Reuptake - Human Systems

Human Systems

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 (SSRI, selective serotonin reuptake inhibitor) 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.

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.

The net effect of amphetamine (AMPH) use is an increase of dopamine, norepinephrine and serotonin in the synapse. It has been shown that AMPH acts upon the serotonin and dopamine transporters to reverse their activity. In DAT knockout mice, dopamine levels in the synapse (as measured by microdialysis) were no different when they were exposed to AMPH relative to baseline levels. In normal mice, levels of dopamine in the synapse rose to ten times normal levels after exposure to AMPH.