Altered mitochondrial function is implicated in disorders characterized by prefrontal cortex activation deficits, including attention deficit hyperactivity disorder (ADHD). The expression of mitochondrial DNA-coded respiratory chain complex I genes (ND1–ND6) in the prefrontal cortex of ADHD animal models was estimated in the present study. ND gene expression was assessed in two publicly available datasets: GSE117357 (Adgrl3 knockout mice) and GSE173926 (MYT1L heterozygous knockout mice). Additionally, we measured NDs gene expression via qPCR in dopamine transporter knockout (DAT-KO) rats and their heterozygous (DAT-Het) littermates. Transcriptomic analysis revealed consistent ND1–ND6 expression profiles across both datasets, and co-expression among ND genes was significantly enhanced in ADHD models compared to wild-type controls. Whole-transcriptome analysis identified associations between ND3 and ND4L expression and genes involved in neural tissue-specific processes, exclusively in ADHD models. In DAT-KO and DAT-Het rats, NDs gene co-expression increased. Furthermore, in DAT-Het rats, which do not exhibit hyperactivity, the upregulation of ND4L expression relative to wild-type littermates was demonstrated. The observed changes in mitochondrial complex I gene co-expression in ADHD models suggest mitochondria may serve as a prospective target for adjuvant therapy. These findings highlight the need for further investigation into mitochondrial contributions to ADHD pathophysiology.

Background: The role of dopamine in brain functions has been well established, and dopamine imbalances can cause problems in working memory and spatial learning. The dopamine transporter (DAT) plays a significant role in dopamine regulation. Rats with a knockout of the dopamine transporter gene (DAT-KO), the model of attention deficit hyperactivity disorder (ADHD), are characterized by hyperdopaminergia and spatial memory impairments. Methods: Rats were trained to manipulate objects and recognize their spatial location and shape using RedBox apparatus. They needed to move a distant object to receive a food reward. After changing the shape and spatial location of objects, the ability to re-learning was evaluated. Results: We demonstrated that including objects to manipulate in the task conditions enables faster and stable learning of DAT-KO rats. The shape of the object did not influence the level of task performance, but changing the spatial location of the object led to the impairment of task performance in hyperactive rats. Conclusions: The data obtained highlight the role of hyperactivity and hyperdopaminergia in DAT-KO rats in spatial learning. We suggest that our findings may help in the further development of new training tasks for individuals with ADHD and spatial memory deficits.

Background/Objectives: Chronic ethanol consumption damages erythrocyte membranes, reducing their deformability and disrupting erythropoiesis. Dopaminergic signalling plays an important role in regulating haematopoietic stem cells. However, the impact of genetic alterations in the dopamine system on the functional properties of erythrocytes and their resistance to the toxic effects of alcohol remains understudied. In this study, we evaluated haematological parameters and the sensitivity of erythrocytes to chronic ethanol exposure in DAT-HET rats (heterozygous for the dopamine transporter gene) compared to Wistar rats. Methods: Both lines of rats were subjected to chronic alcoholisation (10% ethanol for six months). Flow cytometry was used to assess reticulocyte production, intracellular esterase activity (cell viability), and membrane lipid asymmetry disruptions. Laser diffraction was used to evaluate osmotic resistance (deformability). Results: The partial knockout of the DAT gene significantly altered the baseline haematological profile, resulting in pronounced leukopenia, moderate thrombocytopenia, moderate erythrocyte macrocytosis, and reduced intracellular esterase activity. The consequences of chronic ethanol consumption in Wistar rats (anaemia, decreased reticulocyte count, increased osmotic rigidity of erythrocytes, and an increased proportion of annexin-positive cells) were similar to those observed in humans, thus confirming the validity of the experimental model. In contrast, chronic alcohol exposure did not significantly influence haematopoiesis parameters or erythrocyte biophysical properties in DAT-HET rats, indicating that even a 50% loss of the dopamine transporter strongly prevented ethanol’s damaging effects on blood cells. Conclusions: The marked contrast between Wistar rats (which develop alcohol-induced anaemia and erythrocyte dysfunction similar to humans) and DAT-HET rats (which remain largely unaffected) demonstrates that dopaminergic signalling plays a previously unrecognised role in determining erythrocyte sensitivity to alcohol toxicity.

Deregulation of striatal neurotransmission is a key pathogenetic mechanism in neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) and autism. In the present study, we applied a proteomic approach to demonstrate shifts in striatal protein expression in rats with heterozygous (DAT-Het) and homozygous (DAT-KO) dopamine transporter (DAT) gene knockouts. These animals model dose-dependent ADHD- and autism-like behaviors, ranging from slightly increased activity and social disturbances in DAT-Het rats to a pronounced phenotype in DAT-KO rats. We revealed pronounced changes in the proteomic profiles of both groups, associated primarily with deregulation of proteins involved in energy and carbon metabolism. Furthermore, we identified changes in vesicular transport proteins specific to DAT-KO and DAT-Het rats. Since these changes involved SNARE complex components, we evaluated SNARE mRNA expression in our models and public transcriptomic data for mouse models of neurodevelopmental disorders, including Mbd5 gene haploinsufficiency and a polygenic model of ADHD. No significant changes in mRNA levels were revealed in any model. Thus, the identified protein expression changes likely depend on post-transcriptional mechanisms. These data suggest a deregulation of metabolism in DAT-Het rats, which becomes more pronounced in DAT-KO rats.