Intraseptal microinjection of
Substance P (SP) has been shown to depress activity in the septal-hippocampal
cholinergic pathway in the rat.
Pentobarbital also depresses septal-hippocampal
cholinergic activity, and a relationship between this depressed activity and
pentobarbital-induced
narcosis is suggested by a variety of studies. To examine this relationship further, we microinjected SP and its analogs, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP and [D-Pro2, D-Trp7,9]-SP, intraseptally in rats pretreated with
pentobarbital, and measured the duration of loss of righting reflex and change in
choline uptake in hippocampal synaptosomes. The duration of
pentobarbital-induced loss of righting reflex was prolonged and the
pentobarbital-induced reduction of hippocampal
choline uptake was enhanced by all three drugs. A negative correlation (r = -0.96, P less than .02) was seen between duration of loss of righting reflex and synaptosomal
choline uptake. Thus, the two analogs of SP appear to act as SP agonists at the septum, judged by their abilities to potentiate
pentobarbital narcosis and reduce septal-hippocampal
cholinergic activity. This is in contrast to reported actions of these two analogs as SP antagonists in various peripheral tissues.