1. Projections of the NA System Are Highly Divergent

NA is supplied to the forebrain by neurons in seven medullary nuclei. The cortex is innervated by one of those nuclei, the locus coeruleus (LC). LC axons travel to the cortex in the dorsal tegmental bundle and show a spectacular pattern of branching that delivers NA to many separate areas. In each area, the fibers approach the cortical mantle from the underlying white matter, project upward, and give off collaterals in almost all laminae.

NA influences cortical neurons through a and b adrenoceptors. These receptors are differentially distributed across cortical laminae and cortical areas. Each receptor is activated by unique ligands, triggers distinct intracellular second messenger systems, and mediates different physiological responses in postsy-naptic neurons. In the visual cortex, for example, stimulation of b receptors (b and b2 subtypes) with sotalol produces mostly short- and long-term inhibitory effects on cells in lower cortical laminae. Stimulation of a receptors (both a1 and a2 subtypes) with phentolamine produces only short-duration excitatory effects on cells in the upper cortical laminae.

In the primate visual cortex, greater NA innervation is seen in the superficial and deep laminae than in the middle laminae. This suggests that NA has a greater influence on cortical outflow than cortical inflow. Perhaps NA may be important in regulating the amplification of signals sent to other cortical areas.

2. Cellular Effects of Noradrenaline May Be Excitatory or Inhibitory

In vivo application of NA onto cortical and thalamic relay cells produces a slow depolarization of the membrane and an inhibition of the potassium con ductance. This makes the cell react more strongly to its inputs. The effects on the cell's spontaneous activity are more variable. Reductions in activity are seen that effectively increase the salience of evoked responses compared to the unstimulated activity. Thus, the effect of NA is not expressed until a sensory stimulus is present. In other cells, elevations in spontaneous activity are seen. No increase in salience occurs in these cells and decreases in salience may occur. NA's effects on single cells is complex and probably depends on the unique distribution of receptors on each cell. It is to be expected that NA will have complex effects on networks of neurons, but this expectation has not been tested.

What events cause NA to be released onto post-synaptic targets? NA neurons appear to respond phasically to the appearance of nonarousing environmental stimuli and in conjunction with shifts of attention, but they respond more tonically to arousing stimuli (e.g., threatening or appetitive stimuli). In addition, tasks requiring intense focusing of attention are accompanied by a steady rate of firing in LC neurons. When attention wanders, the tonic activity of LC neurons increases and becomes more variable. These results suggest that the rate of LC activity may be positively correlated with attentional lability. Conversely, focused attention reduces the likelihood that the organism will be alerted by unexpected stimuli. This relationship will be discussed later with regard to recent studies of alerting.

The release of NA may also be produced by the application of cholinergic agonist to the LC. This manipulation causes excitation in LC neurons and a reduction in low-frequency EEG activity, similar to that seen during natural arousal. However, it has little effect on the 10- to 30-Hz components that are enhanced during natural arousal. Perhaps isolated stimulation of the LC fails to activate other NMTs that produce increased high-frequency activity during natural arousal.

3. Cortical Arousal May Be Altered by Local Factors

As would be expected from its anatomical organization, stimulation of the LC causes release of NA at many cortical and subcortical sites simultaneously. This has been confirmed empirically and suggests that NA release is governed by activity in LC cell bodies. In many other experiments, however, NA release is regulated by factors near the terminals of LC neurons. In the visual cortex, physiological experiments demon strate that the release of NA in the visual cortex by visual stimulation depends on the efficacy with which the visual stimulus affects the electrical activity in nearby cortical neurons. The same stimuli are ineffective in evoking LC neuronal activity. These results suggest that the release of NA from visually nonspecific LC neurons may be determined by excitation in nonnoradrenergic, cortical cells. In the frontal cortex, local administration of glutamate causes the release of NA from the terminals of LC neurons.

All these observations can be explained by postulating two kinds of control over the LC neurons. The first is produced by synaptic inputs to dendrites or cell bodies, which cause global release of NA. The second is produced by the local regulation of NA release from individual LC terminals, which would account for the local physiological effect of visual stimulation. Indeed, the second type of control, which occurs in the absence of impulse activity generated in the cell bodies, may be the basis for interactions between many neurotrans-mitter systems. For example, cholinergic and gluta-matergic control of DA and NA release and noradrenergic control of ACH by preterminal modulation of transmitter release have been demonstrated.

4. Behavioral Effects of Altering CNS Noradrenaline Are Diverse

Systemic administration of NA agonists and antagonists has both peripheral and central nervous effects. Here, we limit the discussion to drugs that alter CNS arousal. The stimulants methylphenidate and amphetamine increase the levels of both NA and DA by stimulating a2, D1, and D2 receptors and blocking reuptake of DA and NA into the presynaptic cleft. These drugs also increase alerting and vigilance to environmental stimuli.

The effects of nonstimulant drugs on arousal may be more complex. For example, clonidine, an a2 agonist, causes deficits in stimulus alerting in nonhuman primates. Subjects are impaired in using the timing of the stimulus onset to help them respond to visual targets in a rapid fashion. This effect is due to stimulation of presynaptic receptors, which reduces brain NA. Clonidine also ameliorates the memory deficits of aged monkeys by increasing the levels of brain NA through stimulation of postsynaptic receptors. It probably increases their alertness as well. The differences in outcomes may be due primarily to the amount of drug present near the synapse. Low doses stimulate postsynaptic receptors and higher doses stimulate postsynaptic and presynaptic receptors.

The results may also depend on the age of the subject and the type of task used.

In humans, the brain locations at which NA regulates changes arousal are of great interest. Recent efforts to identify these sites using functional magnetic resonance imaging of brain activity have shown that the thalamus is especially important in mediating the interaction between changes in arousal and the performance of cognitive tasks requiring sustained attention.

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