spontaneous release event frequency and impaired reward-evoked dopamine release, leading to a reduction in operant responding rates. These dopaminergic effects were partially, and conditionally, blocked by the opioid antagonist naloxone and required glutamatergic input. In summary, our study reveals a complex interaction between neurotransmitter systems, suggesting that the neurochemical effects of esketamine are both circuit- and state-dependent.

The crosstalk between CREB and PER2 mediates the transition between mania- and depression-like behavior

Bipolar disorder (BD) is a severe psychiatric disorder characterized by alternating manic and depressive episodes. The molecular mechanisms underlying the transition between mania and depression remain unclear. Utilizing a mania animal model induced by ouabain, we observed reduced phosphorylated level of cyclic AMP-responsive element-binding protein (pCREB) and Period (PER)2 expression in the cornu ammonis (CA1) region of the hippocampus, which were restored by lithium treatment. shRNA knockdown of CREB or Per2 in CA1 region induced mania-like behavior, while overexpression of both factors resulted in depression-like behavior. Furthermore, our protein analyses revealed that the upregulation or downregulation of CREB or Per2 influenced each other’s expression. Co-immunoprecipitation results demonstrated that CREB interacts with PER2. Taken together, our data suggest for potential inter-regulatory crosstalk between CREB–PER2 in hippocampal CA1 region, which mediates the transition between mania- and depression-like behaviors.

Coastal wetland resilience through local, regional and global conservation

Coastal wetlands, including tidal marshes, mangrove forests and tidal flats, support the livelihoods of millions of people. Understanding the resilience of coastal wetlands to the increasing number and intensity of anthropogenic threats (such as habitat conversion, pollution, fishing and climate change) can inform what conservation actions will be effective. In this Review, we synthesize anthropogenic threats to coastal wetlands and their resilience through the lens of scale. Over decades and centuries, anthropogenic threats have unfolded across local, regional and global scales, reducing both the extent and quality of coastal wetlands. The resilience of existing coastal wetlands is driven by their quality, which is modulated by both physical conditions (such as sediment supply) and ecological conditions (such as species interactions operating from local through to global scales). Protection and restoration efforts, however, are often localized and focus on the extent of coastal wetlands. The future of coastal wetlands will depend on an improved understanding of their resilience, and on society’s actions to enhance both their extent and quality across different scales.

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