NORADRENERGIC MODULATION OF CHOLINERGIC NUCLEUS BASALIS NEURONS DEMONSTRATED BY IN-VITRO PHARMACOLOGICAL AND IMMUNOHISTOCHEMICAL EVIDENCE IN THE GUINEA-PIG BRAIN

The effects of noradrenalin were tested upon electrophysiologically ch aracterized cholinergic nucleus basalis neurons in guinea-pig brain sl ices. According to their previously established intrinsic membrane pro perties, the cholinergic cells were distinguished by the presence of l ow-threshold Ca2+ spikes and transient outward rectification that endo wed them with the capacity to fire in low-threshold bursts in addition to a stow tonic discharge. A subset of the electrophysiologically ide ntified cholinergic cells that responded to noradrenalin had been fill ed with biocytin (or biotinamide) and documented in previously publish ed reports as choline acetyltransferase (ChAT)-immunoreactive. The nor adrenalin-responsive, biocytin-filled/ChAT + cells were mapped in the present study and shown to be distributed within the substantia innomi nata amongst a large population of ChAT + cells. Slices from another s ubset of noradrenalin-responsive, electrophysiologically identified ch olinergic cells were stained for dopamine-beta-hydroxylase to visualiz e the innervation of the biocytin-filled neurons by noradrenergic fibr es. These biocytin-filled neurons were surrounded by a moderate plexus of varicose noradrenergic fibres and were ostensibly contacted by a s mall to moderate number of noradrenergic boutons abutting their soma a nd dendrites. Applied in the bath, noradrenalin produced membrane depo larization and a prolonged tonic spike discharge. This excitatory acti on was associated with an increase in membrane input resistance, sugge sting that it occurred through reduction of a K+ conductance. These ef fects persisted when synaptic transmission was eliminated (by tetrodot oxin or low Ca2+/high Mg2+) and were therefore clearly postsynaptic. T he excitatory effect of noradrenalin was blocked by the alpha(1)-adren ergic receptor antagonist prazosin and not by the alpha(2)-antagonist yohimbine, and it was mimicked by the alpha(1)-agonist L-phenylephrine but not by the alpha(2)-agonists clonidine and UK14.304, indicating m ediation by an alpha(1)-adrenergic receptor. There was also evidence f or a contribution by a beta-adrenergic receptor to the effect, since t he beta-antagonist propranolol partially attenuated the effect of nora drenalin, and the beta-agonist isoproterenol produced, like noradrenal in, alone or when applied in the presence of the alpha(1)-antagonist p razosin, membrane depolarization and an increase in tonic spike discha rge. These results indicate that through a predominant action upon alp ha(1)-adrenergic receptors, but with the additional participation of b eta-adrenergic receptors, noradrenalin depolarizes and excites choline rgic neurons. This action would tend to drive the cholinergic cells in to a tonic mode of firing and to stimulate or increase the rate of rep etitive spike discharge for prolonged periods. The noradrenergic locus coeruleus neurons could thereby recruit the cholinergic basalis neuro ns to act in tandem with them in facilitating cortical activation duri ng wakefulness.