Modulation of prefrontal NMDA receptors reveals pharmacogenetic differences between SHR and SLA16 rat strains.

Disruptions in glutamatergic signaling within the prefrontal cortex (PFC) have been increasingly implicated in the pathophysiology of Attention-Deficit/Hyperactivity Disorder (ADHD). The Spontaneously Hypertensive Rat (SHR) is widely recognized as the standard animal model for ADHD, though it presents certain experimental limitations. To overcome these, we developed the congenic strain SHR.LEW-(D4Rat76-D4Mgh11) (SLA16). Here, we tested the hypothesis that SHR and SLA16 male rats differ in their PFC sensitivity to NMDA receptor (NMDAR) modulation by MK-801 (a non-selective NMDAR antagonist) and ifenprodil (a GluN2B-selective antagonist). Behavioral performance was evaluated using the open-field and object recognition tests following intra-PFC microinjections. Pharmacological manipulations revealed distinct strain-dependent responses, indicating differential NMDAR sensitivity. Although GluN2A and GluN2B protein levels in the PFC did not differ between strains, SLA16 rats exhibited reduced hippocampal GluN2A and GluN2B expression, accompanied by enhanced hyperactivity and impulsivity compared to SHR. These findings highlight the contribution of NMDAR-mediated glutamatergic mechanisms to ADHD-related behavioral phenotypes and support the SLA16 strain as a model for investigating the molecular and neural pathways underlying this disorder.