Neurokinin-2 receptor antagonism in medial septum influences temporal-order memory for objects and forebrain cholinergic activity

In the mammalian brain the neurokinin NK2 receptors are predominantly located in the hippocampus, thalamus, septum and frontal cortex. It has been shown that administration of the NK2 receptor agonist, neurokinin A (NKA), into the medial septum of rats increases extracellular levels of acetylcholine (ACh) in the hippocampus and that NK2 receptor antagonism blocks this increase. Therefore, given the prominent role of hippocampal ACh in information processing, we hypothesized that NK2 receptor antagonism in the medial septum would negatively affect learning and memory via its influence on the cholinergic neurons of the basal forebrain. We investigated the action of local application of the peptidic NK2 receptor antagonist, Bz-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH (1, 10 and 100 pmol), into the medial septum on object memory for temporal order and spatial location using an object novelty paradigm. By means of in vivo microdialysis and HPLC analyses, we also examined the influence of NK2 receptor antagonism in the medial septum on ACh in major cholinergic projection areas of the basal forebrain, namely, hippocampus, frontal cortex and amygdala. Results: Injection of vehicle alone into the medial septum impaired memory for temporal order and spatial location of objects. Application of 1 pmol of the NK2 receptor antagonist partially reversed this deficit by reinstating memory for temporal order. Injection of 10 pmol of the NK2 receptor antagonist into the medial septum decreased levels of ACh in the hippocampus (at 30 min post-injection), and frontal cortex (at 30 and 80 min post-injection) in comparison to vehicle. However, this apparent decrease was the result of the blockade of a saline-induced increase in ACh levels.