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selective serotonin reuptake inhibitor (SSRI) used as an
A reuptake inhibitor (RI),
also known as a transporter blocker, is a drug which inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to
an increase in the extracellular concentrations of the neurotransmitter and therefore an
increase in neurotransmission.
Many drugs utilize reuptake
inhibition to exert their psychological and physiological effects, including various antidepressants, anxiolytics, stimulants, and anorectics, among others. Most known reuptake
inhibitors affect the monoamine neurotransmitters
and dopamine. There are a
number of pharmaceutical drugs and research chemicals that act as reuptake
inhibitors for other neurotransmitters such as adenosine, GABA, glutamate, and the endocannabinoids as well, however.
Active Site Transporter
, a selective
GABA reuptake inhibitor used as an anticonvulsant in the treatment
of epilepsy and seizures.
Standard reuptake inhibitors are believed to act simply as competitive substrates that work by binding
directly to the plasmalemma transporter of the neurotransmitter in question.
the transporter in place of the respective neurotransmitter and competitively block
it from being transported from the nerve terminal or synapse into the pre-synaptic neuron. With high enough doses, occupation
becomes as much as 80-90%. At this level of inhibition, the transporter will be considerably less
efficient at removing excess neurotransmitter from the synapse and this causes a
substantial increase in the extracellular concentrations of the neurotransmitter and therefore an
increase in overall neurotransmission.
primary active constituent responsible for the therapeutic benefits
of extracts of the herb Hypericum perforatum
Wort), which is used as an antidepressant.
Alternatively, some reuptake inhibitors bind to
allosteric sites and inhibit reuptake indirectly and noncompetitively.
and related drugs such as benocyclidine, tenocyclidine, ketamine, and dizocilpine (MK-801),
have been shown to inhibit the reuptake of the monoamine
They appear to exert their reuptake inhibition by binding to
vaguely characterized allosteric sites on each of the respective monoamine transporters.
Benztropine, fluoxetine, mazindol, and vanoxerine also bind to these sites and have
In addition to their high affinity
for the main site of
the monoamine transporters, several competitive transporter substrates such as cocaine and indatraline have lower affinity for these
allosteric sites as well.
A few of the selective serotonin
reuptake inhibitors (SSRIs) such as fluoxetine and the dextro-enantiomer of citalopram appear to be
serotonin reuptake inhibitors.
Instead of binding to the active site on the serotonin transporter, they bind
to an allosteric site, which exerts its effects by causing conformational changes in the transporter protein, and thereby modulating
the affinity of substrates for the active site.
As a result, escitalopram has been marketed as an allosteric
serotonin reuptake inhibitor. Notably, this allosteric site may
be directly related to the above-mentioned PCP binding sites.
Two of the primary active
constituents of the medicinal herb
Hypericum perforatum (St. John's Wort)
are hyperforin and adhyperforin.
Hyperforin and adhyperforin are inhibitors of the reuptake of
serotonin, norepinephrine, dopamine, GABA, and glutamate, and they exert
these effects allosterically by binding to and activating the
receptor potential cation channel TRPC6.
Activation of TRPC6 induces the entry of calcium (Ca2+) and sodium (Na+) into the cell, which
causes the effect.
, a vesicular
reuptake inhibitor that was used in the past to deplete serotonin,
norepinephrine, and dopamine stores as an antipsychotic and
antihypertensive. It was notorious for causing anxiety and
depression, and as a result, was replaced by newer, more modern
A second type of reuptake inhibition affects vesicular transport, and blocks
the intracellular repackaging of neurotransmitters into cytoplasmic vesicles. In contrast to plasmalemmal reuptake inhibitors, vesicular reuptake inhibitors do not
increase the synaptic concentrations of a
neurotransmitter, only the cytoplasmic concentrations; unless, that is, they
also act as plasmalemmal transporter reversers via phosphorylation
of the transporter protein, also known as a releasing
agent. Pure vesicular reuptake inhibitors tend to
actually lower synaptic neurotransmitter concentrations, as
blocking the repackaging
of, and storage of the neurotransmitter in question leaves
them vulnerable to degradation via enzymes such as monoamine oxidase (MAO) which exist
in the cytoplasm. With
vesicular transport blocked, neurotransmitter stores quickly become
is an irreversible and competitive inhibitor of the vesicular monoamine
transporter 2 (VMAT2), and is a classic example of a vesicular reuptake inhibitor.
Examples of Reuptake Inhibitors
- Adenosine Reuptake
- Dopamine Reuptake Inhibitor
- Endocannabinoid Reuptake Inhibitor (eCBRI)
- AM-404, O-2093, OMDM-2, UCM-707, VDM-11,
- Excitatory Amino Acid Reuptake Inhibitor (EAARI; or Glutamate
Reuptake Inhibitor (GluRI))
- GABA Reuptake Inhibitor (GRI)
- Glycine Reuptake Inhibitor (GlyRI)
- ACPPB, ALX-5407, Glycyldodecylamide, ORG-24,589, Sarcosine, SSR-103,800,
- Norepinephrine Reuptake
Inhibitor (NRI; or Adrenergic Reuptake Inhibitor (ARI))
- Serotonin Reuptake
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