Novel Dopamine Transporter Inhibitor, CE-123, Ameliorates Spatial Memory Deficits Induced by Maternal Separation in Adolescent Rats: Impact of Sex.

Abstract

Maternal separation (MS) is a key contributor to neurodevelopmental disorders, including learning disabilities. To test the hypothesis that dopamine signaling is a major factor in this, an atypical new dopamine transporter (DAT) inhibitor, CE-123, was assessed for its potential to counteract the MS-induced spatial learning and memory deficit in male and female rats. Hence, neonatal rats (postnatal day (PND)1 to 21) were exposed to MS (180 min/day). Next, the acquisition of spatial learning and memory (Barnes maze task) and the expression of dopamine D1 receptor, dopamine transporter (DAT), and the neuronal GTPase, RIT2, which binds DAT in the vehicle-treated rats were evaluated in the prefrontal cortex and hippocampus in the adolescent animals. The results show that MS impairs the acquisition of spatial learning and memory in rats, with a more severe effect in females. Moreover, the MS induced upregulation of DAT and dopamine D1 receptors expression in the prefrontal cortex and hippocampus in adolescent rats. Regarding RIT2, the expression was decreased in the hippocampus for both the males and females, however, in the prefrontal cortex, reduction was found only in the females, suggesting that there are region-specific differences in DAT endocytic trafficking. CE-123 ameliorated the behavioral deficits associated with MS. Furthermore, it decreased the MS-induced upregulation of D1 receptor expression level in the hippocampus. These effects were more noted in females. Overall, CE-123, an atypical DAT inhibitor, is able to restore cognitive impairment and dopamine signaling in adolescent rats exposed to MS-with more evident effect in females than males.

• Authors: Pawel Grochecki, Irena Smaga, Paulina Surowka, Marta Marszalek-Grabska, Predrag Kalaba, Vladimir Dragacevic, Patrycja Kotlinska, Malgorzata Filip, Gert Lubec, Jolanta H Kotlinska
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 18 (Sep 14 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 36142621 (Publication Type: Journal Article)

Chemical References

• Benzhydryl Compounds
• CE-123
• Dopamine Plasma Membrane Transport Proteins
• Receptors, Dopamine D1
• GTP Phosphohydrolases
• Dopamine

Topics

• Animals
• Benzhydryl Compounds
• Dopamine (metabolism)
• Dopamine Plasma Membrane Transport Proteins (metabolism)
• Female
• GTP Phosphohydrolases (metabolism)
• Male
• Maternal Deprivation
• Maze Learning
• Memory Disorders (drug therapy, etiology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Dopamine D1 (metabolism)
• Spatial Memory