Noradrenergic neurons

The site of decarboxylation of levodopa in patients with Parkinson s disease is uncertain, but it may be that there is sufficient enzyme in the remaining dopamine nerve terminals or that conversion takes place in other neurons (noradrenergic or serotoniner-gic) as they also contain decarboxylase enzymes. Release of dopamine replaced in this way must be very abnormal but most patients seem to benefit. 

Neuropeptide Y. Neuropeptide Y [82785 5-3] (NPY) (255) is a 36-amiao acid peptide that is a member of a peptide family including peptide YY (PYY) [81858-94-8, 106338-42-5] (256) and pancreatic polypeptide (PPY) [59763-91-6] (257). In the periphery, NPY is present in most sympathetic nerve fibers, particulady around blood vessels and also in noradrenergic perivascular and selected parasympathetic nerves (66). Neurons containing NPY-like immunoreactivity ate abundant in the central nervous system, particulady in limbic stmctures. Coexistence with somatostatin and NADPH-diaphorase, an enzyme associated with NO synthesis, is common in the cortex and striatum. 

The locus ceruleus is a structure located on the floor of the fourth ventricle in the rostral pons. It contains more than 50% of all noradrenergic neurons in the brain, and projects to almost all areas of the central nervous system. 

NET (SLC6A2) Noradre-naline, dopamine 1 CNS noradrenergic neurons (emanate from locus coeruleus and lateral tegmental area), sympathetic nervous system Clearance of interstitial neuro-transmitter, reuptake into neurons... 

DAT is predominantly expressed by dopaminergic brain neurons, NET by noradrenergic neurons in the central and peripheral nervous system, and SERT is restricted to the axons of serotonergic neurons, which originate in the raphe nuclei and innervate numerous higher brain regions therefore SERT is widely distributed in the brain. Outside the brain, 5HT transport can be measured on non-neuronal cells (e.g. platelets, lympho-blastoid cells and smooth muscle cells) most of the 5HT appearing in the circulation is taken up by platelets. 

Figure 2.4 Noradrenergic inhibition of Ca " currents and transmitter release in sympathetic neurons and their processes, (a) Inhibition of currents through N-type Ca " channels by external application of noradrenaline (NA) or by over-expression of G-protein P y2 subunits, recorded from the soma and dendrite of a dissociated rat superior cervical sympathetic neuron. Currents were evoked by two successive 10 ms steps from —70 mV to OmV, separated by a prepulse to -1-90 mV. Note that the transient inhibition produced by NA (mediated by the G-protein Go) and the tonic inhibition produced by the G-protein Piy2 subunits were temporarily reversed by the -1-90 mV depolarisation. (Adapted from Fig. 4 in Delmas, P et al. (2000) Nat. Neurosci. 3 670-678. Reproduced with permission), (b) Inhibition of noradrenaline release from neurites of rat superior cervical sympathetic neurons by the 2-adrenoceptor stimulant UK-14,304, recorded amperometrically. Note that pretreatment with Pertussis toxin (PTX), which prevents coupling of the adrenoceptor to Gq, abolished inhibition. (Adapted from Fig. 3 in Koh, D-S and Hille, B (1997) Proc. Natl. Acad. Sci. USA 1506-1511. Reproduced with permission)...

Fillenz, M (1990) Noradrenergic neurons, Cambridge University Press, Cambridge. 

Toxins that gain access to a neuron through its uptake process and then destroy it in some way. This approach has been used mainly to destroy monoamine neurons with 5,6 or 5,7-dihydroxytryptamine targeting 5-HT neurons, 6-hydroxydopamine for dopamine (and to a lesser extent noradrenergic) neurons and MPTP for dopamine neurons (see Chapter 7). Only the latter is fully specific and effective systemically. The others need to be administered directly into the appropriate brain areas and while they may only affect the intended NT neurons, the injection may not affect all of them. 

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...

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...

Many electrophysiological studies have shown that single-unit activity of noradrenergic neurons in the locus coeruleus is increased by sensory stimuli. Effective stimuli range from those causing physical discomfort (e.g. footshock) and interoceptive... 

Even if this turns out to be the case, it is likely that noradrenergic neurons in different brain regions make different contributions to this process. This complication is suggested by the results of a recent microdialysis study in which release of noradrenaline in response to the sound of a buzzer alone was provoked after repeated... 

Much remains to be learned about the neurochemical regulation of noradrenergic transmission and even more research is required before we can define the role(s) of this neurotransmitter in the brain. Nevertheless, it is evident that these neurons are a crucial component of the network of monoamine influences on the limbic system and that they... 

Cederbaum, JM and Aghajanian, GK (1976) Noradrenergic neurons of the locus coeruleus inhibition by epinephrine and activation by the alpha-antagonist piperoxane. Brain Res. 112 413-419. 

Schuldiner, S (1998) Vesicular neurotransmitter transporters. In Neurotransmitter Transporters Structure, Function, and Regulation (Ed. Reith, MEA), Humana Press, Totowa, NJ, pp. 215-240. Stanford, SC (1995) Central noradrenergic neurones and stress. Pharmac. Ther. 68 297-342. Stanford, SC (1999) SSRI-induced changes in catecholaminergic transmission. In Selective Serotonin Reuptake Inhibitors (SSRIs) Past, Present and Future (Ed. Stanford, SC), RG Landes Co., Austin, TX, pp. 147-170. 

Until recently, d-fenfiuramine was used to control appetite, in preference to d-amphetamine, because it has a lower affinity for the catecholamine transporter and so its uptake into noradrenergic and dopaminergic neurons is much less than that of amphetamine. This is thought to explain why, at anorectic doses, this compound lacks the psychotropic effects and dependence-liability that are real problems with if-amphetamine. Unfortunately, despite this therapeutic advantage, this compound has had to be withdrawn from the clinic because of worries that it might cause primary pulmonary hypertension, valvular heart disease and even long-term neuropathy. 

Vahabzadeh, A. Boutelle, MG and Fillenz, M (1995) Effects of changes in rat brain glucose on serotonergic and noradrenergic neurons. Eur. J. Neurosci. 7 175-179. 

Localisation of specific NT terminals. After its injection a labelled precursor should be taken up and detected in appropriate nerve terminals (and possibly cell bodies) so that the intensity of emission reflects the density of nerve terminals and the innervation. Using this procedure it has been possible to show that very little [ F] fluorodopa is concentrated in the striatum of Parkinsonian patients, compared with normals (Fig. 14.1). Whether the label remains on dopa or is transferred to dopamine will not greatly affect the result since both will label DA neurons although some will occur in noradrenergic nerve terminals. 

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