CE-123, a novel dopamine transporter inhibitor, attenuates locomotor hyperactivity and improves cognitive functions in rat model of fetal alcohol spectrum disorders
Ewa Gibula-Tarlowska, Volker Korz, Malgorzata Lopatynska-Mazurek, Agnieszka Chlopas-Konowalek, Pawel Grochecki, Predrag Kalaba, Vladimir Dragacevix, Robert Kotlinski, Radoslaw Kujawski, Michal Szulc, Kamila Czora-Poczwardowska, Przemyslaw L. Mikolajczak, Gert Lubec, Jolanta H. Kotlinska|Department of Pharmacology and Pharmacodynamics, Medical University, Lublin, Polan, Center for Brain Research, Medical Univesity of Vienna, Vienna, Austria, Institute of Toxicology Research, Borowa, Poland, Department of Pharmaceutical Chemistry, fdaculty of Life Sciences, university of Vienna, Vienna, Austria, Clinical Department of Cardiac Surgery, University of Rzeszow, Rzeszow, Poland, Paracelsus Private Medical University, Salzburg, Austria, Department of Pharmacology, University of Medical Sciences, Poznan, Poland|Behavioural Brain Research|2021|113326, ISSN 0166-4328, https://doi.org/10.1016/j.bbr.2021.113326.
Children exposed to ethanol during the prenatal period can experience Fetal Alcohol Spectrum Disorder (FASD) which is characterised by hyperactivity, impulsivity and learning and memory disability, among others. In early stages of brain development, dopamine is responsible for neuronal differentiation, migration, axonal and dendritic growth and in adolescents it is involved in learning and cognitive flexibility. Previous research has indicated that impaired dopamine signalling is associated with FASD. The time period of “brain growth spurt” of the rat is between postnatal day (PND)4-10 where the rat embryonic development is characterised by rapid neuronal proliferation and synaptogenesis. These processes occur during the third trimester of the development of human fetuses, making these periods comparable. In this study, neonatal rats were exposed to ethanol intubation across the neonatal period (PND4-9) and after weaning the male rats were randomly split into three groups. Some of the rats were administered various does of DAT inhibitor CE-123 (1, 3 or 10 mg/kg). Dopamine (D1, D2 and D5) receptor mRNA expression in brain structures crucial for learning and memory and locomotion (i.e. prefrontal cortex, hippocampus and striatum) was measured by quantitative RT-qPCR using the Mic qPCR cycler based on REST method. REST uses Pairwise Fixed Reallocation Randomization Test for statistical evaluation and takes target efficiency into account. The study found that neonatal ethanol administration induced changes in dopamine (D1, D2, D5) receptor mRNA expression and CE-123 rescues the behavioural phenotype of adolescent and adult rats by inhibiting hyperactivity (3 and 10 mg/kg)and improving cognitive abilities (10 mg/kg).