A metabolite of buspirone increases locus coeruleus activity via alpha 2-receptor blockade.

Extracellular single unit recording techniques was used to pharmacologically analyze the excitatory action of buspirone on locus coeruleus (LC) noradrenergic neurons. Intravenously administered buspirone (0.5-8 mg/kg) dose-dependently increased LC firing rate. Furthermore, pretreatment with buspirone (8 mg/kg, i.p.) caused a parallel shift to the right of the dose-response curve for the inhibitory action of the alpha 2-receptor agonist clonidine on LC neurons. The inhibitory effect of microiontophoretically applied noradrenaline on LC neurons was not altered by the simultaneous application of buspirone, but almost totally blocked by its major metabolite 1-(2-pyrimidinyl-piperazine) (1-PP). The results indicate that buspirone causes activation of LC neurons via an alpha 2-receptor antagonistic action of its metabolite, 1-PP.