Phospholipase Cβ3 in the hippocampus may mediate impairment of memory by long-term blockade of orexin 1 receptors assessed by the Morris water maze.

Orexin-A is an endogenous peptide with receptors throughout the brain. According to some recent research, learning and memory are affected by the central administration of orexin; however, no study so far has investigated the long-term inhibition of the orexinergic system. The present study has evaluated the effect of pretraining administration of orexin 1 receptor (OXR1) antagonist, SB-334867, on the acquisition of memory. The Morris water maze (MWM) task was used for training and trial purposes in all groups. Memory performance was analyzed by measuring escape latency, traveled distance, and time spent in the target quadrant. Moreover, the effect of SB-334867 on phospholipase Cβ3 (PLCβ3) levels in the CA1 region of hippocampus slices was examined. Hippocampus slices were prepared using an immunohistochemistry (IHC) approach. SB-334867 (20 mg/kg) increased escape latency in SB-treated rats compared to SB-vehicle group (P < 0.01). SB-treated rats spent less time in the target quadrant compared to the SB-vehicle group (P < 0.001). Distance traveled in the target quadrant was significantly more in SB-treated rats compared to the SB-vehicle group (P < 0.001). Furthermore, SB-334867 decreased PLCβ3 levels in the CA1 of the hippocampus (P < 0.01 and P < 0.05, respectively). Put together, our results suggest that the long-term inhibition of OXR1 plays a prominent role in spatial learning and memory, probably by attenuating PLCβ3 in CA1 neurons.