Neuroanatomy Of The Norepinephrine System

The initial steps in the biosynthesis of norepinephrine (NE) are identical to those for DA. The rate-limiting step is the conversion of the amino acid tyrosine into L-dihydroxyphenylalanine, or L-dopa, via the enzyme tyrosine hydroxylase. NE is then formed from dopamine by the enzyme dopamine-¿'-hydroxylase. As for the other monoamines, NE neurotransmission is terminated through the actions of the NE transporter protein. A detailed description of the primate NE system can be found in Foote (i997).

Cell Locations

NE-containing neurons in the central nervous system are located predominantly in the medulla and pons (see Figure 4-i). The principal noradrenergic cell group is the locus coeruleus, the largest group of NE-containing neurons in the mammalian brain. In addition, it is the source of most of the ascending noradrenergic projections. The locus coeruleus is composed of a compact collection of neurons located in the dorsal pons, medial to the mesencephalic tract of the trigeminal nerve. In primate species, NE-containing neurons of the locus coeruleus, like the DA neurons of the substantia nigra, are heavily pigmented with neuromelanin, particularly in mature individuals (Manaye et al. 1995). Consistent with the role of NE in mood disorders, decreases in the neuronal density of locus coeruleus neurons have been reported in postmortem studies of patients with depression (Ressler and Nemeroff 2000).

NE-containing cells are also present in the caudal medulla, including the intermediate reticular zone and the lateral paragigantocellularis nucleus, as well as in the nucleus ambiguus. Collectively, these groups are known as the lateral ventral tegmental fields (Cooper et al. 1996).

Projection Sites

The cerebral cortex is a major recipient of noradrenergic projections, specifically those coming from the locus coeruleus (Gatter and Powell 1977; Porrino and Goldman-Rakic 1982). All areas of the cerebral cortex receive these projections; however, certain areas have higher densities of NE axons than other areas. For example, primary somatosensory and visual cortices have a very high density of NE axons, whereas prefrontal cortical areas (see Figure 4-3) are less densely innervated (Lewis and Morrison 1989; Morrison et al. 1982). Within the prefrontal cortex, the distribution of NE axons is similar to that of DA axons, with areas 9 and 24 having the highest density of NE axons; areas 11, 12, 13, and 25 having an intermediate density of NE axons; and areas 10 and 46 having the lowest density of NE axons (see Figure 4-4). These innervation patterns exhibit interesting comparisons and contrasts with those of DA axons. For example, the primary motor cortex contains high densities of both DA and NE axons, whereas the adjacent primary somatosensory cortex contains a very high density of NE axons but a low density of DA axons (Lewis and Morrison 1989; Morrison et al. 1982).

Other brain regions innervated by the locus coeruleus include the thalamus, cerebellar cortex, hypothalamus, and amygdala. Within the thalamus, the different nuclei display varied densities of NE axons. For example, in the primate, the mediodorsal thalamic nucleus contains a high density of NE axons (see Figure 4-5) (Melchitzky and Lewis 2001), whereas the lateral geniculate nucleus is sparsely innervated (Morrison and Foote 1986). By contrast, the different regions of the cerebellar cortex (i.e., the vermis, intermediate zones, and hemispheres) are all moderately innervated by noradrenergic axons (see Figure

4-6) (Melchitzky and Lewis 2000). In addition, unlike the distribution of DA axons, NE axons are found in both the granule cell and molecular layers. Within the hypothalamus and amygdala, the paraventricular and basolateral nuclei, respectively, contain the highest density of NE axons in these structures (Ginsberg et al. 1993; Li et al. 2001).

The noradrenergic nuclei in lateral tegmental fields appear to project exclusively to the brain stem and spinal cord in primates. By contrast, in rodents, these nuclei have been shown to also project to subcortical structures, such as the amygdala and septum (Delfs et al. 2000; Zardetto-Smith and Gray 1995).


The receptors that recognize NE, the a and 13 adrenoreceptors, belong to the G protein superfamily of receptors. Thus, similar to DA, NE elicits responses in the postsynaptic cell via G protein-mediated second-messenger systems. Both ctand d> adrenoreceptors have two subtypes, namely the cti and 1X2 adrenoreceptors and the and $2 adrenoreceptors (Cooper et al. 1996). All of these receptors are widely distributed across the cerebral cortex, although their regional and laminar patterns differ. For example, in primate prefrontal cortex, autoradiography using appropriate ligands demonstrated that the ai and Cl2 adrenoreceptors are prominent in layers 1-superficial 3, whereas the highest density of and adrenoreceptors is in layers deep 3-4 (Goldman-Rakic et al. 1990). Furthermore, in the human brain, (Xi adrenoreceptors are also present in high density in the cortex, as well as in regions of the thalamus, hypothalamus, and hippocampus (Palacios et al. 1987). Stimulation of 02 adrenoreceptors in the frontal cortex appears to improve attention, raising the possibility of adrenergic system-targeted therapies for attention-deficit disorders and disorders associated with cognitive deficits, such as Alzheimer's disease and schizophrenia (Stahl 1998).

In the rodent, the mRNA for the adrenoreceptor is localized to many areas, including cerebral cortex, reticular nucleus of the thalamus, deep cerebellar nuclei, brain stem nuclei, and spinal cord, while the mRNA for the [$2 adrenoreceptor has a more restricted distribution to the olfactory bulb, hippocampus, cerebellar cortex, and intralaminar thalamic nuclei (Nicholas et al. 1993). Autoradiographic studies have also revealed high densities of the 13 adrenoreceptors in the striatum, the hippocampus and the cerebral cortex in human brain (Pazos et al. 1985). Lower densities of 3 adrenoreceptors have been found in the thalamus, hypothalamus, and amygdala and the molecular and granule cell layers of the cerebellar cortex (Pazos et al. 1985). Dysregulation of noradrenergic transmission via 13 adrenoreceptors has been implicated in the pathophysiology of depression. For example, postmortem studies have revealed increased binding of D adrenoreceptors in the frontal cortex of suicide victims (Mann et al. 1986).

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