The current review has evaluated abundant evidence for the efficacy of monoamine transporter inhibitors and releasers to reduce abuse-related effects of stimulants in preclinical assays of stimulant self-administration, drug discrimination, and reinstatement, providing a strong rationale for developing monoamine transporter inhibitors and releasers as medications for the treatment of stimulant addiction.
Full Answer
How are monoamine transporters used to treat disease?
Several drugs are used to treat disease symptoms by blocking monoamine transporters, which results in an increase in extracellular monoamines. In addition, the levels of monoamine transporters have been shown to be altered in many of these psychiatric and neurological conditions.
What is the mechanism of action of monoamine transporters in cocaine?
Monoamine transporters are established targets for many pharmacological agents that affect brain function, including the psychostimulants cocaine and amphetamine. Cocaine and amphetamine employ different mechanisms that both result in an increase in extracellular monoamines by decreasing reuptake.
What is monoamine reuptake inhibitor?
Monoamine reuptake inhibitor. This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission .
Do piperidine-based monoamine transporter inhibitors have structure-activity relationships?
"Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors".
What is the role of monoamine transporter?
Monoamine transporters (MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters.
What drug blocks the reuptake of monoamine transmitters?
Newer monoamine reuptake inhibitors, such as the serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine, venlafaxine, and milnacipran, have been proposed as more effective treatments for chronic pain conditions associated with depression (Bradley et al., 2003; Barkin and Barkin, 2004).
What happens if the reuptake transporter is blocked?
The reuptake process is susceptible to drug manipulation. By blocking the action of serotonin reuptake inhibitors (SERTs), the amount of serotonin in the synaptic cleft increases.
Which drug binds with high affinity to all three known monoamine transporters?
Amphetamine pharmacology Amphetamine binds to the monoamine transporters and so increases extracellular levels of monoamines including dopamine, noradrenaline (norepinephrine) and serotonin.
What does blocking reuptake of a neurotransmitter do?
SSRIs block the reabsorption (reuptake) of serotonin into neurons. This makes more serotonin available to improve transmission of messages between neurons. SSRIs are called selective because they mainly affect serotonin, not other neurotransmitters.
How do monoamine reuptake inhibitors work?
Monoamine oxidase inhibitors (MAOIs) are an extremely strong class of antidepressants that treat depression by preventing the breakdown of the brain chemicals serotonin, dopamine, and norepinephrine. This helps them do their work of regulating your mood.
What is blocking reuptake?
After carrying a message, serotonin is usually reabsorbed by the nerve cells (known as "reuptake"). SSRIs work by blocking ("inhibiting") reuptake, meaning more serotonin is available to pass further messages between nearby nerve cells.
What is the effect of inhibiting reuptake?
Mechanism of Action As the name suggests, SSRIs exert action by inhibiting the reuptake of serotonin, thereby increasing serotonin activity. Unlike other classes of antidepressants, SSRIs have little effect on other neurotransmitters, such as dopamine or norepinephrine.
Do SSRIs block serotonin transporters?
Drugs known as SSRIs—selective serotonin reuptake inhibitors—work by stopping serotonin from being reused by binding to the serotonin transporter (SERT) and blocking serotonin transport.
What are the 3 monoamine neurotransmitters?
Developmental Disorders The monoamine neurotransmitters include serotonin, dopamine, and norepinephrine.
How do VMAT2 inhibitors work?
VMAT2 inhibitors block VMAT2 causing dopamine depletion in the central nervous system. VMAT2 is a protein that controls the amount of dopamine stored in the nerve cells and the amount released. Inhibiting VMAT2 leads to a lower amount of available dopamine, thereby reducing unwanted body movements.
Which choice is a monoamine neurotransmitter?
The monoamine neurotransmitter, serotonin, regulates mood, appetite, and sleep, as well as cognitive functions such as memory, attention, and learning.
What are monoamine transporters? What are their functions?
The major function of these transporters is to terminate monoamine transmission by inward transport of substrates away from the synaptic cleft. In the membrane of intracellular synaptic vesicles is the vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2), which use a proton gradient as the energy source to sequester cytosolic monoamines into the vesicles and then release the monoamines into the synaptic cleft by exocytosis. Therefore, the overall function of these four transporters is to regulate spatio-temporal components of monoamine transmission. Loss of a transporter could cause severe disease or lethality. For instance, two loss-of-function DAT mutants, L368Q and P395L, cause infantile parkinsonism-dystonia in humans. 3 Complete deletion of the VMAT2 gene causes developmental defect and embryonic lethality in mice. 4–6
Which monoamine transporter is used for depression?
Among monoamine transporters of the SLC6 family, the serotonin transporter, SERT, has been described for decades as a key protein for the physiopathology and treatment of depression.
What is the name of the transporter that removes dopamine, noradrenaline, and serot
Monoamine transporters remove excess dopamine, noradrenaline, and serotonin from the extracellular space and are accordingly named DAT, noradrenaline transporter (NET), and serotonin transporter (SERT). The nomenclature derives from the cell types that the transporters are expressed on and do not indicate selectivity of the transporter.
What is the synaptic monoamine transporter?
Synaptic monoamine transporters are protein structures which rapidly retrieve released neurotransmitter molecules from the synaptic cleft into the originating neuron. By specifically blocking the transporter, the reuptake of the neurotransmitter is hampered, thus increasing its availability in the synapse. Examples of compounds that predominantly or selectively inhibit the reuptake of serotonin are the SSRI listed above, or the tricyclic compound clomipramine. Drugs predominantly or selectively inhibiting the norepinephrine reuptake are reboxetine, and the tricyclic compounds desipramine and nortriptyline. Many antidepressants block both the serotonin and norepinephrine transporter, more or less with the same potency, e.g. imipramine, amitriptyline, doxepine, milnacipran, or venlafaxine. Examples of dopamine reuptake inhibitors are bupropion (also affecting norepinephrine uptake), or amineptine.
Which transporter is used to sequester monoamines?
In the membrane of intracellular synaptic vesicles is the vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2), which use a proton gradient as the energy source to sequester cytosolic monoamines into the vesicles and then release the monoamines into the synaptic cleft by exocytosis.
What drugs are plasma membrane proteins?
On the other hand, the central roles have also presented these plasma membrane proteins as functional targets for drugs of abuse such as alcohol, cocaine, methamphetamine, and MD MA (3,4-methylenedioxymethamphetamine or Ecstasy).
Where are transmembrane proteins located?
They are transmembrane proteins located specifically on monoaminergic neurons. Their expression is highly selective to their respective neurons such that they are often used as markers for their neuron subtype ( Lin, Canales, et al., 2011 ).
What are the roles of dopamine transporters?
The dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters, which are collectively referred to as monoamine transporters (MATs), play significant roles in regulating the neuronal response to these neurotransmitters. MATs terminate the action of these neurotransmitters by translocating them from the synaptic space into ...
What are the three transmitters responsible for?
These three transmitters are responsible for controlling a number of physiological, emotional, and behavioral functions, with their transporters being the site of action of drugs employed for the treatment of a variety of conditions, including depression, anxiety, ADHD, schizophrenia, and psychostimulant abuse.
What is the function of the dopamine transporter?
Dopamine Transporter (DAT-6) Monoamine transporters ( MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs (SERT, DAT, NET) are responsible for the reuptake of their associated amine neurotransmitters ( serotonin, ...
What are the target sites for therapeutic drugs used in the treatment of mood disorders?
Evidence supporting this belief includes that monoamine transporters, DAT, NET, and SERT, are important target sites for therapeutic drugs used in the treatment of mood disorders.
How does amphetamine enter the presynaptic neuron?
In contrast, amphetamine enters the presynaptic neuron directly through the neuronal membrane or through monoamine transporters, competing for reuptake with neurotransmitters. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine binds to TAAR1, it reduces post-synaptic receptor firing rate and triggers protein kinase A and protein kinase C signaling, resulting in transporter phosphorylation. Phosphorylated transporters then either operate in reverse or withdraw into the presynaptic neuron and cease transport. When amphetamine enters the synaptic vesicles through VMAT2, monoamines are released into the cytosol.
What antidepressants are used for depression?
It has been observed that the pathology of depression involves dysfunction of monoamine neurotransmitter circuits in the CNS, particularly of serotonin and norepinephrine. Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressant and include fluoxetine (Prozac), citalopram (Celexa), and fluvoxamine (Luvox). These drugs inhibit the reuptake of serotonin from the extracellular space into the synaptic terminal by selectively inhibiting SERT. It has been recently observed that serotonin, norepinephrine, and dopamine may all be involved in depression. Therefore, drugs such as venlafaxine and paroxetine are being used as effective antidepressants that selectively inhibit both SERT and NET. The tricyclic antidepressant desipramine is an antidepressant drug that is a relatively selective inhibitor of NE uptake. Studies of inhibition of NET correlate with antidepressant activity.
What drugs inhibit DAT?
DAT is also the target of several "DAT-blockers" including amphetamine and cocaine. These chemicals inhibit the action of DAT and, to a lesser extent, the other monoamine transporters, but their effects are mediated by separate mechanisms.
When ionic gradients are altered (extracellular K + increases or extracellular Na + or Cl decrease
When ionic gradients are altered (extracellular K + increases or extracellular Na + or Cl − decreases) transporters can function in reverse resulting in a net efflux of substrates and ions out of a neuron. To return to an outwardly facing conformation SERT requires the transport of intracellular K +.
What are some examples of antidepressants?
Most modern antidepressant drugs work on the principal of blocking re-uptake transporters. SSRI's such as Fluoxetine (Prozac) and SNRI's as with Venlafaxine are the main types of drugs given in first line depression and anxiety treatment. PRC200-SS is an example of an SNRI. JNJ-7925476 is an example of a TRI.
Overview
Associated disorders and treatments
Monoamine transporters are believed to be factors in several neurological conditions due to their role in reuptake of the monoamines dopamine, noradrenaline, and serotonine. These conditions include ADHD, depression, drug abuse, Parkinson's disease, Schizophrenia, and Tourette's syndrome. Evidence supporting this belief includes that monoamine transporters, DAT, NET, and SERT, are important target sites for therapeutic drugs used in the treatment of mood disorders. Several dr…
Types
There are several different monoamine transporters located along the plasma membrane, each belonging to the family of Na /Cl -dependent substrate-specific neuronal membrane transporters.
• The dopamine transporter, DAT.
• The norepinephrine transporter, NET.
• The serotonin transporter, SERT.
Function
DAT is responsible for the Na /Cl -dependent reuptake of extracellular dopamine (DA). DAT can also transport extracellular norepinephrine . DATs can be found in the central nervous system (CNS), where they are localized in the substantia nigra and ventral tegmental area (VTA). DATs are also found in the peripheral nervous system (PNS) where they are localized in the stomach, pancreas, as well as in lymphocytes. Various kinases have been linked to DAT regulation including
Structure and mechanism
Monoamine transporters are members of the group of Na /Cl -dependent substrate-specific neuronal membrane transporters belonging to the SLC6 gene family. MATs are large integral membrane proteins composed of 12 transmembrane domains connected by intracellular and extracellular loops. The NH2 and COOH termini of the MAT proteins are located within the cytoplasm …
Psychostimulants
DAT is also the target of several "DAT-blockers" including amphetamine and cocaine. These chemicals inhibit the action of DAT and, to a lesser extent, the other monoamine transporters, but their effects are mediated by separate mechanisms.
Monoamine transporters are established targets for many pharmacological agents that affect brain function, including the psychostimulants cocaine and amphetamine. Cocaine and ampheta…
Research history
The field of monoamine transporter research began roughly five decades ago with Julius Axelrod's research on NETs. Axelrod eventually received his Nobel Prize for this research, which led to the discovery of DATs and SERTs as well as consequences associated with antidepressant and psychostimulant interactions with MAT proteins. Since Axelrod's initial studies, understanding t…
Double and triple MAT agents (a.k.a. SNRIs and TRIs)
Below are examples of drugs that act directly by inhibiting two or more MATs simultaneously. Serotonin-norepinephrine re-uptake inhibitors (SNRIs) act by blocking both SERTs and NETs. Triple re-uptake inhibitors (TRIs) act by blocking DATs, NETs, and SERTs simultaneously. Most modern antidepressant drugs work on the principal of blocking re-uptake transporters. SSRI's such as Fluoxetine (Prozac) and SNRI's as with Venlafaxine are the main types of drugs given in …