We compared anxiety, neuromotor, and cognitive functions in mutant rats with different allelic variants of dopamine transporter DAT knockout receiving balanced or excess in fat and fructose diet. The experiments were performed in DAT −/− homozygotes, DAT +/− heterozygotes, and DAT +/+ wild type rats. The genotype of DAT ‐ KO rats was confirmed by restriction analysis of DAT gene compared to behavioral responses in the open field test ( OF ). Animals in the first groups of each strain were fed a balanced AIN 93M diet; and those in the second groups with a high‐fat/high‐fructose diet. Neuromotor function was studied as grip strength, and behavioral responses were assessed in the elevated plus maze and conditioned passive avoidance response tests. The mass of the internal organs and white and brown fat, as well as selected lipid and nitrogen metabolism parameters in blood plasma were determined at the end of the experiment. DAT −/− had the highest specific grip strength, and showed an increase in initial exploratory activity in comparison with DAT +/− and DAT +/+. The exploratory activity was significantly reduced in the second test compared to the first one in DAT −/− and DAT +/− of first but not second group. Anxiety decreased with age in the second groups of DAT +/− and DAT +/+ (but not in DAT −/−) and was higher in DAT +/+ than in DAT +/− and DAT −/−. Excess fat and fructose resulted in the deterioration of short‐term memory in DAT +/+. Lipidomic indices of blood plasma were less responsive to diet in DAT −/− and DAT −/+ in comparison to DAT +/+. The increased As AT /Al AT activity ratio in DAT −/− compared with those in DAT +/+ suggests the activation of catabolism activity in the mutants. The consumption of excess fat and fructose significantly modified the effects produced by DAT gene allelic variants presumably due to the influence on the processes of dopamine metabolism.

Cell repair machinery is responsible for protecting the genome from endogenous and exogenous effects that induce DNA damage. Mutations that occur in somatic cells lead to dysfunction in certain tissues or organs, while a violation of genomic integrity during the embryonic period often leads to death. A mammalian embryo’s ability to respond to damaged DNA and repair it, as well as its sensitivity to specific lesions, is still not well understood. In this review, we combine disparate data on repair processes in the early stages of preimplantation development in mammalian embryos.

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Investigation of the precise mechanisms of attention deficit and hyperactivity disorder (ADHD) and other dopamine-associated conditions is crucial for the development of new treatment approaches. In this study, we assessed the effects of repeated and acute administration of α2A-adrenoceptor agonist guanfacine on innate and learned forms of behavior of dopamine transporter knockout (DAT-KO) rats to evaluate the possible noradrenergic modulation of behavioral deficits. DAT-KO and wild type rats were trained in the Hebb–Williams maze to perform spatial working memory tasks. Innate behavior was evaluated via pre pulse inhibition (PPI). Brain activity of the prefrontal cortex and the striatum was assessed. Repeated administration of GF improved the spatial working memory task fulfillment and PPI in DAT-KO rats, and led to specific changes in the power spectra and coherence of brain activity. Our data indicate that both repeated and acute treatment with a non-stimulant noradrenergic drug lead to improvements in the behavior of DAT-KO rats. This study further supports the role of the intricate balance of norepinephrine and dopamine in the regulation of attention. The observed compensatory effect of guanfacine on the behavior of hyperdopaminergic rats may be used in the development of combined treatments to support the dopamine–norepinephrine balance.

Parkinson’s disease is the second most common neurodegenerative pathology. Due to the limitations of existing therapeutic approaches, novel anti-parkinsonian medicines with non-dopamine mechanisms of action are clearly needed. One of the promising pharmacological targets for anti-Parkinson drug development is phosphodiesterase (PDE) 10A. The stimulating motor effects of PDE10A inhibition were detected only under the conditions of partial dopamine depletion. The results raise the question of whether PDE10A inhibitors are able to restore locomotor activity when dopamine levels are very low. To address this issue, we (1) developed and validated the rat model of acute severe dopamine deficiency and (2) tested the action of PDE10A inhibitor MP-10 in this model. All experiments were performed in dopamine transporter knockout (DAT-KO) rats. A tyrosine hydroxylase inhibitor, α-Methyl-DL-tyrosine (αMPT), was used as an agent to cause extreme dopamine deficiency. In vivo tests included estimation of locomotor activity and catalepsy levels in the bar test. Additionally, we evaluated the tissue content of dopamine in brain samples by HPLC analysis. The acute administration of αMPT to DAT-KO rats caused severe depletion of dopamine, immobility, and catalepsy (Dopamine-Deficient DAT-KO (DDD) rats). As expected, treatment with the L-DOPA and carbidopa combination restored the motor functions of DDD rats. Strikingly, administration of MP-10 also fully reversed immobility and catalepsy in DDD rats. According to neurochemical studies, the action of MP-10, in contrast to L-DOPA + carbidopa, seems to be dopamine-independent. These observations indicate that targeting PDE10A may represent a new promising approach in the development of non-dopamine therapies for Parkinson’s disease.