IPSAPIRONE AND 1-(2-PYRIMIDINYL)-PIPERAZINE INCREASE RAT LOCUS COERULEUS NORADRENERGIC ACTIVITY

The effects of systemically administered ipsapirone, an aryl-piperazine compound, and its major metabolite 1-(2-pyrimidinyl)-piperazine (1-PP), on locus coeruleus (LC) noradrenergic activity was investigated. On an equimolar basis both ipsapirone and 1-PP were approximately equipotent in increasing LC neuronal activity. However, pretreatment with 1-PP caused a significantly greater parallel shift to the right of the dose response curve for the inhibitory action of the LC alpha2-receptor agonist clonidine compared to ipsapirone. Biochemically, pretreatment with SKF 525A, a compound which prevents the formation of 1-PP from ipsapirone, diminished the ipsapirone-induced increase in MOPEG-SO4 levels in the brainstem and cortex. These data, together with the findings that 1-PP is more potent than ipsapirone in displacing 3H-clonidine from cerebral cortical membranes, suggest that the parent drug influences LC neuronal activity via the action of 1-PP on LC α2-adrenoceptors. © 1990.