Noradrenaline neurons regulation

The adrenergic system is an essential regulator that increases cardiovascular and metabolic capacity during situations ofstress, exercise, and disease. Nerve cells in the central and peripheral nervous system synthesize and secrete the neurotransmitters noradrenaline and adrenaline. In the peripheral nervous system, noradrenaline and adrenaline are released from two different sites noradrenaline is the principal neurotransmitter of sympathetic neurons that innervate many organs and tissues. In contrast, adrenaline, and to a lesser degree noradrenaline, is produced and secreted from the adrenal gland into the circulation (Fig. 1). Thus, the actions of noradrenaline are mostly restricted to the sites of release from sympathetic nerves, whereas adrenaline acts as a hormone to stimulate many different cells via the blood stream. 

Evidence suggests that co-transmitters in a terminal have their own autoreceptors and, in some cases, activation of their own presynaptic receptor can influence the release of the co-stored, classical transmitter. For instance, activation of P2Y-autoreceptors by ATP is thought to affect the release of noradrenaline from sympathetic neurons. However, in other cases, feedback modulation of release of classical and their associated co-transmitters seems to have separate control mechanisms. This would suggest that either the two types of transmitter are concentrated in different nerve terminals or that mechanisms for regulating release target different vesicles located in different zones of the terminal (Burnstock 1990). 

However, as early as the 1970s, it was obvious that end-product inhibition of TH could not be the main factor regulating the rate of noradrenaline synthesis. Clearly, the hydroxylation of tyrosine takes place in the cytoplasm and so it must be cytoplasmic noradrenaline that governs enzyme activity. Yet, it is vesicle-bound transmitter that undergoes impulse-evoked release from the neuron. Also, when neurons are releasing noradrenaline, its reuptake from the synapse is increased and, even though some of this transmitter ends up in the vesicles, or is metabolised by MAO, there should be a transient increase in the concentration of cytoplasmic noradrenaline which would increase end-product inhibition of TH. 

The first clue to the processes which normally regulate TH activity came from experiments showing that electrical stimulation of sympathetic neurons increased the affinity of this enzyme for its co-factor and reduced its affinity for noradrenaline (for detailed reviews of this topic see Zigmond, Schwarzschild and Rittenhouse 1989 Fillenz 1993 Kaufman 1995 Kumar and Vrana 1996). Several lines of investigation showed that activation of TH was in fact paralleled by its phosphorylation and it was this process that accounted for the changes in the enzyme s kinetics (Table 8.2). 

Some less obvious phenomena of catecholamine transport and biosynthesis further illustrate the complexities of deciphering how efferents from midbrain dopamine neurons contribute to sleep-wake regulation. The plasma membrane norepinephrine transporter (NET), which is responsible for the uptake of extracellular noradrenaline, can also readily transport dopamine, and does so in vivo. This... 

The Rauwolfla alkaloid reserpine was originally used as a neuroleptic/antipsychotic agent. It was then discovered to be an effective antihypertensive agent. Reserpine causes depletion of the noradrenaline stores in peripheral postganglionic sympathetic neurons. In addition it causes depletion of noradrenalin in central nervous structures involved in the regulation of blood pressure. 

In various brain areas neuronal histamine release and synthesis is regulated presynaptically by histamine H3 receptors [1]. Recent studies revestl that H3 receptors not only act as autoreceptors to regulate the release euid synthesis of histamine [2, 3], but also modulate the release of other neurotransmitters, like acetylcholine [4], serotonin [5], dopamine [6] and noradrenaline [7]. In view of these widespread modulatory activities of the histamine H3 receptors, important roles for this receptor subtype in the various mammalian brain functions have been indicated [8, 9]. Consequently, selective ligands for the H3 receptor have been suggested to be benificial in the treatment of e.g. epilepsia, Alzheimer disease, sleeping and attention-deficit disorders [10, 11,12, 13, 14, 15,16],... 

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