Synapse, noradrenergic

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... 

Bremner, JD, Krystal, JH, Southwick, SM and Charney, DS (1996) Noradrenergic mechanisms in stress and anxiety. II. Clinical studies. Synapse 23 39-51. 

Taiwo YO, Levine JD. (1988). Prostaglandins inhibit endogenous pain control mechanisms by blocking transmission at spinal noradrenergic synapses. J Neurosci. 8(4) 1346-49. 

Bremner JD, Krystal JH, Southwick SM, Charney DS (1996a) Noradrenergic mechanisms in stress and anxiety 1. Preclinical studies. Synapse 23 28-38... 

While much emphasis has been placed on alterations in noradrenergic neurotransmission, TCA drugs are not without effect on serotonin (5-HT) neurotransmission. Long-term studies with TCA drugs in animals have demonstrated postsynaptic supersensitivity to serotonin (5-HTia) receptor agonists at serotonin synapses, with an associated enhancement of serotonergic neurotransmission. The sensitization to 5-HTia agonists is mediated in part by an increase in the density of postsynaptic 5-HTia receptors. Enhancement of trans-... 

Norepinephrine is released into the synapse from vesicles [(1) in Fig. 2.7] amphetamine facilitates this release. Norepinephrine acts in the CNS at two different types of noradrenergic receptors, the a and the P [see (2a), (2b) and (3) in Fig. 2.7]. a-Adrenergic receptors can be subdivided into receptors (coupled to phospholipase and located postsynaptically) and tt2 receptors (coupled to Gj and located primarily presynapti-cally) (Insel, 1996). P-Adrenergic receptors in the CNS are predominantly of the P subtype (3 in Fig. 2.7). P receptors are coupled to and lead to an increase in cAMP. Cyclic AMP triggers a variety of events mediated by protein kinases, including phosphorylation of the P receptor itself and regulation of gene expression via phosphorylation of transcription factors. 

FIGURE 2.7 Noradrenergic synapse. The release of norepinephrine (1) can be enhanced by compounds such as amphetamine. Once released, norepinephrine binds to a2 receptors (2a), al receptors (2b), and pi receptors (3). Norepinephrine is removed from the synapse via cleavage by catechol-O-methyl-transferase (COMT) or via reuptake by the norepinephrine transporter (4). 

Control of transmitter release is not limited to modulation by the transmitter itself. Nerve terminals also carry regulatory receptors that respond to many other substances. Such heteroreceptors may be activated by substances released from other nerve terminals that synapse with the nerve ending. For example, some vagal fibers in the myocardium synapse on sympathetic noradrenergic nerve terminals and inhibit norepinephrine release. Alternatively, the ligands for these receptors may diffuse to the receptors from the blood or from nearby tissues. Some of the transmitters and receptors identified to date are listed in Table 6-4. Presynaptic regulation by a variety of endogenous chemicals probably occurs in all nerve fibers. 

Atomoxetine is a selective inhibitor of the norepinephrine reuptake transporter. Its actions, therefore, are mediated by potentiation of norepinephrine levels in noradrenergic synapses. It is used in the treatment of attention deficit disorders (see below). Atomoxetine has surprisingly little cardiovascular effect because it has a clonidine-like effect in the central nervous system to decrease sympathetic outflow while at the same time potentiating the effects of norepinephrine in the periphery. However, it may increase blood pressure in some patients. Norepinephrine reuptake is particularly important in the heart, particularly during sympathetic stimulation, and this... 

Cocaine is a local anesthetic with a peripheral sympathomimetic action that results from inhibition of transmitter reuptake at noradrenergic synapses (see Chapter 6 Introduction to Autonomic Pharmacology). It readily enters the central nervous system and produces an amphetamine-like effect that is shorter lasting and more intense. The major action of cocaine in the central nervous system is to inhibit dopamine reuptake into neurons in the "pleasure centers" of the brain. These properties and the fact that it can be smoked, "snorted" into the nose, or injected for rapid onset of... 

Mammalian y-aminobutyric addB receptors structure and function. Pharmacol Rev 54 247-64 Brakeman PR, Lanahan AA, O Brien R et al (1997) Homer a protein that selectively binds metabotropic glutamate receptors. Nature 386 284—8 Bremner JD, Krystal JH, Southwick SM, Chamey DS (1996) Noradrenergic mechanisms in stress and anxiety II. Preclinical studies. Synapse 23 28-38 Breysse N, Baunez C, Spooren W et al (2002) Chronic but not acute treatment with a metabotropic glutamate 5 receptor antagonist reverses the akinetic deficits in a rat model of parkinsonism. J Neurosd 22 5669-78... 

Scanziani M, Capogna M, Gahwiler BH, Thompson SM (1992) Presynaptic inhibition of miniature excitatory synaptic currents by baclofen and adenosine in the hippocampus. Neuron 9 919-27 Schlicker E, Gothert M (1998) Interactions between the presynaptic alpha2-autoreceptor and presynaptic inhibitory heteroreceptors on noradrenergic neurones. Brain Res Bull 47 129-32. Schmitz D, Mellor J, Nicoll RA (2001) Presynaptic kainate receptor mediation of frequency facilitation at hippocampal mossy fiber synapses. Science 291 1972-6 Schneggenburger R, Neher E (2005) Presynaptic calcium and control of vesicle fusion. Curr Opin Neurobiol 15 266-74... 

Another important mechanism whereby the release of a neurotransmitter may be altered is by presynaptic inhibition. Initially this mechanism was thought to be restricted to noradrenergic synapses, but it is now known to occur at GABA-ergic, dopaminergic and serotonergic terminals also. 

---