In recent years, enough evidence has accumulated to assert that cardiotonic steroids, Na⁺,K⁺-ATPase ligands, play an integral role in the physiological and pathophysiological processes in the body. However, little is known about the function of these compounds in the central nervous system. Endogenous cardiotonic steroids are involved in the pathogenesis of affective disorders, including depression and bipolar disorder, which are linked to dopaminergic system dysfunction. Animal models have shown that the cardiotonic steroid ouabain induces mania-like behavior through dopamine-dependent intracellular signaling pathways. In addition, mutations in the alpha subunit of Na⁺,K⁺-ATPase lead to the development of neurological pathologies. Evidence from animal models confirms the neurological consequences of mutations in the Na⁺,K⁺-ATPase alpha subunit. This review is dedicated to discussing the role of cardiotonic steroids and Na⁺,K⁺-ATPase in dopaminergic system pathologies—both the evidence supporting their involvement and potential pathways along which they may exert their effects are evaluated. Since there is an association between affective disorders accompanied by functional alterations in the dopaminergic system and neurological disorders such as Parkinson’s disease, we extend our discussion to the role of Na⁺,K⁺-ATPase and cardiotonic steroids in neurodegenerative diseases as well.

Background/Objectives: G protein-coupled trace amine-associated receptors (TAARs) belong to a family of biogenic amine-sensing receptors. TAAR1 is the best-investigated receptor of this family, and TAAR1 agonists are already being tested in clinical studies for the treatment of schizophrenia, anxiety, and depression. Meanwhile, other TAARs (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9 in humans) are mostly known for their olfactory function, sensing innate odors. At the same time, there is growing evidence that these receptors may also be involved in brain function. TAAR8 is the least studied TAAR family member, and currently, there is no data on its function in the mammalian central nervous system. Methods: We generated triple knockout (tTAAR8-KO) mice lacking all murine Taar8 isoforms (Taar8a, Taar8b, and Taar8c) using CRISPR-Cas9 technology. In this study, we performed the first phenotyping of tTAAR8-KO mice for behavioral, electrophysiological, and neurochemical characteristics. Results: During the study, we found a number of alterations specific to tTAAR8-KO mice compared to controls. tTAAR8-KO mice demonstrated better short-term memory, more depressive-like behavior, and higher body temperature. Also, we observed changes in the dopaminergic system, brain electrophysiological activity, and adult neurogenic functions in mice lacking Taar8 isoforms. Conclusions: Based on the data obtained, it can be assumed that the physiological TAAR8 role is not limited only to the innate olfactory function, as previously proposed. TAAR8 could be involved in brain function, in particular in dopamine function regulation.

Currently, there is a growing amount of evidence for the involvement of dopamine receptors and the functionally related trace amine-associated receptor, TAAR1, in upper intestinal function. In the present study, we analyzed their expression in the duodenum using publicly accessible transcriptomic data. We revealed the expression of DRD1, DRD2, DRD4, DRD5, and TAAR1 genes in different available datasets. The results of the gene ontology (GO) enrichment analysis for DRD2 and especially TAAR1 co-expressed genes were consistent with the previously described localization of D2 and TAAR1 in enteric neurons and secretory cells, respectively. Considering that co-expressed genes are more likely to be involved in the same biological processes, we analyzed genes that are co-expressed with TAAR1, DRD2, DRD4, and DRD5 genes in healthy mucosa and duodenal samples from patients with functional dyspepsia (FD) or diabetes-associated gastrointestinal symptoms. Both pathological conditions showed a deregulation of co-expression patterns, with a high discrepancy between DRDs and TAAR1 co-expressed gene sets in normal tissues and patients’ samples and a loss of these genes’ functional similarity. Meanwhile, we discovered specific changes in co-expression patterns that may suggest the involvement of TAAR1 and D5 receptors in pathologic or compensatory processes in FD or diabetes accordingly. Despite our findings suggesting the possible role of TAAR1 and dopamine receptors in functional diseases of the upper intestine, underlying mechanisms need experimental exploration and validation.

Objective: The Transformer maze was developed to evaluate the effectiveness of spatial navigation, learning, and memory. The modular design of the maze allows to create different routes inside the maze, varying the color of the walls and the presence of passages in them. Previously, this modification of the maze was used only for training rats. In this article, we demonstrate the possibilities of a Transformer maze for studying mouse behavior. Methods: The study was conducted on 15 male mice, divided into two groups: trained and untrained one. Previously, all animals were subjected to mild food deprivation, handling and getting used to the maze space. For trained group the experiment consisted of 4 days of maze training and 1 day of testing. Unlike trained mice, which underwent both training and testing phases, untrained mice underwent only the testing phase. Results and Discussion: In the experiment, we highlighted a number of parameters that allow us to assess the efficacy of learning of mice: the length of the path traveled, the number of visits to cul-de-sac sectors, the latency of entry into the finish sector and others. Our experiments have shown that trained mice perform the task better than untrained animals. Conclusions: The experiments demonstrated the potential of using a transforming maze to study spatial memory and learning characteristics in mice. This method is of translational significance, as it could potentially be used to identify cognitive impairments in transgenic mice or when studying pharmacological models of neuropsychiatric disorders.