Pathways Within The

The cell bodies of central noradrenergic neurons are all clustered within two bilateral groups of nuclei (numbered A1 to A7) in the brainstem (Fig. 8.2). These comprise the locus coeruleus complex and the lateral tegmental nuclei. The locus coeruleus proper (nucleus A6) has attracted most interest because it accounts for approximately 45% of all the noradrenergic neurons in the brain. In the rat, there are only about 1500 noradrenergic cell bodies in the locus coeruleus of each hemisphere but their neurons branch extensively and project throughout the neuraxis. Retrograde tracing has shown that over 50% of neurons within the locus coeruleus innervate both the cortex and the cerebellum, for instance. The majority, if not all, of these fibres are thought to be retained ipsilaterally. The density of innervation varies from brain region to brain region and this is reflected, to some extent, by regional variation in tissue noradrenaline content (Table 8.1).

Neurotransmitters, Drugs and Brain Function. Edited by R. A. Webster ©2001 John Wiley & Sons Ltd

Hippocampus Thalamus Cerebellum

Hippocampus Thalamus Cerebellum

Figure 8.2 The distribution of noradrenergic neurons in the brain. The cell bodies are clustered in nuclei (A1-A7) in the pons/medulla regions of the brainstem and their axons project both rostrally and caudally to most regions of the neuraxis. The major nucleus is the locus coeruleus (A6)

The activity of noradrenergic neurons within the locus coeruleus is governed by two major afferent systems: a GABAergic (inhibitory) input from the nucleus prepositus hyperglossi and an (excitatory) glutamatergic projection from the nucleus para-gingantocellularis (Aston-Jones et al. 1991). However, dendrites of neurons with cell bodies lying within the locus coeruleus can extend into the area surrounding the nucleus (the pericoerulear region) and could well be influenced by other neurotransmitters and neuromodulators.

Many brain areas are innervated by neurons projecting from both the locus coeruleus and the lateral tegmental system but there are exceptions (Fig. 8.3). The frontal cortex, hippocampus and olfactory bulb seem to be innervated entirely by neurons with cell bodies in the locus coeruleus whereas most hypothalamic nuclei are innervated almost exclusively by neurons projecting from the lateral tegmental system. The paraven-tricular nucleus (and possibly the suprachiasmatic nucleus, also) is an exception and receives an innervation from both systems.

Table 8.1 The concentration of noradrenaline in different brain regions (^g/g wet weight of tissue)

Cortex 0.1

Hippocampus 0.25

Hypothalamus 0.2

Pons medulla 0.35

The locus coeruleus complex

(A4, A6, subcoeruleus)

(A4, A6, subcoeruleus)

Lateral tegmental nuclei

Spinal cord Cerebellum

Thalamus Hypothalamus

(paraventricular nucleus) Amygdala Septum

Brainstem nuclei

Brainstem nuclei (sensory)

Hippocampus Cerebral cortex

Spinal cord Cerebellum

Thalamus Hypothalamus

(paraventricular nucleus) Amygdala Septum

Lateral tegmental nuclei

Brainstem nuclei

(motor) Hypothalamus (all nuclei)

Figure 8.3 Brain areas receiving a prominent noradrenergic innervation. Most brain regions are innervated by neurons projecting from both the locus coeruleus and the lateral tegmental system. However, the frontal cortex, hippocampus and olfactory bulb are innervated exclusively by neurons with cell bodies in the locus coeruleus. With the exception of the paraventricular nucleus (and possibly the suprachiasmatic nucleus) hypothalamic nuclei are innervated by neurons projecting from the lateral tegmental system

The extensive branching and widespread distribution of noradrenergic neurons within the CNS has long been cited as evidence that this is a spatially and functionally diffuse neuronal system. This view was reinforced by an early report that few of these neurons formed specialised synaptic contacts. This fostered the impression that the locus coeruleus represents a 'switch' which, when activated, causes noradrenaline to be discharged from neurons, throughout the brain, in a non-selective manner. However, it is now known that, in the cortex at least, over 90% of the noradrenergic nerve terminals form specialised synaptic contacts with postsynaptic elements (Papadopoulos and Parnavelas 1991). There is also evidence that neurons in different zones of the locus coeruleus are morphologically distinct (at least six different types of noradrenaline-containing cells have been identified) and project to different brain regions or brain systems. In fact, neurons from different noradrenergic nuclei even innervate different types of neuron in the terminal field but, although it is certain that different noradrenergic nuclei have different functions, little is known about their physiological specialisations, largely because of their extensive reciprocal connections. All this evidence (reviewed in Stanford 1995) challenges the view that the central noradrenergic system operates in a non-selective manner.

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