Tag: Neurotransmitter

What is a Dopamine Transporter?

Published on by Andrew Marshall10 Comments

Introduction

The dopamine transporter (DAT) also (sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in the human by the SLC6A3 gene, (also known as DAT1), 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.

DAT is implicated in a number of dopamine-related disorders, including attention deficit hyperactivity disorder, bipolar disorder, clinical depression, eating disorders, and substance use disorders. The gene that encodes the DAT protein is located on chromosome 5, consists of 15 coding exons, and is roughly 64 kbp long. Evidence for the associations between DAT and dopamine related disorders has come from a type of genetic polymorphism, known as a variable number tandem repeat, in the SLC6A3 gene, which influences the amount of protein expressed.

Function

DAT is an integral membrane protein that removes dopamine from the synaptic cleft and deposits it into surrounding cells, thus terminating the signal of the neurotransmitter. Dopamine underlies several aspects of cognition, including reward, and DAT facilitates regulation of that signal.

Mechanism

DAT is a symporter that moves dopamine across the cell membrane by coupling the movement to the energetically-favourable movement of sodium ions moving from high to low concentration into the cell. DAT function requires the sequential binding and co-transport of two Na+ ions and one Cl− ion with the dopamine substrate. The driving force for DAT-mediated dopamine reuptake is the ion concentration gradient generated by the plasma membrane Na+/K+ ATPase.

In the most widely accepted model for monoamine transporter function, sodium ions must bind to the extracellular domain of the transporter before dopamine can bind. Once dopamine binds, the protein undergoes a conformational change, which allows both sodium and dopamine to unbind on the intracellular side of the membrane.

Studies using electrophysiology and radioactive-labelled dopamine have confirmed that the dopamine transporter is similar to other monoamine transporters in that one molecule of neurotransmitter can be transported across the membrane with one or two sodium ions. Chloride ions are also needed to prevent a build-up of positive charge. These studies have also shown that transport rate and direction is totally dependent on the sodium gradient.

Because of the tight coupling of the membrane potential and the sodium gradient, activity-induced changes in membrane polarity can dramatically influence transport rates. In addition, the transporter may contribute to dopamine release when the neuron depolarises.

DAT–Cav Coupling

Preliminary evidence suggests that the dopamine transporter couples to L-type voltage-gated calcium channels (particularly Cav1.2 and Cav1.3), which are expressed in virtually all dopamine neurons. As a result of DAT–Cav coupling, DAT substrates that produce depolarising currents through the transporter are able to open calcium channels that are coupled to the transporter, resulting in a calcium influx in dopamine neurons. This calcium influx is believed to induce CAMKII-mediated phosphorylation of the dopamine transporter as a downstream effect; since DAT phosphorylation by CAMKII results in dopamine efflux in vivo, activation of transporter-coupled calcium channels is a potential mechanism by which certain drugs (e.g. amphetamine) trigger neurotransmitter release.

Protein Structure

The initial determination of the membrane topology of DAT was based upon hydrophobic sequence analysis and sequence similarities with the GABA transporter. These methods predicted twelve transmembrane domains (TMD) with a large extracellular loop between the third and fourth TMDs. Further characterisation of this protein used proteases, which digest proteins into smaller fragments, and glycosylation, which occurs only on extracellular loops, and largely verified the initial predictions of membrane topology. The exact structure of the Drosophila melanogaster dopamine transporter (dDAT) was elucidated in 2013 by X-ray crystallography.

Location and Distribution

Regional distribution of DAT has been found in areas of the brain with established dopaminergic circuitry, including the nigrostriatal, mesolimbic, and mesocortical pathways. The nuclei that make up these pathways have distinct patterns of expression. Gene expression patterns in the adult mouse show high expression in the substantia nigra pars compacta.

DAT in the mesocortical pathway, labelled with radioactive antibodies, was found to be enriched in dendrites and cell bodies of neurons in the substantia nigra pars compacta and ventral tegmental area. This pattern makes sense for a protein that regulates dopamine levels in the synapse.

Staining in the striatum and nucleus accumbens of the mesolimbic pathway was dense and heterogeneous. In the striatum, DAT is localized in the plasma membrane of axon terminals. Double immunocytochemistry demonstrated DAT colocalisation with two other markers of nigrostriatal terminals, tyrosine hydroxylase and D2 dopamine receptors. The latter was thus demonstrated to be an autoreceptor on cells that release dopamine. TAAR1 is a presynaptic intracellular receptor that is also colocalised with DAT and which has the opposite effect of the D2 autoreceptor when activated; i.e. it internalises dopamine transporters and induces efflux through reversed transporter function via PKA and PKC signalling.

Surprisingly, DAT was not identified within any synaptic active zones. These results suggest that striatal dopamine reuptake may occur outside of synaptic specializations once dopamine diffuses from the synaptic cleft.

In the substantia nigra, DAT is localised to axonal and dendritic (i.e. pre- and post-synaptic) plasma membranes.

Within the perikarya of pars compacta neurons, DAT was localised primarily to rough and smooth endoplasmic reticulum, Golgi complex, and multivesicular bodies, identifying probable sites of synthesis, modification, transport, and degradation.

Genetics and Regulation

The gene for DAT, known as DAT1, is located on chromosome 5p15. The protein encoding region of the gene is over 64 kb long and comprises 15 coding segments or exons. This gene has a variable number tandem repeat (VNTR) at the 3’ end (rs28363170) and another in the intron 8 region. Differences in the VNTR have been shown to affect the basal level of expression of the transporter; consequently, researchers have looked for associations with dopamine-related disorders.

Nurr1, a nuclear receptor that regulates many dopamine-related genes, can bind the promoter region of this gene and induce expression. This promoter may also be the target of the transcription factor Sp-1.

While transcription factors control which cells express DAT, functional regulation of this protein is largely accomplished by kinases. MAPK, CAMKII, PKA, and PKC can modulate the rate at which the transporter moves dopamine or cause the internalisation of DAT. Co-localised TAAR1 is an important regulator of the dopamine transporter that, when activated, phosphorylates DAT through protein kinase A (PKA) and protein kinase C (PKC) signalling. Phosphorylation by either protein kinase can result in DAT internalisation (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux). Dopamine autoreceptors also regulate DAT by directly opposing the effect of TAAR1 activation.

The human dopamine transporter (hDAT) contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro. In contrast, the human serotonin transporter (hSERT) and human norepinephrine transporter (hNET) do not contain zinc binding sites. Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of attention deficit hyperactivity disorder.

Biological Role and Disorders

The rate at which DAT removes dopamine from the synapse can have a profound effect on the amount of dopamine in the cell. This is best evidenced by the severe cognitive deficits, motor abnormalities, and hyperactivity of mice with no dopamine transporters. These characteristics have striking similarities to the symptoms of ADHD.

Differences in the functional VNTR have been identified as risk factors for bipolar disorder and ADHD. Data has emerged that suggests there is also an association with stronger withdrawal symptoms from alcoholism, although this is a point of controversy. An allele of the DAT gene with normal protein levels is associated with non-smoking behaviour and ease of quitting. Additionally, male adolescents particularly those in high-risk families (ones marked by a disengaged mother and absence of maternal affection) who carry the 10-allele VNTR repeat show a statistically significant affinity for antisocial peers.

Increased activity of DAT is associated with several different disorders, including clinical depression.

Mutations in DAT have been shown to cause dopamine transporter deficiency syndrome, an autosomal recessive movement disorder characterised by progressively worsening dystonia and parkinsonism.

Pharmacology

The dopamine transporter is the target of substrates, dopamine releasers, transport inhibitors and allosteric modulators.

Cocaine blocks DAT by binding directly to the transporter and reducing the rate of transport. In contrast, amphetamine enters the presynaptic neuron directly through the neuronal membrane or through DAT, competing for reuptake with dopamine. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine binds to TAAR1, it reduces the firing rate of the postsynaptic neuron and triggers protein kinase A and protein kinase C signalling, resulting in DAT phosphorylation. Phosphorylated DAT then either operates in reverse or withdraws into the presynaptic neuron and ceases transport. When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol. Amphetamine also produces dopamine efflux through a second TAAR1-independent mechanism involving CAMKIIα-mediated phosphorylation of the transporter, which putatively arises from the activation of DAT-coupled L-type calcium channels by amphetamine.

The dopaminergic mechanisms of each drug are believed to underlie the pleasurable feelings elicited by these substances.

Interactions

Dopamine transporter has been shown to interact with:

  • Alpha-synuclein
  • PICK1
  • TGFB1I1

Apart from these innate protein-protein interactions, recent studies demonstrated that viral proteins such as HIV-1 Tat protein interacts with the DAT and this binding may alter the dopamine homeostasis in HIV positive individuals which is a contributing factor for the HIV-associated neurocognitive disorders.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Dopamine_transporter >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is a Serotonin Releasing Agent?

Published on by Andrew Marshall3 Comments

Introduction

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons.

SSRAs have been used clinically as appetite suppressants, and they have also been proposed as novel antidepressants and anxiolytics with the potential for a faster onset of action and superior efficacy relative to the selective serotonin reuptake inhibitors (SSRIs).

A closely related type of drug is a serotonin reuptake inhibitor (SRI).

Examples and Use of SRAs

Amphetamines like MDMA, MDEA, MDA, and MBDB, among other relatives, are recreational drugs termed entactogens. They act as serotonin-norepinephrine-dopamine releasing agents (SNDRAs) and also agonise serotonin receptors such as those in the 5-HT2 subfamily. Fenfluramine, chlorphentermine, and aminorex, which are also amphetamines and relatives, were formerly used as appetite suppressants but were discontinued due to concerns of cardiac valvulopathy. This side effect has been attributed to their additional action of potent agonism of the 5-HT2B receptor. The designer drug 4-methylaminorex, which is an SNDRA and 5-HT2B agonist, has been reported to cause this effect as well.

Many tryptamines, such as DMT, DET, DPT, DiPT, psilocin, and bufotenin, are SRAs as well as non-selective serotonin receptor agonists. These drugs are serotonergic psychedelics, which is a consequence of their ability to activate the 5-HT2A receptor. αET and αMT, also tryptamines, are SNDRAs and non-selective serotonin receptor agonists that were originally thought to be monoamine oxidase inhibitors and were formerly used as antidepressants. They have since been discontinued and are now encountered solely as recreational drugs.

Indeloxazine is an SRA and norepinephrine reuptake inhibitor that was formerly used as an antidepressant, nootropic, and neuroprotective.

List of SSRAs

Pharmaceutical Drugs

  • Chlorphentermine (Apsedon, Desopimon, Lucofen)
  • Cloforex (Oberex) (prodrug of chlorphentermine)
  • Dexfenfluramine (Redux) (enantiomer of fenfluramine)
  • Etolorex (prodrug of chlorphentermine; never marketed)
  • Fenfluramine (Pondimin, Fen-Phen)
  • Flucetorex (related to chlorphentermine; never marketed)
  • Indeloxazine (Elen, Noin) (non-selective; discontinued)
  • Levofenfluramine (enantiomer of fenfluramine)
  • Carbamazepine (Equetro, Epitol, and many other variations)

Research Chemicals

  • Amiflamine (FLA-336)
  • Viqualine (PK-5078)
  • 2-Methyl-3,4-methylenedioxyamphetamine (2-Methyl-MDA)
  • 3-Methoxy-4-methylamphetamine (MMA)
  • 3-Methyl-4,5-methylenedioxyamphetamine (5-Methyl-MDA)
  • 3,4-Ethylenedioxy-N-methylamphetamine (EDMA)
  • 4-Methoxyamphetamine (PMA)
  • 4-Methoxy-N-ethylamphetamine (PMEA)
  • 4-Methoxy-N-methylamphetamine (PMMA)
  • 4-Methylthioamphetamine (4-MTA)
  • 5-(2-Aminopropyl)-2,3-dihydrobenzofuran (5-APDB)
  • 5-Indanyl-2-aminopropane (IAP)
  • 5-Methoxy-6-methylaminoindane (MMAI)
  • 5-Trifluoromethyl-2-aminoindane (TAI)
  • 5,6-Methylenedioxy-2-aminoindane (MDAI)
  • 5,6-Methylenedioxy-N-methyl-2-aminoindane (MDMAI)
  • 6-Chloro-2-aminotetralin (6-CAT)
  • 6-Tetralinyl-2-aminopropane (TAP)
  • 6,7-Methylenedioxy-2-aminotetralin (MDAT)
  • 6,7-Methylenedioxy-N-methyl-2-aminotetralin (MDMAT)
  • N-Ethyl-5-trifluoromethyl-2-aminoindane (ETAI)
  • 6-(2-aminopropil)benzofurans (6-APB)
  • 5-(2-aminopropyl)benzofuran (5-APB)

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Serotonin_releasing_agent >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is a Dopamine Reuptake Inhibitor?

Published on by Andrew Marshall4 Comments

Introduction

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

DRIs are used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy for their psychostimulant effects, and in the treatment of obesity and binge eating disorder for their appetite suppressant effects. They are sometimes used as antidepressants in the treatment of mood disorders, but their use as antidepressants is limited given that strong DRIs have a high abuse potential and legal restrictions on their use. Lack of dopamine reuptake and the increase in extracellular levels of dopamine have been linked to increased susceptibility to addictive behavior given increase in dopaminergic neurotransmission. The dopaminergic pathways are considered to be strong reward centers. Many DRIs such as cocaine are drugs of abuse due to the rewarding effects evoked by elevated synaptic concentrations of dopamine in the brain.

Brief History

Until the 1950s, dopamine was thought to only contribute to the biosynthesis of norepinephrine and epinephrine. It was not until dopamine was found in the brain in similar levels as norepinephrine that the possibility was considered that its biological role might be other than the synthesis of the catecholamines.

Pharmacotherapeutic Uses

The following drugs have DRI action and have been or are used clinically specifically for this property: amineptine, dexmethylphenidate, difemetorex, fencamfamine, lefetamine, levophacetoperane, medifoxamine, mesocarb, methylphenidate, nomifensine, pipradrol, prolintane, and pyrovalerone.

The following drugs are or have been used clinically and possess only weak DRI action, which may or may not be clinically-relevant: adrafinil, armodafinil, bupropion, mazindol, modafinil, nefazodone, sertraline, and sibutramine.

The following drugs are or have been clinically used but only coincidentally have DRI properties: benzatropine, diphenylpyraline, etybenzatropine, ketamine, nefopam, pethidine (meperidine), and tripelennamine.

The following are a selection of some particularly notably abused DRIs: cocaine, ketamine, MDPV, naphyrone, and phencyclidine (PCP). Amphetamines, including amphetamine, methamphetamine, MDMA, cathinone, methcathinone, mephedrone, and methylone, are all DRIs as well, but are distinct in that they also behave, potentially more potently, as dopamine releasing agents (DRAs) (due to Yerkes–Dodson’s law, ‘more potently stimulated’ may not equal more optimally functionally stimulated). There are very distinct differences in the mode of action between dopamine releasers/substrates & dopamine re-uptake inhibitors; the former are functionally entropy-driven (i.e. relating to hydrophobicity) and the latter are enthalpy-driven (i.e. relating conformational change). Reuptake inhibitors such as cocaine induce hyperpolarization of cloned human DAT upon oocytes that are naturally found on neurons, whereas releasing agents induce de-polarization of the neuron membrane.

The wakefulness-promoting agent modafinil and its analogues (e.g. adrafinil, armodafinil) have been approved to treat narcolepsy and shift work sleep disorder. These act as weak (micromolar) DRIs, but this effect does not correlate with wakefulness-promoting effects, suggesting the effect is too weak to be of clinical significance. The conclusion is these drugs promote wakefulness via some other mechanism.

DRIs have been explored as potential antiaddictive agents in the context of replacement therapy strategies, analogous to nicotine replacement for treating tobacco addiction and methadone replacement in the case of opioid addiction. DRIs have been explored as treatment for cocaine addiction, and have shown to alleviate cravings and self-administration.

Monoamine reuptake inhibitors, including DRIs, have shown effectiveness as therapy for excessive food intake and appetite control for obese patients. Though such pharmacotherapy is still available, the majority of stimulant anorectics marketed for this purpose have been withdrawn or discontinued due to adverse side effects such as hypertension, valvulopathy, and drug dependence.

List of DRIs

Only DRIs which are selective for the DAT over the other monoamine transporters (MATs) are listed below. For a list of DRIs that act at multiple MATs, see other monoamine reuptake inhibitor pages such as NDRI and SNDRI.

Selective Dopamine Reuptake Inhibitors

  • 4-Hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone
  • Altropane (O-587)
  • Amfonelic acid (WIN 25978)
  • Amineptine (has a reasonable degree of selectivity for dopamine over norepinephrine reuptake inhibition)
  • BTCP (GK-13), same acronym as for breakthrough cancer pain.
  • 3C-PEP
  • DBL-583
  • Difluoropine (O-620)
  • GBR-12783
  • GBR-12935
  • GBR-13069
  • GBR-13098
  • GYKI-52895
  • Iometopane (β-CIT, RTI-55)
  • Ethylphenidate (more selective for DA vs NE reuptake inhibition compared to methylphenidate, but still has a marked effect on both)
  • Modafinil (relatively weak but very selective for the dopamine transporter, with little to no effect on the norepinephrine or serotonin transporters)
  • Armodafinil (R-enantiomer of modafinil; somewhat more potent at inhibiting DAT than racemic modafinil, with equally negligible action on NET and SERT)
  • RTI-229
  • Vanoxerine (GBR-12909)

DRIs with Substantial Activity at Other Sites

  • Adrafinil (weak, possibly stressful on liver)
  • Amantadine (also a weak NMDA receptor antagonist)
  • Benztropine (also muscarinic antagonist)
  • Bupropion (also a more potent NRI and likely NRA due to bupropion’s major metabolite hydroxybupropion)
  • Cocaine
  • Fluorenol (extremely weak)
  • Medifoxamine (relatively weak)
  • Metaphit (irreversible; depletes dopamine)
  • Methylphenidate (has a mild degree of selectivity for dopamine over norepinephrine reuptake inhibition, although it significantly affects both)
  • Nomifensine (Dual selective 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.
  • Phenylpiracetam
  • Isopropylphenidate
  • Rimcazole
  • Venlafaxine (weak)
  • Solriamfetol (also norepinephrine reuptake inhibitor)

Other DRIs

  • Chaenomeles speciosa (Flowering quince)
  • Oroxylin A (found in Oroxylum indicum and Scutellaria baicalensis (Skullcap))

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Dopamine_reuptake_inhibitor >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is a Norepinephrine Reuptake Inhibitor?

Published on by Andrew Marshall7 Comments

Introduction

A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase adrenergic neurotransmission.

Medical Use

NRIs are commonly used in the treatment of conditions like ADHD and narcolepsy due to their psychostimulant effects and in obesity due to their appetite suppressant effects. They are also frequently used as antidepressants for the treatment of major depressive disorder, anxiety and panic disorder. Additionally, many addictive substances such as cocaine and methylphenidate possess NRI activity, though NRIs without combined dopamine reuptake inhibitor (DRI) properties are not significantly rewarding and hence are considered to have negligible potential for addiction. However, norepinephrine has been implicated as acting synergistically with dopamine when actions on the two neurotransmitters are combined (e.g. in the case of NDRIs) to produce rewarding effects in psychostimulant addictive substances.

Depression

A meta analysis published in BMJ in 2011 concluded that the selective NRI reboxetine is indistinguishable from placebo in the treatment of depression. A second review by the European Medicines Agency concluded that reboxetine was significantly more effective than placebo, and that its risk/benefit ratio was positive. The latter review, also examined the efficacy of reboxetine as a function of baseline depression, and concluded that it was effective in severe depression and panic disorder but did not show effects significantly superior to placebo in mild depression.

A closely related type of drug is a norepinephrine releasing agent (NRA).

List of Selective NRIs

Many NRIs exist, including the following:

  • Selective norepinephrine reuptake inhibitors
    • Marketed
      • Atomoxetine (Strattera)
      • Reboxetine (Edronax, Vestra)
      • Viloxazine (Qelbree, Vivalan)
    • Never marketed
      • Amedalin (UK-3540-1)
      • Daledalin (UK-3557-15)
      • Edivoxetine (LY-2216684)
      • Esreboxetine (AXS-14; PNU-165442G)
      • Lortalamine (LM-1404)
      • Nisoxetine (LY-94,939)
      • Talopram (tasulopram) (Lu 3–010)
      • Talsupram (Lu 5–005)
      • Tandamine (AY-23,946)
  • NRIs with activity at other sites
    • Marketed
      • Bupropion (Wellbutrin, Zyban)
      • Desipramine (Norpramin)
      • Maprotiline (Ludiomil)
      • Nortriptyline (Pamelor)
      • Protriptyline (Vivactil)
      • Tapentadol (Nucynta)
      • Teniloxazine (Lucelan, Metatone)
    • Never marketed
      • Ciclazindol (Wy-23,409)
      • CP-39,332
      • Manifaxine (GW-320,659)
      • Radafaxine (GW-353,162)

Note: Only NRIs selective for the NET greater than the other two monoamine transporters (MATs) are listed here. For a list of NRIs that act at multiple MATs, refer to the other monoamine reuptake inhibitor pages such as NDRI, SNRI, and SNDRI.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Norepinephrine_reuptake_inhibitor >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

An Overview of the 5-HT7 Receptor

Published on by Andrew Marshall9 Comments

Introduction

The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). The 5-HT7 receptor is coupled to Gs (stimulates the production of the intracellular signalling molecule cAMP) and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various blood vessels. This receptor has been a drug development target for the treatment of several clinical disorders. The 5-HT7 receptor is encoded by the HTR7 gene, which in humans is transcribed into 3 different splice variants.

Function

When the 5-HT7 receptor is activated by serotonin, it sets off a cascade of events starting with release of the stimulatory G protein Gs from the GPCR complex. Gs in turn activates adenylate cyclase which increases intracellular levels of the second messenger cAMP.

The 5-HT7 receptor plays a role in smooth muscle relaxation within the vasculature and in the gastrointestinal tract. The highest 5-HT7 receptor densities are in the thalamus and hypothalamus, and it is present at higher densities also in the hippocampus and cortex. The 5-HT7 receptor is involved in thermoregulation, circadian rhythm, learning and memory, and sleep. Peripheral 5-HT7 receptors are localised in enteric nerves; high levels of 5-HT7 receptor-expressing mucosal nerve fibres were observed in the colon of patients with irritable bowel syndrome. An essential role of 5-HT7 receptor in intestinal hyperalgesia was demonstrated in mouse models with visceral hypersensitivity, of which a novel 5-HT7 receptor antagonist administered perorally reduced intestinal pain levels. It is also speculated that this receptor may be involved in mood regulation, suggesting that it may be a useful target in the treatment of depression.

Variants

Three splice variants have been identified in humans (designated h5-HT7(a), h5-HT7(b), and h5-HT7(d)), which encode receptors that differ in their carboxy terminals. The h5-HT7(a) is the full length receptor (445 amino acids), while the h5-HT7(b) is truncated at amino acid 432 due to alternative splice donor site. The h5-HT7(d) is a distinct isoform of the receptor: the retention of an exon cassette in the region encoding the carboxyl terminal results a 479-amino acid receptor with a c-terminus markedly different from the h5-HT7(a). A 5-HT7(c) splice variant is detectable in rat tissue but is not expressed in humans. Conversely, rats do not express a splice variant homologous to the h5-HT7(d), as the rat 5-HT7 gene lacks the exon necessary to encode this isoform. Drug binding affinities are similar across the three human splice variants; however, inverse agonist efficacies appear to differ between the splice variants.

Discovery

In 1983, evidence for a 5-HT1-like receptor was first found. Ten years later, 5-HT7 receptor was cloned and characterised. It has since become clear that the receptor described in 1983 is 5-HT7.

Ligands

Numerous orthosteric ligands of moderate to high affinity are known. Signalling biased ligands were discovered and developed in 2018.

Agonists

Agonists mimic the effects of the endogenous ligand, which is serotonin at the 5-HT7 receptor (↑cAMP).

  • 5-Carboxamidotryptamine (5-CT)
  • 5-methoxytryptamine (5-MT, 5-MeOT)
  • 8-OH-DPAT (mixed 5-HT1A/5-HT7 agonist)
  • Aripiprazole (weak partial agonist)
  • AS-19
  • E-55888
  • E-57431
  • LP-12 (4-(2-Diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide)
  • LP-44 (4-[2-(Methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-piperazinehexanamide)
  • LP-211
  • MSD-5a
  • Nω-Methylserotonin
  • N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides (can function as either an agonist or antagonist depending on side chain substitution)
  • N,N-Dimethyltryptamine
  • AGH-107 (water-soluble, brain penetrating full agonist)
  • AH-494 (3-(1-ethyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide)
  • AGH-192 (orally bioavailable, water-soluble, brain penetrating full agonist)

Antagonists

Neutral antagonists (also known as silent antagonists) bind the receptor and have no intrinsic activity but will block the activity of agonists or inverse agonists. Inverse agonists inhibit the constitutive activity of the receptor, producing functional effects opposite to those of agonists (at the 5-HT7 receptor: ↓cAMP). Neutral antagonists and inverse agonists are typically referred to collectively as “antagonists” and, in the case of the 5-HT7 receptor, differentiation between neutral antagonists and inverse agonists is problematic due to differing levels of inverse agonist efficacy between receptor splice variants. For instance, mesulergine and metergoline are reported to be neutral antagonists at the h5-HT7(a) and h5-HT7(d) receptor isoforms but these drugs display marked inverse agonist effects at the h5-HT7(b) splice variant.

  • 3-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-butyl}-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one
  • Amisulpride
  • Amitriptyline
  • Amoxapine
  • Brexpiprazole
  • Clomipramine
  • Clozapine
  • CYY1005 (a highly selective, orally active 5-HT7 antagonist)
  • DR-4485
  • EGIS-12233 (mixed 5-HT6/5-HT7 antagonist)
  • AVN-101 (mixed 5-HT6/5-HT7 antagonist)
  • Fluphenazine
  • Fluperlapine
  • ICI 169,369
  • Imipramine
  • JNJ-18038683
  • Ketanserin
  • Loxapine
  • Lurasidone
  • LY-215,840
  • Maprotiline
  • Mesulergine
  • Methysergide
  • Mianserin
  • Olanzapine
  • Pimozide
  • RA-7 (1-(2-diphenyl)piperazine)
  • Ritanserin
  • SB-258,719
  • SB-258741
  • SB-269970 (highly 5-HT7 selective)
  • SB-656104-A
  • SB-691673
  • Sertindole
  • Spiperone
  • Tenilapine
  • TFMPP
  • Vortioxetine
  • Trifluoperazine
  • Ziprasidone
  • Zotepine

Inactivating Antagonists

Inactivating antagonists are non-competitive antagonists that render the receptor persistently insensitive to agonist, which resembles receptor desensitisation. Inactivation of the 5-HT7 receptor, however, does not arise from the classically described mechanisms of receptor desensitisation via receptor phosphorylation, beta-arrestin recruitment, and receptor internalization. Inactivating antagonists all likely interact with the 5-HT7 receptor in an irreversible/pseudo-irreversible manner, as is the case with risperidone.

  • Bromocriptine
  • Lisuride
  • Metergoline
  • Methiothepin
  • Paliperidone
  • Risperidone

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An Overview of the 5-HT6 Receptor

Published on by Andrew Marshall7 Comments

Introduction

The 5HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.

Distribution

The 5HT6 receptor is expressed almost exclusively in the brain. It is distributed in various areas including, but not limited to, the olfactory tubercle, cerebral cortex (frontal and entorhinal regions), nucleus accumbens, striatum, caudate nucleus, hippocampus, and the molecular layer of the cerebellum. Based on its abundance in extrapyramidal, limbic, and cortical regions it can be suggested that the 5-HT6 receptor plays a role in functions like motor control, emotionality, cognition, and memory.

Function

Blockade of central 5-HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas, whereas activation enhances GABAergic signaling in a widespread manner. Antagonism of 5-HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex, while stimulation has the opposite effect.

As a Drug Target for Antagonists

Despite the 5HT6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity. In parallel with this, 5-HT6 antagonists are hypothesized to improve cognition, learning, and memory. Agents such as latrepirdine, idalopirdine (Lu AE58054), and intepirdine (SB-742,457/RVT-101) were evaluated as novel treatments for Alzheimer’s disease and other forms of dementia. However, phase III trials of latrepirdine, idalopirdine, and intepirdine have failed to demonstrate efficacy.

5HT6 antagonists have also been shown to reduce appetite and produce weight loss, and as a result, PRX-07034, BVT-5,182, and BVT-74,316 are being investigated for the treatment of obesity.

As a Drug Target for Agonists

Recently, the 5-HT6 agonists WAY-181,187 and WAY-208,466 have been demonstrated to be active in rodent models of depression, anxiety, and obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions. Additionally, indirect 5HT6 activation may play a role in the therapeutic benefits of serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

Ligands

A large number of selective 5HT6 ligands have now been developed.

Agonists

  • Full Agonists:
    • 2-Ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT)
    • WAY-181,187
    • WAY-208,466
    • N-(inden-5-yl)imidazothiazole-5-sulfonamide (43): Ki = 4.5nM, EC50 = 0.9nM, Emax = 98%
    • E-6837 – Full agonist at human 5-HT6 receptors
  • Partial Agonists:
    • E-6801
    • E-6837 – partial agonist at rat 5-HT6 receptors. Orally active in rats, and caused weight loss with chronic administration
    • EMD-386,088 – potent partial agonist (EC50 = 1 nM) but non-selective
    • LSD – Emax = 60%

Antagonists and Inverse Agonists

  • ALX-1161
  • AVN-211
  • BVT-5182
  • BVT-74316
  • Cerlapirdine – selective
  • EGIS-12233 – mixed 5-HT6 / 5-HT7 antagonist
  • Idalopirdine (Lu AE58054) – selective
  • Intepirdine (SB-742,457/RVT-101) – selective antagonist
  • Landipirdine (RO-5025181, SYN-120)
  • Latrepirdine and analogues
  • MS-245
  • PRX-07034
  • SB-258,585
  • SB-271,046
  • SB-357,134
  • SB-399,885
  • SGS 518 Fb: [445441-26-9]
  • Ro 04-6790
  • Ro-4368554
  • Atypical antipsychotics (sertindole, olanzapine, asenapine, clozapine)
  • WAY-255315 / SAM-315: Ki = 1.1 nM, IC50 = 13 nM
  • Rosa rugosa extract

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An Overview of the 5-HT5A Receptor

Published on by Andrew Marshall4 Comments

Introduction

5-Hydroxytryptamine (serotonin) receptor 5A, also known as HTR5A, is a protein that in humans is encoded by the HTR5A gene. Agonists and antagonists for 5-HT receptors, as well as serotonin uptake inhibitors, present promnesic (memory-promoting) and/or anti-amnesic effects under different conditions, and 5-HT receptors are also associated with neural changes.

Function

The gene described in this record is a member of 5-hydroxytryptamine receptor family and encodes a multi-pass membrane protein that functions as a receptor for 5-hydroxytryptamine and couples to G proteins, negatively influencing cAMP levels via Gi and Go. This protein has been shown to function in part through the regulation of intracellular Ca2+ mobilisation. The 5-HT5A receptor has been shown to be functional in a native expression system.

Rodents have been shown to possess two functional 5-HT5 receptor subtypes, 5-HT5A and 5-HT5B, however while humans possess a gene coding for the 5-HT5B subtype, its coding sequence is interrupted by stop codons, making the gene non-functional, and so only the 5-HT5A subtype is expressed in human brain.

It also appears to serve as a presynaptic serotonin autoreceptor.

Clinical Significance

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in a wide range of psychiatric conditions and also has vasoconstrictive and vasodilatory effects.

Selective Ligands

Few highly selective ligands are commercially available for the 5-HT5A receptor. When selective activation of this receptor is desired in scientific research, the non-selective serotonin receptor agonist 5-Carboxamidotryptamine can be used in conjunction with selective antagonists for its other targets (principally 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT7). Research in this area is ongoing.

Agonists

  • LSD:(+)-lysergic acid
  • Lisuride, partial agonist
  • 5-CT, full agonist
  • Methylergometrine, full agonist
  • Valerenic acid, a component of valerian, has been shown to act as a 5HT5A partial agonist
  • Olanzapine, an atypical antipsychotic
  • Psilocin
  • Another ligand that has been recently disclosed is shown below, claimed be a selective 5-HT5A agonist with Ki = 124 nM

Antagonists

  • ASP-5736
  • AS-2030680
  • AS-2674723
  • MS112, selective potent antangonist
  • Latrepirdine (non-selective)
  • Risperidone (non-selective), moderate 206 nM affinity.
  • SB-699,551

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An Overview of the 5-HT4 Receptor

Published on by Andrew Marshall4 Comments

Introduction

5-Hydroxytryptamine receptor 4 (5-HT4 receptor) is a protein that in humans is encoded by the HTR4 gene.

Refer to 5-HT receptor.

Function

This gene is a member of the family of human serotonin receptors, which are G protein-coupled receptors that stimulate cAMP production in response to serotonin (5-hydroxytryptamine). The gene product is a glycosylated transmembrane protein that functions in both the peripheral and central nervous system to modulate the release of various neurotransmitters. Multiple transcript variants encoding proteins with distinct C-terminal sequences have been described, but the full-length nature of some transcript variants has not been determined.

Location

The receptor is located in the alimentary tract, urinary bladder, heart and adrenal gland as well as the central nervous system (CNS). In the CNS the receptor appears in the putamen, caudate nucleus, nucleus accumbens, globus pallidus, and substantia nigra, and to a lesser extent in the neocortex, raphe, pontine nuclei, and some areas of the thalamus. It has not been found in the cerebellum.

Isoforms

Internalisation is isoform-specific.

Ligands

Several drugs that act as 5-HT4 selective agonists have recently been introduced into use in both scientific research and clinical medicine. Some drugs that act as 5-HT4 agonists are also active as 5-HT3 antagonists, such as mosapride, metoclopramide, renzapride, and zacopride, and so these compounds cannot be considered highly selective. Research in this area is ongoing. Amongst these agonists prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors.

SB-207,145 radiolabelled with carbon-11 is used as a radioligand for 5-HT4 in positron emission tomography pig and human studies.

Agonists

  • Tropisetron – partial agonist
  • BIMU-8
  • Cisapride
  • CJ-033,466 – partial agonist
  • ML-10302
  • Mosapride
  • Prucalopride
  • Renzapride
  • RS-67506
  • RS-67333 – partial agonist
  • SL65.0155 – partial agonist
  • Tegaserod
  • Zacopride
  • Metoclopramide
  • Sulpiride
  • Naronapride

Antagonists

  • l-lysine
  • Piboserod
  • GR-113,808 (1-methyl-1H-indole-3-carboxylic acid, [1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl ester)
  • GR-125,487
  • RS-39604 (1-[4-Amino-5-chloro-2-(3,5-dimethoxyphenyl)methyloxy]-3-[1-[2-methylsulphonylamino]piperidin-4-yl]propan-1-one)
  • SB-203,186
  • SB-204,070
  • ([Methoxy-11C]1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate
  • Chamomile (ethanol extract)

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What is 5-HT1 Receptor?

Published on by Andrew Marshall37 Comments

Introduction

The 5-HT1 receptors are a subfamily of the 5-HT serotonin receptors that bind to the endogenous neurotransmitter serotonin (also known as 5-hydroxytryptamine, or 5-HT). The 5-HT1 subfamily consists of five G protein-coupled receptors (GPCRs) that share 40% to 63% overall sequence homology, including 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F. Receptors of the 5-HT1 type, specifically, the 5-HT1A and 5-HT1D receptor subtypes, are present on the cell bodies. Receptors of the 5-HT1 type, specifically, the 5-HT1B and 5-HT1D receptor subtypes, are also present on the nerve terminals. These receptors are broadly distributed throughout the brain and are recognised to play a significant part in regulating synaptic levels of 5-HT.

The receptor subfamily is coupled to Gi/Go and mediate inhibitory neurotransmission by inhibiting the function of adenylate cyclase and modulating downstream ionic effects. This R-coupling to Gi/Go proteins leads to a reduction in local concentrations of cAMP, proving that 5-HT1 are primarily inhibitory. There is no 5-HT1C receptor, as it was reclassified as the 5-HT2C receptor.

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What is Reuptake?

Published on by Andrew Marshall1 Comment

Introduction

Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmitting a neural impulse.

Reuptake is necessary for normal synaptic physiology because it allows for the recycling of neurotransmitters and regulates the level of neurotransmitter present in the synapse, thereby controlling how long a signal resulting from neurotransmitter release lasts. Because neurotransmitters are too large and hydrophilic to diffuse through the membrane, specific transport proteins are necessary for the reabsorption of neurotransmitters. Much research, both biochemical and structural, has been performed to obtain clues about the mechanism of reuptake.

Protein Structure

The first primary sequence of a reuptake protein was published in 1990. The technique for protein sequence determination relied upon the purification, sequencing, and cloning of the transporter protein in question, or expression cloning strategies in which transport function was used as an assay for cDNA species coding for that transporter. After separation, it was realised that there were many similarities between the two DNA sequences. Further exploration in the field of reuptake proteins found that many of the transporters associated with important neurotransmitters within the body were also very similar in sequence to the GABA and norepinephrine transporters. The members of this new family include transporters for dopamine, norepinephrine, serotonin, glycine, proline and GABA. They were called Na+/Cl− dependent neurotransmitter transporters. Sodium and chloride ion dependence will be discussed later in the mechanism of action. Using the commonalities among sequences and hydropathy plot analyses, it was predicted that there are 12 hydrophobic membrane spanning regions in the ‘Classical’ transporter family. In addition to this, the N– and C-termini exist in the intracellular space. These proteins also all have an extended extracellular loop between the third and fourth transmembrane sequences. Site-directed chemical labelling experiments verified the predicted topological organisation of the serotonin transporter.

In addition to neurotransmitter transporters, many other proteins in both animals and prokaryotes were found with similar sequences, indicating a larger family of Neurotransmitter:Sodium Symporters (NSS). One of these proteins, LeuT, from Aquifex aeolicus, was crystallised by Yamashita et al. with very high resolution, revealing a molecule of leucine and two Na+ ions bound near the centre of the protein. They found that the transmembrane (TM) helices 1 and 6 contained unwound segments in the middle of the membrane. Along with these two helices, TM helices 3 and 8 and the areas surrounding the unwound sections of 1 and 6 formed the substrate and sodium ion binding sites. The crystal structure revealed pseudo-symmetry in LeuT, in which the structure of TM helices 1-5 is reflected in the structure of helices 6–10.

There is an extracellular cavity in the protein, into which protrudes a helical hairpin formed by extracellular loop EL4. In TM1, an aspartate distinguishes monoamine NSS transporters from amino acid transporters which contain a glycine at the same position. External and internal “gates” were assigned to pairs of negatively and positively charged residues in the extracellular cavity and near the cytoplasmic ends of TM helices 1 and 8.

Mechanism of Action

The classic transporter proteins use transmembrane ion gradients and electrical potential to transport neurotransmitter across the membrane of the presynaptic neuron. Typical neurotransmitter sodium symport (NSS) transporters, which are Na+ and Cl− ion dependent, take advantage of both Na+ and Cl− gradients, inwardly directed across the membrane. The ions flow down their concentration gradients, in many cases leading to transmembrane charge movement that is enhanced by the membrane potential. These forces pull the neurotransmitter substrate into the cell, even against its own concentration gradient. At a molecular level, Na+ ions stabilise amino acid binding at the substrate site and also hold the transporter in an outward-open conformation that allows substrate binding. The role of the Cl− ion in the symport mechanism has been proposed to be for stabilising the charge of the symported Na+.

After ion and substrate binding have taken place, some conformational change must occur. From the conformational differences between the structure of TMs 1-5 and that of TMs 6–10, and from the identification of a substrate permeation pathway between the binding site of SERT and the cytoplasm, a mechanism for conformational change was proposed in which a four-helix bundle composed of TMs 1, 2, 6 and 7 changes its orientation within the rest of the protein. A structure of LeuT in the inward-open conformation subsequently demonstrated that the major component of the conformational change represents movement of the bundle relative to the rest of the protein.

Mechanism of Reuptake Inhibition

The main objective of a reuptake inhibitor is to substantially decrease the rate by which neurotransmitters are reabsorbed into the presynaptic neuron, increasing the concentration of neurotransmitter in the synapse. This increases neurotransmitter binding to pre- and postsynaptic neurotransmitter receptors. Depending on the neuronal system in question, a reuptake inhibitor can have drastic effects on cognition and behaviour. Non-competitive inhibition of the bacterial homologue LeuT by tricyclic antidepressants resulted from binding of these inhibitors in the extracellular permeation pathway. However, the competitive nature of serotonin transport inhibition by antidepressants suggests that in neurotransmitter transporters, they bind in a site overlapping the substrate site.

Human Systems

Refer to Pharmacology of Antidepressants.

Horschitz et al.[12] 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 (an SSRI) 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, although this hypothesis has been challenged since as early as the 1980s. It was initially supported by the successful reduction of depressive symptoms after administration of tricyclic antidepressants (such as desipramine) and SSRIs. Tricyclic 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 desensitisation must occur, but the net result is the same. This increases serotonin signaling, which according to the hypothesis is believed 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 trace amine-associated receptor 1 (TAAR1) to induce efflux and reuptake inhibition in the serotonin, norepinephrine, and dopamine transporters. This effect requires the transporter and TAAR1 to be co-localised (occur together) within the same neuron.

Neuroprotective Role

Astrocytes seem to utilise reuptake mechanisms for a neuroprotective role. Astrocytes use excitatory amino acid transporter 2 (EAAT2, aka GLT-1) to remove glutamate from the synapse. EAAT2 knockout mice were more prone to lethal and spontaneous seizures and acute brain injuries among the cortex. These effects could be linked to increased concentrations of glutamate in the brains of EAAT2 knockout mice, analysed post-mortem.

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