Synaptic clefts

Dopamine. Dopamine (DA) (2) is an intermediate in the synthesis of NE and Epi from tyrosine. DA is localized to the basal ganglia of the brain and is involved in the regulation of motor activity and pituitary hormone release. The actions of DA are terminated by conversion to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase-A and -B (MAO-A and -B) in the neuron following reuptake, or conversion to homovanillic acid (HVA) through the sequential actions of catechol-0-methyl transferase (COMT) and MAO-A and -B in the synaptic cleft. 

Neurotransmitter transporters terminate the time interval of synaptic neurotransmission localization of transporters in the vicinity of exocytotic sites is crucial for their clearance of neurotransmitter molecules following their exocytotic release into the synaptic cleft. 

Non-selective Cation Channels. Figure 1 The nicotinic acetylcholine receptor (nAChR) is localized within the cell membrane above the cell membrane is the synaptic cleft, below the cytoplasm. Drawing of the closed (left) and open (right) nAChR showing acetylcholine (ACh) binding and cation movement. Dimensions of the receptor were taken from references [2, 3]. 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

Psychostimulants. Figure 2 Dopamine molecules have two different possible targets. Both ways are initially increased by DAT inhibition caused by methylphenidate pre- and postsynaptic dopamine receptors. Stimulation of postsynaptic receptors results in inhibition of presynaptic action potential generation. On the other hand, presynaptic receptor stimulation leads to a transmission inhibition of action potentials. Therefore, both mechanisms are responsible for a decrease in vesicular depletion of dopamine into the synaptic cleft (adapted from [2]). 

Selective noradrenaline reuptake inhibitors (SNRIs) are a group of drugs, which act as antidepressants by the selective inhibition of the reuptake of noradrenaline from the synaptic cleft via the selective blockade of the noradrenaline-specific neurontransmitter transporter (e.g. reboxetine). 

The amphetamine-like properties of trace amines are best described for PEA which shares close structural similarity to amphetamine and can displace monoamine neurotransmitters from synaptic vesicles and trigger their release into the synaptic cleft by acting on the dopamine transporter. However, this effect is only observed at high, supra-physiological PEA concentrations and thus might not occur under physiological conditions. 

Atropine acts as an antagonist of acetylcholine at muscarinic receptors, but not at nicotinic receptors. By acting as an antagonist, it can prevent overstimulation of muscarinic receptors by the excessive quantities of acetylcholine remaining in the synaptic cleft when AChE is inhibited. The dose of atropine needs to be carefully controlled because it is toxic. 

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

Figure 3.1 Schematic representation of a generic excitatory synapse in the brain. The presynaptic terminal releases the transmitter glutamate by fusion of transmitter vesicles with the nerve terminal membrane. Glutamate diffuses rapidly across the synaptic cleft to bind to and activate AMPA and NMDA receptors. In addition, glutamate may bind to metabotropic G-protein-coupled glutamate receptors located perisynaptically to cause initiation of intracellular signalling via the G-protein, Gq, to activate the enzyme phospholipase and hence produce inositol triphosphate (IP3) which can release Ca from intracellular calcium stores...

Many early studies of transmitter release depended on measuring its concentration in the effluent of a stimulated, perfused nerve/end-organ preparation. This technique is still widely used to study drug-induced changes in noradrenaline release from sympathetic neurons and the adrenal medulla. However, it is important to realise that the concentration of transmitter will represent only that proportion of transmitter which escapes into the perfusate ( overflow ) (Fig. 4.2). Monoamines, for instance, are rapidly sequestered by uptake into neuronal and non-neuronal tissue whereas other transmitters, such as acetylcholine, are metabolised extensively within the synapse. Because of these local clearance mechanisms, the amount of transmitter which overflows into the perfusate will depend not only on the frequency of nerve stimulation (i.e. release rate) but also on the dimensions of the synaptic cleft and the density of innervation. 

In common with other monoamines, the actions of released noradrenaline are terminated by its rapid reuptake from the synaptic cleft. This uptake process relies on membrane-bound noradrenaline transporters which are glycoproteins closely related... 

After neurotransmitter molecules have influenced the firing of a receiving neuron (more technically called a postsynaptic neuron), some of them are destroyed by enzymes in the synaptic cleft (the synapse), some are reabsorbed by the sending presynaptic neuron in a process that is called reuptake , and the rest remain in the space between the two neurons. The chemical-imbalance hypothesis is that there is not enough serotonin, norepinephrine and/or dopamine in the synapses of the brain. This is more specifically termed the monoamine theory of depression, because both serotonin and norepinephrine belong to the class of neurotransmitters called monoamines. 

Against this backdrop, researchers reported evidence that iproniazid, the antitubercular drug that was to become the first antidepressant, might increase norepinephrine and serotonin levels in the brain. How did it have this effect Recall that some of the neurotransmitter molecules released by a neuron are destroyed by enzymes in the synaptic cleft between the sending presynaptic neuron and the receiving postsynaptic neuron. When the neurotransmitter is a monoamine - like norepinephrine and serotonin - this process is called monoamine oxidase (MAO). As early as 1952 researchers at the Northwestern University Medical School in Chicago reported that iproniazid inhibited the oxidation of monoamines. This meant that iproniazid was a... 

Describe how neurotransmitters are removed from the synaptic cleft... 

Figure 5.1 Mechanism of action at a chemical synapse. The arrival of an action potential at the axon terminal causes voltage-gated Ca++ channels to open. The resulting increase in concentration of Ca++ ions in the intracellular fluid facilitates exocytosis of the neurotransmitter into the synaptic cleft. Binding of the neurotransmitter to its specific receptor on the postsynaptic neuron alters the permeability of the membrane to one or more ions, thus causing a change in the membrane potential and generation of a graded potential in this neuron.

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