5-HT1A and NMDA Receptors Interact in the Rat Medial Septum and Modulate Hippocampal-Dependent Spatial Learning

Cholinergic an d GABAergic neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) projecting to the hippocampus, constitute the septohippocampal projection, which is important for hippocampal-dependent learning and memory. There is also evidence for an extrinsic as well as an intrinsic glutamatergic network within the MS/vDB. GABAergic and cholinergic septohippocampal neurons express the serotonergic 5-HT1A receptor and most likely also glutamatergic NMDA receptors. The aim of the present study was to examine whether septal 5-HT1A receptors are important for hippocampal-dependent long-term memory and whether these receptors interact with glutamatergic NMDA receptor transmission in a manner important for hippocampal-dependent spatial memory. Intraseptal infusion of the 5-HT1A receptor agonist (R)-8-OH-DPAT (1 or 4 mu g/rat) did not affect spatial learning in the water maze task but impaired emotional memory in the passive avoidance task at the higher dose tested (4 mu g/rat). While intraseptal administration of (R)-B-OH-DPAT (4 mu g) combined with a subthreshold dose of the NMDA receptor antagonist D-AP5 (1 mu g) only marginally affected spatial acquisition, it produced a profound impairment in spatial memory. In conclusion, septal 5-HT1A receptors appears to play a more prominent role in emotional than in spatial memory. Importantly, septal 5-HT1A and NMDA receptors appear to interact in a manner, which is particularly critical for the expression or retrieval of hippocampal-dependent long-term spatial memory. It is proposed that NMDA receptor hypofunction in the septal area may unmask a negative effect of 5-HT1A receptor activation on memory, which may be clinically relevant. (C) 2009 Wiley-Liss, Inc.