Intraseptal microinjections of substance P and analogs potentiate pentobarbital-induced narcosis and depression of hippocampal cholinergic activity.

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.