Effect of adrenaline synthesis inhibition on brain noradrenaline neurons in locus coeruleus

The functional significance of the morphologically identified adrenaline (A)-mediated input to the noradrenergic nucleus locus coeruleus (LC) was pharmacologically analyzed. By means of single unit recording techniques the LC neurons in the rat brain were studied following administration of SK&F 64139 and DCMB, drugs which are both potent inhibitors of the A-forming enzyme phenylethanolamine-N-methyltransferase (PNMT). SK&F 64139 (1-200 mg/kg i.v.) caused an immediate, dose-dependent and long-lasting increase in firing rate of the LC neurons. The dose-response curve for the LC inhibitory effect of the alpha 2-receptor agonist clonidine was shifted in parallel to the right by pretreatment with SK&F 64139. All the above mentioned effects of SK&F 64139 were mimicked by SK&F 72223, a structurally analogous compound which is reported to lack PNMT inhibitory activity. Consequently, the activation of LC neurons by SK&F 64139 is probably not related to its capacity to inhibit the synthesis of A but rather to some other action of the drug, such as an alpha 2-receptor blocking effect. In contrast to SK&F 64139, the other PNMT inhibitor tested, DCMB (1-60 mg/kg), produced no significant activation of the LC neurons and but little clonidine antagonistic action. Thus, judging from these experiments, DCMB is devoid of significant alpha 2-receptor blocking properties. At the time for maximal brain A depletion after DCMB administration (4-6 h) the average firing rate of randomly encountered LC neurons was unaltered when compared with controls. In contrast, pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine methylester, which causes depletion also of brain noradrenaline, significantly increased LC neuronal firing rates. These data indicate that if there exists a physiologically relevant A-mediated input to the LC, this is not of critical importance for the tonic activity of the LC neurons.