Septal alpha-noradrenergic antagonism in vivo blocks the testing-induced activation of septo-hippocampal cholinergic neurones and produces a concomitant deficit in working memory performance of mice.

In order to test the hypothesis that alpha-noradrenergic receptors in the septum 1) play an important functional role in the mediation of trans-synaptic control of the neurones of the cholinergic septo-hippocampal pathway and 2) produce resultant modulation of working memory performance, we have investigated the effects in vivo of the acute intraseptal injection of an alpha-antagonist, phenoxybenzamine, in mice. Neurochemical analysis was performed using measures of the kinetics of sodium-dependent high-affinity choline uptake in samples of hippocampus from injected mice and their relevant controls in both quiet conditions and immediately following selective working memory testing in an 8-arm radial maze. Results show that whereas the injection of phenoxybenzamine produces no significant alteration of the activity of the cholinergic septo-hippocampal neurones in quiet conditions, the pretrial (20 min) administration of this drug almost totally abolished the usually observed increase in hippocampal cholinergic activity induced by testing. This inhibition of cholinergic activation was associated with a parallel working memory deficit. The results provide further direct support for the hypothesis that septal noradrenergic afferents via alpha-receptors mediate a phasic and net excitatory trans-synaptic influence on the cholinergic septo-hippocampal pathway during working memory testing and thereby significantly contribute to the modulation of the level of working memory performance.