Drugs that affect the reuptake of neurotransmitters are in widespread use for th

Question

Drugs that affect the reuptake of neurotransmitters are in widespread use for the treatment of attention-deficit/hyperactivity disorder and clinical depression. In molecular terms, explain what effect(s) such reuptake inhibitors have on postsynaptic neurons if the neurotransmitter in question is excitatory for that postsynaptic neuron. In your answer include what would happen to the postsynaptic neuron with and without the reuptake inhibitors. Also, include the concept of summation (and be specific as to what type of summation would happen in the presence of the reuptake inhibitors).

Explanation / Answer

Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synapticneuron after it has performed its function of transmitting a neural impulse.Reuptake is necessary for normal synaptic physiology because it allows for the recycling of neurotransmitters and regulates the level of neurotransmitter present in the synapse, thereby controlling how long a signal resulting from neurotransmitter release lasts. Because neurotransmitters are too large and hydrophilic to diffuse through the membrane, specific transport proteins are necessary for the reabsorption of neurotransmitters.

The main objective of a reuptake inhibitor is to substantially decrease the rate by which neurotransmitters are reabsorbed into the presynaptic neuron, increasing the concentration of neurotransmitter in the synapse. This increases neurotransmitter binding to pre- and postsynaptic neurotransmitter receptors.

Depending on the neuronal system in question, a reuptake inhibitor can have drastic effects on cognition and behavior. Non-competitive inhibition of the bacterial homologue LeuT by tricyclic antidepressants resulted from binding of these inhibitors in the extracellular permeation pathway. However, the competitive nature of serotonin transport inhibition by antidepressants suggests that in neurotransmitter transporters, they bind in a site overlapping the substrate site.

Depression has been suggested to be a result of a decrease of serotonin found in the synapse. This theory has been supported by the successful reduction of depressive symptoms after administration of tri-cyclic antidepressants (such as desipramine) and SSRI’s(selective serotonin reuptake inhibitor). Tri-cyclic antidepressants inhibit the reuptake of both serotonin and norepinephrine by acting upon both the SERT (serotonin transporter) and NET. SSRIs selectively inhibit the reuptake of serotonin by acting upon SERT. The net result is an increased amount of serotonin in the synapse, thus increasing the probability that serotonin will interact with a serotonin receptor of the postsynaptic neuron. There are additional mechanisms by which serotonin autoreceptor desensitization must occur, but the net result is the same. This increases serotonin signaling, which then acts to elevate mood and thus relieve depressive symptoms. This proposal for the antidepressant mechanism of serotonin reuptake inhibitors does not account for the time course of the therapeutic effect, which takes weeks to months, while transporter inhibition is essentially immediate.

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