Postsynaptic effects

Two different peptides (TRH and enkephalin, substance P and CCK) coming from different precursors. These combinations are intriguing in that TRH is excitatory yet enkephalins are inhibitory — complex postsynaptic effects can be envisaged. Substance P is excitatory and CCK acts on two receptors, A and B, with the former being the predominant CNS form. 

Figure 17.4 The effect of neuroleptics on the activity of DA neurons. Although neuroleptics (DA antagonists) are used primarily to inhibit the postsynaptic effects of released DA they also increase the activity of the DA neuron itself since they (1) inhibit the effect of synaptic DA on nerve terminal autoreceptors and so increase DA release (2) block inhibitory DA autoreceptors on the soma of the DA neuron so that they cannot be stimulated by endogenous DA, possibly released from the neuron s own dendrites and (3) facilitate feedback excitation to the DA neuron from those neurons normally inhibited by distally released DA. All the DA receptors involved are D2 (or possibly D3). — Blocked by D2 antagonists (neuroleptics)...

Opioids act in the brain and within the dorsal horn of the spinal cord, where their actions are better understood. The actions of opioids important for analgesia and their side-effects involve pre- and postsynaptic effects (1) reduced transmitter release from nerve terminals so that neurons are less excited by excitatory transmitters, and (2) direct inhibitions of neuronal firing so that the information flow from the neuron is reduced but also inhibitions of inhibitory neurons leading to disinhibition. This dual action of opioids can result in a total block of sensory inputs as they arrive in the spinal cord (Fig. 21.5). Thus any new drug would have to equal this dual action in controlling both transmitter release and neuronal firing. 

Chemical transmission between nerve cells involves multiple steps 167 Neurotransmitter release is a highly specialized form of the secretory process that occurs in virtually all eukaryotic cells 168 A variety of methods have been developed to study exocytosis 169 The neuromuscular junction is a well defined structure that mediates the presynaptic release and postsynaptic effects of acetylcholine 170 Quantal analysis defines the mechanism of release as exocytosis 172 Ca2+ is necessary for transmission at the neuromuscular junction and other synapses and plays a special role in exocytosis 174 Presynaptic events during synaptic transmission are rapid, dynamic and interconnected 175... 

The neuromuscular junction is a well-defined structure that mediates the presynaptic release and postsynaptic effects of acetylcholine. The first detailed studies of... 

The metabolic unity of the neuron requires that the same transmitter is released at all its synapses. This is known as Dale s Law (or principle) which Sir Henry Dale proposed in 1935. Dale s Law only applies to the presynaptic portion of the neuron, not the postsynaptic effects which the transmitter may have on other target neurons. For example, acetylcholine released at motor neuron terminals has an excitatory action at the motor neuron junction, whereas the same transmitter released at vagal nerve terminals has an inhibitory action on the heart. 

Since predators of snakes (and humans) have to deal with snake venoms as defenses, they are included here, even though they serve in predation. Snake venoms are primarily enzymes (proteins), especially of the phospholipase A2 type, which breaks down cell membrane phospholipids hydrolytically. Other snake venoms such as cobrotoxin contain peptides with 60-70 amino acid residues. Pharmacologically, they have neurotoxic, cytotoxic, anticoagulant, and other effects. The neurotoxins, in turn, can have pre- or postsynaptic effects. Snake venoms with both neurotoxic and hemolytic effects on the heart are known as cardiotoxins. Cytotoxins attach to the cells of blood vessels and cause hemorrhage. Snake venom factors may stimulate or inhibit blood clotting. Finally, platelet-active factors can contribute to hemorrhage. 

Pharmacology has provided powerful tools to characterize the neurochemical pathways of stress and anxiety in the brain, and how these pathways are involved in the pathophysiology and treatment of anxiety disorders. In the past, this work has largely focused on classical neurotransmitter systems, including the synthesis, release, and metabolism of monoamines and receptor subtypes that control presynaptic release of neurotransmitters and their postsynaptic effects. Increasing the specihcity of drugs but also the combination of mechanisms has been pursued to improve anxiolytic drugs. 

Adrenergic drugs may also exert postsynaptic effects. There is a considerable body of classical structure-activity correlation studies in the adrenergic field for these effects. It may be summarized as follows ... 

Monoamine oxidase inhibitors (MAOIs) are useful as thymoleptic (antidepressant) drugs, especially since the action of some of these agents is very rapid, as compared to the lag period of days or even weeks shown by tricyclic antidepressants. All MAOIs act by increasing the available concentration of the neurotransmitters NE and 5-HT which, because they are not metabolized, accumulate in the synaptic gap and exert an increased postsynaptic effect. The drugs show hypotensive activity as a side effect, and some MAOIs are used as hypotensive drugs. 

Alpha-adrenoceptor antagonists inhibit the activation of a adrenoceptors by catecholamines. In the cardiovascular system these receptors are mainly located on the surface of smooth muscle cells in the walls of arteries and veins. On activation, they mediate an increase in intracellular free calcium, which induces smooth muscle contraction. Inhibition by an a antagonist causes arterial or venous vasodilatation. The postsynaptic effect is mainly mediated by ol adrenoceptors whereas o2 adrenoceptors are found on the presynaptic membranes of the sympathetic neurones. Activation of o2-adreno-ceptors results in auto-inhibition of catecholamine release. 

Considerable attention has been paid to the ultimate postsynaptic effects of increased neurotransmitters in the synapses. In tests of postsynaptic effects, cAMP concentrations have consistently decreased rather than increased, in spite of the presumably longer duration of action of the transmitters. In addition, the number of postsynaptic -adrenoceptors has shown a measurable decrease that follows the same delayed time course as clinical improvement in patients. Thus, the initial increase in neurotransmitter seen with some antidepressants appears to produce, over time, a compensatory decrease in receptor activity, ie, down-regulation of receptors. Decreases in norepinephrine-stimulated cAMP and in B-adrenoceptor binding have been conclusively shown for selective norepinephrine uptake inhibitors, those with mixed action on norepinephrine and serotonin, monoamine oxidase inhibitors, and even electroconvulsive therapy. Such changes do not consistently occur after the selective serotonin uptake inhibitors, 2 receptor antagonists, and mixed serotonin antagonists. 

Modulatory effects may be postsynaptically mediated by interactions within the spiny projection neurons, or involve presynaptic regulation of neurotransmitter release from corticostriatal terminals. Postsynaptic effects may be mediated by direct actions of intracellular signaling pathways (cAMP, calcineurin) on receptor status (phosphorylation/ dephosphorylation of receptor proteins), and actions on voltage-dependent channels, which may amplify or attenuate the electrical response of the cell to synaptic currents. 

The postsynaptic transduction of the dopamine signal, whether steady-state, pulse increase, or the pulse decrease in concentration, depends on the relative predominance of Dl-like or D2-like dopamine receptors in the postsynaptic cell. The steady-state levels appear to be sufficient to activate both subtypes of receptor, as locally applied antagonists of either receptor subtype produce physiological effects. Two broad classes of postsynaptic effects can be identified immediate, short-term effects which reverse rapidly, and longer-term effects which persist after the removal of the dopamine signal. 

LMS was isolated on the basis of its action upon visceral muscle. However, it also effects motor neurons (26). IMS attenuated the evoked transmitter release from the presynaptic membrane of excitatory motor neurons terminating on the skeletal muscle of the mealworm, Tenebrio molitor. but had no postsynaptic effects on that preparation. Although the mechanisms of IMS-induced inhibition of excitatory presynaptic potentials have not been precisely identified, one preliminary experiment suggested that metabolites of arachidonic acid may function as a second messenger for IMS at that site (26). 

Postsynaptic a2-receptors are involved in suppression of pain perception, and their stimulation with the 02 agonist clonidine is used therapeutically. Some data even suggest that postsynaptic effects are also important in the blood pressure-reducing effects of 02 agonists. E.g., contrary to what one would expect from the textbook model (which ascribes the antihypertensive effect to presynaptic inhibition), the effect of clonidine persists after ablation of the presynaptic nerve terminals with 6-hydrox-ydopamine (see below). 

In electrophysiological experiments, cannabinoids inhibited neurotransmission. The inhibition was always due to inhibition of transmitter release from axon terminals and never to interference of cannabinoids with the postsynaptic effects of the neurotransmitters. The experiments in which transmitter release was determined neurochemically also indicated that cannabinoids inhibit transmitter release from axon terminals. In most instances the presynaptic cannabinoid receptors can be classified as CBi receptors (but some exceptions are given in Tables 1 and 2). Effects of cannabinoids on the release of individual transmitters are discussed below. Effects of cannabinoids on neurotransmission have also been reviewed by Schlicker and Kathmann (2001). 

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