Abstract:

Dopamine (DA) is one of the brain’s fundamental neurotransmitters. Despite the fact that the dopaminergic synapses constitute less than 1% of all brain synapses, DA is implicated in a number of critical physiological functions and in the pathogenesis of important psychiatric diseases such as schizophrenia, attention-deficit/hyperactivity disorder (ADHD), Parkinson’s disease (PD) and others. Genetically modified animals represent important tools in understanding the role of DA in the regulation of brain functions and pathology. The most known transgenic animal models to investigate DA abnormalities are dopamine transporter (DAT) knock-out (KO) mice, DAT knock-down mice and DAT over-expressing mice. It is not surprising, since DAT (Slc6a3), the major target of psychostimulant drugs of abuse such as amphetamine (AMPH) and cocaine, plays a key role in maintaining both the extraneuronal and intraneuronal DA levels via selective re-uptake of released DA back in the presynaptic dopaminergic neurons. The data gained from studies using the transgenic mice have provided numerous advances in understanding not only basic principles of DA transmission, but also the mechanisms of psychotropic drugs action, interaction between neurotransmitter systems, pathological mechanisms involved in the DA-related brain disorders and uncovered new principles of therapy of these disorders. However, certain questions, particularly concerning the investigation of cognitive behavioural processes that are critical for modelling neuropsychiatric conditions can be more reliably addressed in transgenic rats. A rat has larger brain size for neurosurgery and electrophysiological recordings, richer behaviour and demonstrate more robust and reproducible performance in cognitive tasks . Thus, rats with deficient DAT function were developed by two groups independently. DAT-KO rat line from Leo and colleagues was created in outbred Wistar Han rats by using zinc finger nuclease technology. DAT-KO rats have no DAT protein and function due to the 5 bp deletion and an early stop codon insertion. DATN157K mutant rats from Vengeliene et al. were generated in an inbred F344 line by N-ethyl-N-nitrosourea (ENU)-induced spontaneous mutation. The rat DAT-N157K protein is transcribed and translated but is not correctly processed to the cell surface resulting in dramatically decreased (> 95%) of DAT function. Thus, by the level of DAT deficiency DATN157K mutant rats are more comparable to DAT knockdown, rather than DAT-KO mice. Since a well-known draw-back of the ENU technology is the induction of bystander mutations, DAT-N157K founder rats were backcrossed with intact female rats for up to 13 generations to reduce the chance of contribution of additional mutations to the observed phenotype.