Noradrenergic transmission

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

Certainly, such a complex system for metabolism of noradrenaline (which is shared with the other catecholamines) strongly suggests that its function extends beyond that of merely destroying transmitter sequestered from the synapse. However, as yet, little is known about the regulation of this pathway and any influence it might have on noradrenergic transmission. One crucial, additional role for MAO appears to be the... 

Obviously, it is extremely unlikely that noradrenergic transmission is the sole factor to determine the behavioural response to even simple environmental stimuli. Indeed, a bell-shaped dose-response curve immediately suggests the intervention of one or more additional factors (neurotransmitters ). Such interactions with other neurotransmitters could well define the relationship between noradrenergic transmission and the coding of the coping response. 

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... 

A final, important distinction between sibutramine and (7-fenfluramine is that the actions of the former, but not the latter, rest on its modification of both 5-HT and noradrenergic transmission. Thus, the reduction in food intake by sibutramine is partially blocked by ai- or jSi-adrenoceptor antagonists as well as 5-HT2a/2C or 5-HT2b/2c antagonists. In fact, there appears to be a synergistic interaction between these two transmitter systems. This is illustrated by a study of the effects of the selective serotonin... 

The first suggestion that abnormal noradrenergic transmission was linked with anxiety came from Redmond s laboratory in the 1970s when he drew attention to the similarities in the symptoms and signs of anxiety with those of the acute stress response (Redmond and Huang 1979). He went on to stimulate the locus coeruleus of (chair-restrained) monkeys and showed that this caused behavioural changes, some of which resembled a cluster of behaviours displayed by the animals when under threat. This work led to the proposal that anxiety was due to (or exacerbated by) excessive... 

These observations question the role of noradrenaline as an initiator of anxiety as does the finding that the anti-anxiety drug, buspirone (see Chapter 9), increases the concentration of noradrenaline in the extracellular fluid in the frontal cortex of freely-moving rats (Done and Sharp 1994). Whether this is because buspirone is metabolised to l-(2-pyrimidinyl)-piperazine (1-PP), which is an a2-adrenoceptor antagonist, is uncertain. Unfortunately, no studies have investigated the effects of chronic administration of this drug on noradrenergic transmission this could be important because, unlike benzodiazepines, buspirone is effective therapeutically only after several weeks of treatment. 

If excessive noradrenergic transmission is a causal factor in anxiety, then it would be predicted that a lesion of central noradrenergic neurons would have an anti-anxiety effect in behavioural models of this condition. Unfortunately, the behavioural effects of such lesions are notoriously inconsistent and there are many reports of negative findings (e.g. Salmon, Tsaltas and Gray 1989). One study has even shown that a lesion of central noradrenergic neurons, induced by the selective neurotoxin, DSP-4, abolishes the anti-anxiety effects of tricyclic antidepressants and MAO inhibitors, but not those of the benzodiazepine, alprazolam, or the barbiturate, phenobarbitone (Fontana,... 

Drawing all this evidence together, Schildkraut (1965) concluded that depression was caused by a functional deficit of noradrenergic transmission in the brain. He also thought that the rebound depression and fatigue, which are experienced after the arousing effects of amphetamine have worn off, were due to depletion of neuronal stores of noradrenaline. However, Schildkraut made a clear distinction between the effects of antidepressants and the arousal induced by amphetamine, describing the latter as stimulation and excitement . To this day, there is controversy over whether or not amphetamine has a beneficial effect in depression. 

One problem with both these theories is that disruption of noradrenergic transmission by selective adrenoceptor antagonists has little impact on the development of escape deficits. However, such antagonists do prevent the reversal of learned helplessness by antidepressants (reviewed by Stanford 1995). Also, it would be most unlikely that a deficit in only one neurotransmitter system fully accounts for learned helplessness. Indeed, there is plenty of evidence for a role for 5-HT in learned helplessness for instance, this behaviour is reversed by microinjection of 5-HT into the prefrontal cortex (Davis et al. 1999). Finally, it is clear that opioid, GABAergic and cholinergic systems (among others) are all linked with this behavioural deficit and even dihydropyridine antagonists of Ca + channels prevent its development. 

A logical conclusion from this work was that depression is caused by hyperresponsive )S-adrenoceptors. At first, this might seem to undermine Schildkraut s suggestion that depression is caused by a deficit in noradrenergic transmission. However, proliferation of receptors is the normal response to a deficit in transmitter release and so the opposite change, dowmegulation of jS-adrenoceptors by antidepressants, would follow an increase in the concentration of synaptic noradrenaline. This would be consistent with both their proposed mechanism of action and the monoamine theory for depression. 

However, experience proves that depression can be reversed by drugs that augment serotonergic and noradrenergic transmission (and reinstated by a deficit in the synthesis of these monoamines). These, then seem to be crucial targets that ultimately determine mood. This would explain why, despite numerous neurochemical options for the causes of depression, all antidepressants developed so far (and even those discovered by chance) target these neuronal systems. Whatever the cause of depression, therefore, its relief seems to rest on appropriate secretion of these monoamines. This would be entirely... 

L Heureux R, Dennis T, Curet O, Scatton B. 1986. Measurement of endogenous noradrenaline release in the rat cerebral cortex in vivo by transcortical dialysis effects of drugs affecting noradrenergic transmission. J Neurochem 46(6) 1794-1801. 

Beta Blockers. The beta blockers, which act by interfering with noradrenergic transmission, have been used to manage aggression and other behavioral disturbances in patients who have suffered brain injury due to trauma and stroke for over 25 years. Several beta blockers have been tested including propranolol (Inderal), pindolol (Visken), nadolol (Corgard), and metoprolol (Lopressor). Fat-soluble beta blockers such as propranolol and pindolol more readily cross the blood-brain barrier and are thus better suited to managing psychiatric symptoms such as behavioral lability. 

Transmission in noradrenergic neurons is somewhat more complex, particularly in regard to the mechanisms by which the transmitter is removed from the biophase subsequent to its release. Noradrenergic transmission is represented diagrammatically in Figure 9.3. 

Precursor therapy as a means of increasing dopaminergic transmissions is limited to L-tyrosine and L-dopa. Although under basal conditions the exogenous administration of tyrosine leads to specific enhancement of noradrenergic transmission, it can enhance dopaminergic transmission in conditions of DA deficiency [Kapur and Mann 1992). Only one adequately controlled clinical trial has been reported, in which 65 patients with major depression were randomly selected to treatment for 4 weeks with oral L-tyrosine 100 mg/kg/day, imipramine 2.5 mg/kg/day, or placebo [Gelenberg et al. 1990). Tyrosine increased and imipramine decreased excretion of the main metabolite of NA, but no evidence was found that tyrosine had antidepressant activity in contrast with imipramine. 

Clonidine reduces opiate withdrawal symptoms because it acts on the noradrenergic system, and some opiate withdrawal symptoms are due to noradrenergic overactivity. Specifically, it is an alpha-adrenergic agonist which acts preferentially on presynaptic alpha-2 neurons to inhibit noradrenergic transmission, with the action in the locus... 

Opioid-induced antinociception depends, to some degree, on monoaminergic signaling in the spinal dorsal horn. While opioids can act directly on dorsal horn terminals of primary afferent nociceptive fibers or on excitatory interneurons in lamina II of the dorsal horn to reduce the release of excitatory transmitters (Glaum et al., 1994), the supraspinally mediated analgesic effects of opioids, at least in part, involve interactions with central and spinal serotonergic and noradrenergic transmission. 

In the mouse uterus H3 receptors seem to be absent, since both agonists and antagonists of this receptor failed to modify noradrenaline release evoked by 100 mM K+ or electrical stimulation (Montesino et al., 1995). It would seem that prejunctional histamine receptors which modulate noradrenergic transmission belong to the Hj subtype. 

Montesino, H., Villar, M., Vega, E., Rudolph, M.I., 1995. Histamine, a neuromodulator of noradrenergic transmission in uterine horns from mice in diestrus. Biochem. Pharmacol. 50, 407-411. 

Deyama, S., Katayama, T., Kondoh, N., Nakagawa, T., Kaneko, S., Yamaguchi, T., Yoshioka, M., and Minami, M. (2009). Role of enhanced noradrenergic transmission within the ventral bed nucleus of the stria terminalis in visceral pain-induced aversion in rats. Behav. Brain Res. 197, 279-283. 

Millan MJ, Lejeune F, Gobert A. Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex relevance to the actions of antidepressant agents. J Psychopharmacol... 

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