Dopamine Transporter Deficient Rodents: Perspectives and Limitations for Neuroscience.

The key element of dopamine (DA) neurotransmission is undoubtedly DA transporter (DAT), a transmembrane protein responsible for the synaptic reuptake of the mediator. Changes in DAT's function can be a key mechanism of pathological conditions associated with hyperdopaminergia. The first strain of gene-modified rodents with a lack of DAT were created more than 25 years ago. Such animals are characterized by increased levels of striatal DA, resulting in locomotor hyperactivity, increased levels of motor stereotypes, cognitive deficits, and other behavioral abnormalities. The administration of dopaminergic and pharmacological agents affecting other neurotransmitter systems can mitigate those abnormalities. The main purpose of this review is to systematize and analyze (1) known data on the consequences of changes in DAT expression in experimental animals, (2) results of pharmacological studies in these animals, and (3) to estimate the validity of animals lacking DAT as models for discovering new treatments of DA-related disorders.

Noradrenergic Modulation of Learned and Innate Behaviors in Dopamine Transporter Knockout Rats by Guanfacine.

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.

Effects of Atomoxetine on Motor and Cognitive Behaviors and Brain Electrophysiological Activity of Dopamine Transporter Knockout Rats.

Changes in dopaminergic and noradrenergic transmission are considered to be the underlying cause of attention deficit and hyperactivity disorder (ADHD). Atomoxetine (ATX) is a selective norepinephrine transporter (NET) inhibitor that is currently used for ADHD treatment. In this study, we aimed to evaluate the effect of atomoxetine on the behavior and brain activity of dopamine transporter knockout (DAT-KO) rats, which are characterized by an ADHD-like behavioral phenotype. Prepulse inhibition (PPI) was assessed in DAT-KO and wild type rats after saline and ATX injections, as well as behavioral parameters in the Hebb-Williams maze and power spectra and coherence of electrophysiological activity. DAT-KO rats demonstrated a pronounced behavioral and electrophysiological phenotype, characterized by hyperactivity, increased number of errors in the maze, repetitive behaviors and disrupted PPI, changes in cortical and striatal power spectra and interareal coherence. Atomoxetine significantly improved PPI and decreased repetitive behaviors in DAT-KO rats and influenced behavior of wild-type rats. ATX also led to significant changes in power spectra and coherence of DAT-KO and wild type rats. Assessment of noradrenergic modulation effects in DAT-KO provides insight into the intricate interplay of monoaminergic systems, although further research is still required to fully understand the complexity of this interaction.

Different sensitivity to anesthesia according to ECoG data in dopamine transporter knockout and heterozygous rats.

Dopamine in the brain is involved in many important functions, including the regulation of wakefulness. There is also some evidence suggesting that the dopamine function is crucial in anesthetic function. The state of anesthesia is characterized by a change in the level of consciousness and a change in brain electrical activity. Due to impaired mechanisms of dopamine transportation back to the synaptic terminal, dopamine transporter (DAT) knockout and heterozygous rats have increased levels of the extracellular dopamine. In our work, we registered ECoG disturbances in knockout and heterozygous rats, as well as disturbances in tone and activity in acute experiments under the anesthesia Zoletil (tiletamine and zolazepam) from the somatosensory cortex using a NeuroNexus flat multielectrode array to study gamma activity. We also used four low-resistance electrodes to control the slow rhythm. Both low-resistance and high-resistance electrodes showed differences in the ECoG spectrum of heterozygotes and total knockouts from the wild type and from each other. Heterozygous rats for the DAT gene (HET) showed increased rapid beta and gamma activity and decreased slow delta activity, while complete knockouts (KO), on the contrary, showed increased delta activity and decreased beta and gamma activity. Thus, the ECoG spectrum of HET is shifted to the right, while that of KO is shifted to the left. Full knockouts also showed decreased spatial synchronization in the 30-100 Hz gamma range compared to the wild type (WT). It is assumed that sedation of HET and KO is shifted towards opposite directions compared to WT under the same anesthesia conditions.

Inhibition of PDE10A in a New Rat Model of Severe Dopamine Depletion Suggests New Approach to Non-Dopamine Parkinson's Disease Therapy.

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.

Features of DNA Repair in the Early Stages of Mammalian Embryonic Development.

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.

Comparative analysis of the influence of a high-fat/high-carbohydrate diet on the level of anxiety and neuromotor and cognitive functions in Wistar and DAT-KO rats.

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 AIN93M 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 AsAT/AlAT 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.