Noradrenergic

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. 

Correlation between clinical effectiveness and receptor affinities, however, can be seen with other receptors in addition to the dopamine D2 receptor. These include other dopaminergic receptors, as well as noradrenergic and serotonergic receptors. For example, most antipsychotics also have high affinity for a -adrenoceptors and 5-HT2 receptors (225). Some antipsychotics have been shown to be selective for the adrenoceptor versus the a -adrenoceptor, for example, spiperone [749-02-0] (226) and risperidone (61) (221]... 

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. 

The locus cemleus is important for the regulation of attentional states and autonomic nervous system activity. It has also been implicated in the autonomic and stress-like effects of opiate withdrawal. A noradrenergic pathway originating from the locus cemleus which descends into the spinal cord is part of the descending inhibitory control system, which has an inhibitory effect on nociceptive transmission in the dorsal horn. 

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. 

It has been suggested that modafinil increases wakefulness by activating ai noradrenergic receptors or hypothalamic cells that contain the peptide hypocre-tin [3], or that it may act by modulating the GABAergic tone that might lead to an increased dopamine release in the nucleus accumbens. On the other hand, modafinil does not have any effect in DAT knockout mice. 

Ethanol also reduces the activity of the noradrenergic system in the locus coeruleus, and alterations in norepinephrine activity may account for some aspects of intoxication and the abstinence syndrome. The 0.2 antagonist clon-idine and the P-receptor antagonist propranolol reduce some symptoms of alcohol withdrawal (Bailly et al. 1992 Carlsson and Fasth 1976 Dobrydnjov et al. 2004 Kahkonen 2003 Petty et al. 1997 Wong et al. 2003). 

McDougle CJ, Price LH, Palumbo JM, et al Dopaminergic responsivity during cocaine abstinence a pilot smdy. Psychiatry Res 43 77-85, 1992 McDougle CJ, Black JE, Malison RT, et al Noradrenergic dysregulation during discontinuation of cocaine use in addicts. Arch Gen Psychiatry 51 713-719,1994 Misra L, Kofoed L Risperidone treatment of methamphetamine psychosis (letter). Am J Psychiatry 154 1170, 1997... 

Nortriptyline. Nortriptyhne, a tricychc antidepressant, has been shown in double-blind, placebo-controlled randomized trials to be superior to placebo for smoking cessation (Prochazka et al. 1998). Nortriptyline appears to have efficacy comparable to that of bupropion for smoking cessation (Hall et al. 2002). The efficacy of this agent may be improved with more intensive behavioral therapies (Hall et al. 1998). Nortriptyline s mechanism of action is thought to relate to its noradrenergic and serotonergic reuptake blockade, because these two neurotransmitters have been implicated in the neurobiology of nicotine dependence. Side effects of nortiptyline are typical of tricyclic antidepressants and include dry mouth, blurred vision, constipation, and orthostatic hypotension. Nortriptyline appears to have some utility for smokers with a past history of major depression, and it can be recommended as a second-... 

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...

Figure 8.4 The site of action of drugs that modify noradrenergic transmission...

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