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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.

Previously brain norepinephrine (NE) neurons in the locus coeruleus (LC) have been shown to respond profoundly to external, environmental stimuli and are thought to be involved in behavioral functions such as vigilance, alarm and anxiety reactions to novel and, especially, threatening stimuli. Here we have used electrophysiological techniques to show that distension of the urinary bladder, the distal colon, rectum or the stomach causes pronounced activation responses of brain NE-LC neurons of the rat essentially without concomitant responses in splanchnic, sympathetic nerve activity (NE-SNA), thus indicating the non-noxious character of these internal stimuli. Our findings directly implicate the LC in micturition and, probably, defecation and we suggest that a high NE-LC activity may facilitate these phasic, vegetative events. In addition, the results implicate the LC as a pivotal system by which autonomic or visceral functions can affect behavior and, conversely, by which environmental stress can affect autonomic functions, for example in the opiate withdrawal syndrome.

The brain norepinephrine (NE) neurons in the nucleus locus coeruleus (LC) have been claimed to be involved both in the regulation of behavioral functions, e.g. vigilance and arousal reactions, and in cardiovascular control. Recent studies from this laboratory have also shown that cardiovascular, vagal afferents can participate in the regulation of the LC neurons in the rat. Utilizing electrophysiological techniques, we have now studied the effects of activation of blood volume receptors or arterial baroreceptors on the firing rate of single cells in the LC and, parallelly, on splanchnic, sympathetic discharge in the chloral hydrate anesthetized rat. Blood volume load (0.5–5 ml heparinized blood, intravenously administered) induced a reduction in both LC neuronal firing rate and splanchnic nerve activity (SNA), effects which were readily and completely reversed by withdrawal of the corresponding amount of blood. In comparison, the central LC neurons were more sensitive to blood volume expansion than the peripheral splanchnic nerves. The effects of blood volume load on LC and SNA remained unaffected after deafferention of arterial baroreceptors. Blood pressure elevation, induced by slow intravenous infusion of NE or angiotensin (AII) (total dose 2 μg/kg), caused an immediate reduction in both the firing rate of most of the LC cells tested as well as in SNA. While the effect on SNA was abolished by deafferentation of arterial baroreceptors, the effect on central LC activity remained largely unaffected. Consequently, these data strengthen the concept that brain NE neurons in the LC are subject to control by peripheral blood volume receptors, analogously to peripheral sympathetic nerves. Arterial baroreceptors may still participate in the control of central noradrenergic nerve activity, but in contrast to their function for SNA they are not critical for the inhibition of LC neurons by blood pressure elevation. Rather, these two cardiovascular afferent systems may participate in the physiological regulation of the LC activity in a complimentary and convergent fashion.

Utilizing single cell recording techniques to study brain norepinephrine (NE) neurons in the locus coeruleus (LC) and, in the same rats, registration of splanchnic nerve activity (SNA) the effects on these systems of hypercapnia and hypoxia, respectively, were studied. Hypercapnia (pCO2 36–103 mm Hg) caused a rapid increase in the firing rate of LC neurons as well as in SNA. This effect was directly correlated with the added amount of CO2 in the inspired gas mixture. This finding indicates a similar chemoreceptor-mediated regulation of LC neurons and SNA. Since deafferentation of peripheral chemoreceptors did not alter the response of these systems to hypercapnia, the chemoreceptors involved must be centrally located. In hypoxia (pO2 105-31 mm Hg) the overall effect on LC neurons was activation, whereas SNA was reduced. These effects were, however, not dose-dependent. Peripheral receptor deafferentation abolished the activation by hypoxia, suggesting that the LC neurons are influenced also by peripheral chemoreceptors. The results indicate that the previously observed increase in brain NE turnover in hypercapnia is largely secondary to increased neuronal activity and not due to, e.g., changes in metabolic enzymes. In addition, the data implicate chemoreceptors, centrally but also peripherally located, in the regulation of brain NE neurons in the LC. The activation of these neurons in hypercapnia, generally associated with increased apprehension in man, is consistent with the notion that the LC may serve as an alarm system in the brain.

The effects of mechanical and thermal cutaneous sensory stimulation on the activity of central norepinephrine (NE) neurons in the locus coeruleus (LC) and on peripheral sympathetic nerve activity (NE-SNA) in a renal branch of the splanchnic nerve were studied, using electrophysiological techniques in the anesthetized rat. Noxious, mechanical sensory stimulation caused a parallel and virtually identical change in central NE-LC activity and peripheral NE-SNA and both neuronal systems showed a biphasic excitation-inhibition response. Both non-noxious and noxious thermal sensory stimulation above 36 degrees C caused a parallel increase in NE-LC firing rate and NE-SNA, changes that were accompanied by increases in arterial blood pressure and heart rate. The increases in central and peripheral NE neuronal activity were linearly correlated. However, the two neuronal systems differed in their ability to adapt during prolonged noxious thermal stimulation. NE-LC neurons adapted completely and returned to baseline firing rate within 5 min during ongoing noxious thermal stimulation. In contrast, an increase in NE-SNA remained throughout the stimulation period. In recent studies in this laboratory, blood volume depletion was found associated with a marked NE-LC activation. In contrast to the present results during prolonged noxious stimulation, there was no attenuation of the NE-LC activation during prolonged hemorrhage. Taken in conjunction, these data indicate a discriminatory capacity of the NE-LC system in monitoring sensory or autonomic stimuli. Thus, only those stimuli of imperative importance for the animal were found to be associated with continuing robust NE-LC discharge.

The activity of brain norepinephrine (NE) neurons in the locus coeruleus (LC) and peripheral sympathetic nerve activity (NE-SNA) in the splanchnic/renal nerve were recorded simultaneously during alterations of arterial blood pressure and circulating blood volume. Utilizing this experimental procedure we have previously found that both central and peripheral NE neurons are inhibited during blood pressure elevation. Furthermore, both neuronal systems were found to be inhibited during blood volume load, an effect apparently mediated by vagal afferents. In the present study both brain NE-LC activity and NE-SNA were increased during blood volume depletion. However, during prolonged hemorrhage the initial excitation of NE-SNA was followed by a marked inhibition. In contrast, the increase in NE-LC activity remained throughout the volume depletion period. The responses of central and peripheral NE neurons during hemorrhage were abolished in animals subjected to bilateral cervical vagotomy. Nitroprusside- or phenylephrine-induced blood pressure variations were associated with reciprocal changes in both central and peripheral NE neuronal activity. The NE-LC responses to blood pressure variations were abolished after bilateral vagotomy. NE-SNA responses, on the other hand, persisted after bilateral vagotomy. Our present and previous findings show that brain NE-LC neurons, similarly to peripheral NE neurons in the splanchnic/renal nerve, are regulated by tonically active cardiovascular afferents. Whereas peripheral NE-SNA is regulated by both arterial (high pressure) baroreceptors and cardiac volume (low pressure) receptors, the NE-LC neurons seem exclusively regulated by cardiac volume (low pressure) receptors.