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 are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through phosphorylation and posttranslational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.
The serotonin transporter also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein that transports serotonin from the synaptic cleft back to the presynaptic neuron.
The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membrane of synaptic vesicles of presynaptic neurons. It acts to transport monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, and histamine – into the vesicles, which release the neurotransmitters into synapses as chemical messages to postsynaptic neurons. VMATs utilize a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.
An autoreceptor is a type of receptor located in the membranes of presynaptic nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the autoreceptor sits. Similarly, a heteroreceptor is sensitive to neurotransmitters and hormones that are not released by the cell on which it sits. A given receptor can act as either an autoreceptor or a heteroreceptor, depending upon the type of transmitter released by the cell on which it is embedded.
Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.
Ethylphenidate (EPH) is a psychostimulant and a close analog of methylphenidate.
A reuptake inhibitor (RI) is a type of drug known as a reuptake modulator that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.
RTI(-4229)-336, is a phenyltropane derivative which acts as a potent and selective dopamine reuptake inhibitor and stimulant drug. It binds to the dopamine transporter with around 20x the affinity of cocaine, however it produces relatively mild stimulant effects, with a slow onset and long duration of action. These characteristics make it a potential candidate for treatment of cocaine addiction, as a possible substitute drug analogous to how methadone is used for treating heroin abuse. RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration, and significantly reduces rates of cocaine use, especially when combined with SSRIs, and research is ongoing to determine whether it could be a viable substitute drug in human cocaine addicts.
In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to is not the same one to which an endogenous agonist of the receptor would bind. Modulators and agonists can both be called receptor ligands.
SKF-83,959 is a synthetic benzazepine derivative used in scientific research which acts as an agonist at the D1-D2 dopamine receptor. It behaves as a full agonist at the D1 protomer and a high-affinity partial agonist at the D2 protomer. It was further shown to act as an allosteric modulator of the sigma-1 receptor. SKF-83,959 is a racemate that consists of the R-(+)- and S-(−)-enantiomers MCL 202 and MCL 201, respectively. SKF-83,959 inhibits sodium channels as well as delayed rectifier potassium channels.
A norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson's disease. The drug acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.
3β-(4-Methylphenyl)-2β-[3-(4-chlorophenyl)isoxazol-5-yl]tropane (RTI-4229-371) is a phenyltropane derived drug which acts as a potent and selective dopamine reuptake inhibitor in vitro, yet unusually for this class of compound, both RTI-371 and the closely related compound RTI-370 failed to produce locomotor stimulation in mice. In addition to this, in drug substitution tests RTI-370 weakly generalized to cocaine whereas RTI-371 did not generalize at all.
PNU-120596 is a drug that acts as a potent and selective positive allosteric modulator for the α7 subtype of neural nicotinic acetylcholine receptors. It is used in scientific research into cholinergic regulation of dopamine and glutamate release in the brain.
A reuptake enhancer (RE), also sometimes referred to as a reuptake activator, is a type of reuptake modulator which enhances the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to a decrease in the extracellular concentrations of the neurotransmitter and therefore a decrease in neurotransmission.
Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.
SoRI-20041 is an "antagonist-like" allosteric modulator of amphetamine-induced dopamine release. SoRI-20041 is believed to be the first example of a drug that separately modulates uptake versus release in the dopamine transporter ; it produces the same effects as SoRI-20040 and SoRI-9804 in uptake assays and binding assays, inhibiting the re-uptake of dopamine, but does not modulate d-amphetamine-induced DA release by inhibiting that as well, like 'agonists' of the series do.
An excitatory amino acid reuptake inhibitor (EAARI) is a type of drug which inhibits the reuptake of the excitatory neurotransmitters glutamate and aspartate by blocking one or more of the excitatory amino acid transporters (EAATs).
