Noradrenergic System

Named sympathine because it was initially encountered as being released by sympathetic nerve terminals, the molecule was later given the name norepinephrine after meeting the criteria for a neurotransmitter in the CNS (see Cooper et al. 2001). NE is produced from the amino acid precursor

L-tyrosine found in neurons in the brain, chromaffin cells, sympathetic nerves, and ganglia. The enzyme dopamine L -hydroxylase (DBH) converts DA to NE, and as is the case for DA synthesis, tyrosine hydroxylase is the rate-limiting enzyme for NE synthesis (Figure 1-5B). The dietary depletion of tyrosine and (X -methyl-p-tyrosine (a TH inhibitor) has played an important part in efforts aimed at delineating the role of catecholamines in the pathophysiology and treatment of mood and anxiety disorders (Coupland et al. 2001; McCann et al. 1995).

FIGURE 1-5. The noradrenergic system.

FIGURE 1-5. The noradrenergic system.

This figure depicts the noradrenergic projections throughout the brain (A) and the various regulatory processes involved in norepinephrine (NE) neurotransmission (B). NE neurons innervate nearly all parts of the neuroaxis, with neurons in the locus coeruleus being responsible for most of the NE in the brain (90% of NE in the forebrain and 70% of total NE in the brain). The amino acid L-tyrosine is actively transported into presynaptic NE nerve terminals, where it is ultimately converted into NE. The rate-limiting step is conversion of L-tyrosine to L-di hydroxy phenylalanine (L-dopa) by the enzyme tyrosine hydroxylase (TH). ct-Methyl-p-tyrosine (AMPT) is a competitive inhibitor of tyrosine hydroxylase and has been used to assess the impact of reduced catecholaminergic function in clinical studies. Aromatic amino acid decarboxylase (AADC) converts L-dopa to dopamine (DA). L-dopa then becomes decarboxylated by decarboxylase to form dopamine (DA). DA is then taken up from the cytoplasm into vesicles, by vesicle monoamine transporters (VMATs), and hydroxylated by dopamine B-hydroxylase (DBH) in the presence of O2 and ascorbate to form NE. Norm eta nephrine (NM), which is formed by the action of COMT (catechol-O-methyltransferase) on NE, can be further metabolized by monoamine oxidase (MAO) and aldehyde reductase to 3-methoxy-4-hydroxyphenylglycol (MHPG). Reserpine causes a depletion of NE in vesicles by interfering with uptake and storage mechanisms (depressive-like symptoms have been reported with this hypertension). Once released from the presynaptic terminal, NE can interact with a variety of presynaptic and postsynaptic receptors. Presynaptic regulation of NE neuron firing activity and release occurs through somatodendritic (not shown) and nerve-terminal 0:2 adrenoreceptors, respectively. Yohimbine potentiates

NE neuronal firing and NE release by blocking these «2 adrenoreceptors, thereby disinhibiting these neurons from a negative feedback influence. Conversely, clonidine attenuates NE neuron firing and release by activating these receptors. Idazoxan is a relatively selective adrenoreceptor antagonist primarily used for pharmacological purposes. The binding of NE to G protein receptors (G0, Gj, etc.) that are coupled to a deny ly I cyclase (AC) and phospholipase C(PLC-b) produces a cascade of second-messenger and cellular effects (see diagram and later sections of the text). NE has its action terminated in the synapse by rapidly being taken back into the presynaptic neuron via NE transporters (NETs). Once inside the neuron, it can either be repackaged into vesicles for reuse or undergo enzymatic degradation. The selective NE reuptake inhibitor and antidepressant reboxetine and older-generation tricyclic antidepressant desipramine are able to interfere/block the reuptake of NE. On the other hand, amphetamine is able to facilitate NE release by altering NET function. Green spheres represent DA neurotransmitters; blue spheres represent NE neurotransmitters. DAG = diacylglycerol; IP3 = inositol-1,4,5-triphosphate.

Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970, 1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc. Modified from Nestler et al. 2001.

There are seven NE cell groups in the mammalian CNS, designated Al through A7. In the brain stem, these are the lateral tegmental neurons (A5 and A7) and the locus coeruleus (A6) (Dahlstrom 1971) (see Figure 1-5B). In general, the projections from A5 and A7 are more restricted to brain stem areas and do not interact with those of A6. The term locus coeruleus (LC) was derived from the Greek because of its saddle shape and its "bluish color" (caeruleum). The LC is the most widely projecting CNS nucleus known (Foote et al. 1983), responsible for approximately 90% of the NE innervation of theforebrain and 70% of the total NE in the brain (Figure 1-5A). Indeed, the LC NE neurons, although small in number, constitute a diffuse system of projections to widespread brain areas via highly branched axons. The extensive efferent innervation suggests that the LC plays a modulatory and integrative role, rather than a role in specific sensory or motor processing (Foote et al. 1983).

A number of physiological roles have been ascribed to the LC, notably in the control of vigilance and the initiation of adaptive behavioral responses (Foote et al. 1983). Considerable data support the hypothesis that NE neurons in the LC constitute a CNS response or defense system, since the neurons are activated by "challenges" in both the behavioral/environmental and the physiological domains (Jacobs et al. 1991). Thus, while a variety of sensory stimuli are capable of increasing LC activity, noxious or stressful stimuli are particularly potent in this regard. Moreover, considerable evidence also supports a role for LC NE neurons in the learning of aversively motivated tasks and in the conditioned response to stressful stimuli (Rasmussen et al. 1986a, 1986b), with obvious implications for a variety of psychiatric conditions (see Gould et al. 2003; Szabo and Blier 2001). Indeed, tonic activation of the LC appears to occur preferentially in the response to stressful stimuli, in contrast to stimuli limited to simply evoking activation or arousal (Rasmussen et al. 1986a, 1986b).

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