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Chapter: Biochemical Pharmacology : G protein-coupled receptors

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Inhibitors of presynaptic transmitter reuptake

Presynaptic reuptake of catecholamines works by cotrans-port of sodium and chloride ions.

Inhibitors of presynaptic transmitter reuptake

Presynaptic reuptake of catecholamines works by cotrans-port of sodium and chloride ions. While the reuptake trans-porters are homologous among the various types of cate-cholaminergic and serotoninergic synapses, the stoichiom-etry of transmitter molecules and co-transported ions ap-pears to vary, as depicted in Figure 10.11a. The transport process is facilitated both by ion concentration gradients and by the resting membrane potential (note that reuptake will cause a net transport of positive charge to the cytosol). Inhibition of presynaptic transmitter reuptake is another very important principle of drug action at adrenergic and serotoninergic synapses. It will have several consequences (Figure 10.11b):

 


1.  It will increase the concentration of transmitter in the synaptic cleft and, therefore, the postsynaptic stimulato-ry action.

2.  The postsynaptic cells will respond with a reduction of receptors exposed on the surface. This is one of the ef-fects leading to a fairly rapid and noticeable decrease in drug efficacy, and to habituation and possibly ad-diction.

3.   It will increase the presynaptic negative feedback, reducing both the rate of transmitter release and (by regulation at the genetic level) the amount of synthetic enzymes, e.g. of tyrosine hydroxylase.

4.  The intracellular pool of transmitter will be depleted.

5.  This will disinhibit tyrosine hydroxylase at the protein level, and therefore the actual turnover of synthesis will be increased, despite the reduced prevalence of synthetic enzymes.

 

Again, there are various drugs with different ranges and specificities. Cocaine has a particularly broad spectrum, affecting the reuptake of norepinephrine, dopamine, and serotonin alike. The effect of cocaine can be quantita-tively studied in mice by observing their excitement in re-sponse to being placed into a new environment, which is measured simply as the distance travelled within their new home over time. In experiments with transgenic mice, the reuptake transporters for both dopamine and serotonin had to be deleted in order to abolish the increase in excitement induced by cocaine.

 

In humans, a prominent effect of cocaine consists in in-creased vigilance and elevated mood. While cocaine itself is not used clinically, several catecholamine and serotonin reuptake blockers are used as antidepressants. Imipramine (Figure 10.13) is a `classic' but not so very specific; in ad-dition to inhibiting the reuptake of serotonin and of nore-pinephrine, it also has antihistaminic and antimuscarinic5 activity. This will lead to side effects in both the central nervous system and the peripheral autonomic system. A prominent one is the causation or deterioration of cardiac arrhythmias due to its antimuscarinic action.


Imipramine and its many structurally similar congeners are collectively referred to as the `tricyclic antidepressants'. A more modern drug is fluoxetine, which has similar an-tidepressant action but lacks most of the side effects of imipramine. Its selectivity for serotonin reuptake supports the notion that this transmitter, indeed, has a major role in regulating mood.

Since inhibition of transmitter reuptake depletes both the presynaptic transmitter and the postsynaptic receptors, it is clear that immediately after sudden discontinuation of a reuptake inhibitor the level of postsynaptic excitation would be very much reduced. Therefore, termination of antidepressant therapy must always be done carefully and slowly.

 

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