Dopamine type 1- and 2-like signaling in the modulation of spatial reference learning and memory.

Spatial reference memory is known to be modulated by the dopaminergic system involving different brain regions. Here, we sought to identify the contribution of D1 (D1R) and D2 (D2R)-like dopamine receptor signaling on learning and memory in a food rewarded hole-board task by intracerebroventricular infusing D1R- and D2R- like receptor agonists (SKF-81297 and Sumanirole) and antagonists (SCH 23390 and Remoxipride) once 30 min prior to daily training sessions. D1R agonism induced persistent enhancement of performance, whereas D1R antagonism impaired reference memory formation. D2R agonist and antagonist exerted no effects. Phase specific comparisons revealed an enhancement of spatial acquisition in the presence of the D1R but not D2R agonism on acquisition, but not during retention. Since task difficulty might skew dopamine-induced improvements in learning and memory, we tested the D1R agonist in the hole-board task with increased difficulty. Drug treated animals performed significantly better during all training phases, with results better resolved than in the easy task. Additionally, proteomic analysis of the prefrontal cortex revealed ninety six proteins to be regulated by D1R agonism, from which 35 were correlated with behavioral performance. Obtained targets were grouped by function, showing synaptic transmission, synaptic remodeling, and dendritic spine morphology as the major functional classes affected. In sum, we find that activation of D1R signaling during spatial acquisition and retention improved reference memory index, depended on the task difficulty, and altered the proteome landscape of the prefrontal cortex indicative of massive organizational synaptic restructuring.

R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity.

Modafinil is a wake promoting drug approved for clinical use and also has cognitive enhancing properties. Its enantiomer R-Modafinil (R-MO) is not well studied in regard to cognitive enhancing properties. Hence we studied its effect in a spatial memory paradigm and its possible effects on dentate gyrus long-term potentiation (DG-LTP). Clinically relevant doses of R-MO, vehicle dimethyl sulfoxide (DMSO) or saline were administered for three days during the hole-board test and in in vivo DG-LTP. Synaptic levels of dopamine receptors D1R, D2R, dopamine transporter (DAT), and its phosphorylated form (ph-DAT) in DG tissue 4 h after LTP induction were quantified by western blot analysis. Monoamine reuptake and release assays were performed by using transfected HEK-293 cells. Possible neurotoxic side effects on general behaviour were also studied. R-MO at both doses significantly enhanced spatial reference memory during the last training session and during memory retrieval compared to DMSO vehicle but not when compared to saline treated rats. Similarly, R-MO rescues DG-LTP from impairing effects of DMSO. DMSO reduced memory performance and LTP magnitude when compared to saline treated groups. The synaptic DR1 levels in R-MO groups were significantly decreased compared to DMSO group but were comparable with saline treated animals. We found no effect of R-MO in neurotoxicity tests. Thus, our results support the notion that LTP-like synaptic plasticity processes could be one of the factors contributing to the cognitive enhancing effects of spatial memory traces. D1R may play an important regulatory role in these processes.