Neurotransmission presynaptic

The sympathetic or adrenergic nervous system operates in juxtaposition to the parasympathetic nervous system to maintain homeostasis in response to physical activity and physical or psychological stress. Sympathomimetic neurotransmission is generally mediated by norepinephrine [51-41 -2] (1), CgH NO, released from presynaptic storage granules upon stimulation. A second endogenous sympathomimetic agent, epinephrine [51-43-4] (2),... 

At low doses, both psychostimulants could theoretically stimulate tonic, extracellular levels of monoamines, and the small increase in steady state levels would produce feedback inhibition of further release by stimulating presynaptic autoreceptors. While this mechanism is clearly an important one for the normal regulation of monoamine neurotransmission, there is no direct evidence to support the notion that the doses used clinically to treat ADHD are low enough to have primarily presynaptic effects. However, alterations in phasic dopamine release could produce net reductions in dopamine release under putatively altered tonic dopaminergic conditions that might occur in ADHD and that might explain the beneficial effects of methylphenidate in ADHD. 

Rgure 22-2. Neurotransmission in the central nervous system. Neurotransmitter molecules (eg, norepinephrine), released by the presynaptic nerve, cross the synapse and bind with receptors in the cell membrane of the postsynaptic nerve, resulting in the transmission of the nerve impulse. 

The AMPA receptors mediate the majority of fast excitatory neurotransmission in the mammalian brain. The rapid kinetics and the low Ca permeability make these receptors ideal for fast neurotransmission without sufficient changes in the intracellular calcium concentration to activate Ca2+-dependent processes. The NMDA receptors are co-localized with the AMPA receptors on many synapses, but the slow kinetics of the NMDA receptor minimize the receptor activation after a single presynaptic glutamate release where the neuron quickly repolarizes, resulting in Mg2+ block... 

Figure 1.1 The dopamine transporter terminates the action of released dopamine by transport back into the presynaptic neuron. Dopamine transport occurs with the binding of one molecule of dopamine, one chloride ion, and two sodium ions to the transporter the transporter then translocates from the outside of the neuronal membrane into the inside of the neuron.22 Cocaine appears to bind to the sodium ion binding site. This changes the conformation of the chloride ion binding site thus dopamine transport does not occur. This blockade of dopamine transport potentiates dopaminergic neurotransmission and may be the basis for the rewarding effects of cocaine.

Psychoactive drugs can influence neurotransmission at its five different stages (Chapter 2). First, they may modify the biosynthesis of a neurotransmitter. Second, they can increase or decrease their storage within the presynaptic neuron. Third, they may stimulate or inhibit neurotransmitter release from the synaptic bouton. Fourth, they may affect the binding of the neurotransmitters to its receptor. Finally, they can retard the neurotransmitter s inactivation. Some examples of each of these stages will be given below, but it should be noted that many drugs affect several of these processes. 

It is now possible to image not only postsynaptic, but pre-synaptic and intrasynaptic neurotransmission (Fig. 58-5). Presynaptic sites, such as the dopamine transporter and the serotonin transporter the presynaptic dopamine vesicular transporter (VMAT-2) and the acetylcholine transporter extrasynaptic sites such as the enzymes which break down neurotransmitters, e.g. MAO A and MAO B with radioligands that bind to post or pre-synaptic sites, i.e. dopamine competing with radioligands such as UC raclopride (see Fig. 58-9) (PET (Fig. 58-10) can be measured under basal conditions or following drugs which either decrease (e.g. AMPT) or increase (e.g. intravenous amphetamine) intrasynaptic dopamine. 

Fig. 2. Schematic drawing of the adrenergic neurotransmission. Dependent on the target organ, the postsynaptic, G-protein-coupled receptors are of the a -, 2- or /Sj-adrenoceptor subtype. A presynaptic 2-adrenoceptor acts as an inhibitory autoreceptor. The predominant elimination pathway of the transmitter noradrenaline (NA) is the neuronal re-uptake...

Presynaptic receptors for nonadrenomimetic substances (e.g., acetylcholine, adenosine) also have been found on the sympathetic presynaptic nerve ending. Their importance and role in the modulation of neurotransmission have not been definitively established. 

Transmission through autonomic ganglia is more complex than neurotransmission at the neuromuscular and postganglionic neuroeffector junctions and is subject to numerous pharmacological and physiological influences. In some ganglionic synapses, especially at parasympathetic ganglia, there is a simple presynaptic to postsynaptic cell relationship in others, the presynaptic to postsynaptic cell relationship may involve neurons interposed between the presynaptic and postsynaptic elements (interneurons). 

Mirtazapine (Remeron) enhances both serotonergic and noradrenergic neurotransmission. By blocking presynaptic aj-adrenoceptors, mirtazapine causes release of norepinephrine. Indirectly, through noradrenergic modulation of serotonin systems, mirtazapine also causes increased release of serotonin. It is an antagonist... 

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