MadSci Network: Neuroscience

Re: what is the precise effect of reuptake inhibitors on synaptic transmission?

Date: Tue Dec 5 23:23:09 2000
Posted By: Amanda Kahn, Grad student, neuroscience, UCSF
Area of science: Neuroscience
ID: 975961579.Ns

Hi Mike!

Reuptake inhibitors, such as fluoxetine (prozac) and other drugs of the SSRI 
(Selective Serotonin Reuptake Inhibitor) category, function by inhibiting 
synaptic reuptake transporters.  These are transmembrane proteins found at 
synapses (primarily in the presynaptic cell), whose job it is to clear 
neurotransmitters from the synaptic cleft.  Cloned transporters include the 
norepinephrine transporter (NET), the dopamine transporter (DAT), and the 
serotonin transporter (SERT).   The molecular mechanisms of transporter 
function are a subject of vigorous research -- for the most current details, 
see the Blakely and Bauman review, cited below.  SSRIs and other reuptake 
inhibitors bind to the appropriate transporter and impair its ability to 
clear neurotransmitter, thereby allowing more neurotransmitter into the 
synaptic cleft.  In situations where neurotransmitter release and/or 
response is at nonoptimal levels, use of a SSRI can bring levels closer to a 
'normal' baseline.  Side effects of SSRIs and similar compounds can be 
attributed to nonspecific effects on other transporters or different 
synaptic proteins.

Amphetamines are thought to function by essentially reversing the dopamine 
transporter (DAT)  so that it spills dopamine into the synaptic cleft in an 
unregulated fashion.  This is in contrast to the effects of another 
stimulant, cocaine, which exerts its effect by inhibiting (but not 
reversing) DAT -- and perhaps other targets, as studies of the DAT knockout 
mouse suggest.  

Curare works on a different synaptic mechanism: neurotransmitter response.  
It is a competitive (and reversible) antagonist of a receptor for the 
neurotransmitter acetylcholine.  This receptor is found at the neuromuscular 
junction (where motor neurons meet skeletal muscle), where acetylcholine is 
the primary neurotransmitter.  So, curare poisoning manifests itself as 
severe paralysis.  

Here is a great website on the pharmacology of acetylcholine (and the many 
drugs which interfere with cholinergic neurotransmission):

Additional sources are below.

Hope this helps!
Amanda Kahn

Here are some abstracts which pertain to your question; more information may 
be found by doing a MEDLINE search or going to the journal's website.

MEDLINE searches can be made for free using PubMed:

Blakely, RD; Bauman, AL.  Biogenic amine transporters: regulation in flux.
Current Opinion in Neurobiology, 2000 Jun, 
10(3):328-36. (UI: 20311316)

Abstract: Following vesicular release, the biogenic amine
neurotransmitters dopamine, norepinephrine and serotonin are actively
cleared from extracellular spaces by presynaptic transporters. These
transporters interact with multiple psychoactive agents including
cocaine, amphetamines and antidepressants. Recent findings indicate
that amine reuptake is likely to be a tightly regulated component of
synaptic plasticity rather than a constitutive determinant of
transmitter clearance. Protein kinase C activation and transporter
phosphorylation have been linked to regulatory protein trafficking,
and both phosphorylation and trafficking may be influenced by
transporter ligands. Recognition that transmitters, antagonists and
second messengers can modify the intrinsic activity, surface
expression or protein levels of amine transporters raises new
questions about the fundamental nature of drug actions in vivo. The
theory that dysregulation of transporters may contribute to disease
states is supported by the recent discovery that a coding mutation in
the human norepinephrine transporter contributes to orthostatic

Schloss, P; Williams, DC.  The serotonin transporter: a primary target for 
antidepressant drugs.
Journal of Psychopharmacology, 1998, 
12(2):115-21. (UI: 98357395)

Abstract: The serotoninergic system is known to modulate mood,
emotion, sleep and appetite and thus is implicated in the control of
numerous behavioural and physiological functions. Decreased
serotoninergic neurotransmission has been proposed to play a key role
in the aetiology of depression. The concentration of synaptic
serotonin is controlled directly by its reuptake into the pre-
synaptic terminal and, thus, drugs blocking serotonin transport have
been successfully used for the treatment of depression. In addition to
tricyclic antidepressants (TCAs; e.g. imipramine) which also block
noradrenaline reuptake, highly specific serotonin reuptake inhibitors
(SSRIs) such as fluoxetine and paroxetine have been developed, which
are increasingly prescribed for depressed patients. The mode of action
of these antidepressant drugs on their direct target, the serotonin
transport protein, and possible regulatory mechanisms with respect to
long-term alleviation of depression, although having been investigated
both neurobiologically and clinically over the last years, are not yet
understood. The cloning of the cDNA encoding the serotonin transporter
has allowed a more precise characterization of this protein at the
molecular level. This will show how antidepressants act at this
target, thereby affecting the biochemical, pharmacological and
electrophysiological properties of the serotoninergic system and give
an introduction of how they might exert their therapeutic effect. This
review gives an overview of the recent developments in this field,
discusses mechanisms of antidepressant action on this target, and also
possible interactions with other components of serotoninergic


Jones, SR; Joseph, JD; Barak, LS; Caron, MG; Wightman, RM.  Dopamine 
neuronal transport kinetics and effects of
Journal of Neurochemistry, 1999 Dec, 
73(6):2406-14. (UI: 20047425)

Abstract: The dopamine (DA) transporter (DAT) regulates DA
neurotransmission by recycling DA back into neurons. Drugs that
interfere with DAT function, e.g., cocaine and amphetamine, can have
profound behavioral effects. The kinetics of DA transport by DAT in
isolated synaptosomal or single cell preparations have been previously
studied. To investigate how DA transport is regulated in intact tissue
and to examine how amphetamine affects the DAT, the kinetics of DA
uptake by the DAT were examined in tissue slices of the mouse
caudate-putamen with fast-scan cyclic voltammetry. The data
demonstrate that inward DA transport is saturable and
sodium-dependent. Elevated levels of cytoplasmic DA resulting from
disruption of vesicular storage by incubation with 10 microM Ro 4-1284
did not generate DA efflux or decrease its uptake rate. However,
incubation with 10 microM amphetamine reduced the net DA uptake rate
and increased extracellular DA levels due to DA efflux through the
DAT. In addition, a new, elevated steady-state level of extracellular
DA was established after electrically stimulated DA release in the
presence of amphetamine, norepinephrine, and exogenous DA.  These
results from intact tissue are consistent with a kinetic model of the
DAT established in more purified preparations in which amphetamine and
other transported substances make the inwardly facing DAT available
for outward transport of intracellular DA.

Rocha, BA; Fumagalli, F; Gainetdinov, RR; Jones, SR; Ator, R; Giros, B; 
Miller, GW; Caron, MG.  Cocaine self-administration in  dopamine-transporter 
knockout mice [see 
comments] [published erratum appears in Nat Neurosci 1998 Aug;1(4):330]
Nature Neuroscience, 1998 Jun, 1(2):132-7. 
(UI: 99211032)

Abstract: The plasma membrane dopamine transporter (DAT) is
responsible for clearing dopamine from the synapse.  Cocaine blockade
of DAT leads to increased extracellular dopamine, an effect widely
considered to be the primary cause of the reinforcing and addictive
properties of cocaine. In this study we tested whether these
properties are limited to the dopaminergic system in mice lacking
DAT. In the absence of DAT, these mice exhibit high levels of
extracellular dopamine, but paradoxically still self- administer
cocaine. Mapping of the sites of cocaine binding and neuronal
activation suggests an involvement of serotonergic brain regions in
this response. These results demonstrate that the interaction of
cocaine with targets other than DAT, possibly the serotonin
transporter, can initiate and sustain cocaine self-administration in
these mice.

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