<P> After ion and substrate binding have taken place, some conformational change must occur . From the conformational differences between the structure of TMs 1 - 5 and that of TMs 6 - 10, and from the identification of a substrate permeation pathway between the binding site of SERT and the cytoplasm, a mechanism for conformational change was proposed in which a four - helix bundle composed of TMs 1, 2, 6 and 7 changes its orientation within the rest of the protein . A structure of LeuT in the inward - open conformation subsequently demonstrated that the major component of the conformational change represents movement of the bundle relative to the rest of the protein . </P> <P> 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 . </P> <P> Horschitz et al. examined reuptake inhibitor selectivity among the rat serotonin reuptake protein (SERT) expressed in human embryonic kidney cells (HEK - SERT). They presented SERT with varying doses of either citalopram (an SSRI) or desipramine (an inhibitor of norepinephrine reuptake protein, NET). By examining the dose - response curves (using a normal medium as control), they were able to quantify that citalopram acted on SERT as an SSRI, and that desipramine had no effect on SERT . In a separate experiment, Horschitz et al. exposed HEK - SERT with citalopram on a long - term basis . They noticed that long - term exposure led to a down - regulation of binding sites . These results suggest some mechanism for long - term changes in the pre-synaptic neuron after drug therapy . Horschitz et al. found that after removing citalopram from the system, normal levels of SERT binding site expression returned . </P> <P> 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 . Tri-cyclic antidepressants inhibit the reuptake of both serotonin and norepinephrine by acting upon both the SERT 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 . </P>

Drugs block reuptake of neurotransmitters back into the presynaptic axon terminal