Effects of beta-adrenoceptor antagonists on the firing rate of noradrenergic neurones in the locus coeruleus of the rat.

Acute i.v. administration of the non-selective beta-adrenoceptor antagonist dl-propranolol given in incremental doses (less than 40 mg/kg) did not affect the firing rate of locus coeruleus (LC) neurones in the rat, as revealed by single cell recording techniques. Furthermore, no effect was seen 4 h after a single i.p. dose of this beta-blocker (10 mg/kg). However, repeated treatment with dl-propranolol (1, 5, 10 or 20 mg/kg i.p., twice daily for 4 days) produced a significant, dose-dependent decrease of the average LC neuronal firing rate in comparison to controls. The dextro isomer of propranolol, which has negligible beta-blocking activity but the same local anaesthetic potency as the racemate, had no corresponding effect. The non-selective beta-adrenoceptor antagonist sotalol, which is one of the most hydrophilic beta-blockers, had much less inhibitory effect on LC neurones than dl-propranolol. The beta 1-selective antagonist metoprolol did not change the firing of noradrenergic neurones in the LC after similar treatment for 4 days. However, when the rats were subjected to oral treatment for 28 days, metoprolol was found to produce a slight inhibitory effect although much less than dl-propranolol. In view of these findings we propose a stimulatory and mainly beta 2-adrenoceptor-mediated control mechanism for the noradrenergic neurones in the LC. This mechanism seems to be characterized by a delayed responsiveness.