Category: Mental Health

What is a Monoamine Releasing Agent?

Published on by Andrew Marshall3 Comments

Introduction

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

Types of MRAs

MRAS can be classified by the monoamines they mainly release, although these drugs lie on a spectrum.

Mechanism of Action

MRAs cause the release of monoamine neurotransmitters by various complex mechanism of actions. They may enter the presynaptic neuron primarily via plasma membrane transporters, such as the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). Some, such as exogenous phenethylamine, amphetamine, and methamphetamine, can also diffuse directly across the cell membrane to varying degrees. Once inside the presynaptic neuron, they may inhibit the reuptake of monoamine neurotransmitters through vesicular monoamine transporter 2 (VMAT2) and release the neurotransmitters stores of synaptic vesicles into the cytoplasm by inducing reverse transport at VMAT2. MRAs can also bind to the intracellular receptor TAAR1 as agonists, which triggers a phosphorylation cascade via protein kinases that results in the phosphorylation of monoamine transporters located at the plasma membrane (i.e. the dopamine transporter, norepinephrine transporter, and serotonin transporter); upon phosphorylation, these transporters transport monoamines in reverse (i.e. they move monoamines from the neuronal cytoplasm into the synaptic cleft). The combined effects of MRAs at VMAT2 and TAAR1 result in the release of neurotransmitters out of synaptic vesicles and the cell cytoplasm into the synaptic cleft where they bind to their associated presynaptic autoreceptors and postsynaptic receptors. Certain MRAs interact with other presynaptic intracellular receptors which promote monoamine neurotransmission as well (e.g. methamphetamine is also an agonist at σ1 receptor).

Effects

Monoamine releasing agents can have a wide variety of effects depending upon their selectivity for monoamines. Selective serotonin releasing agents such as fenfluramine and related compounds are described as dysphoric and lethargic in lower doses, and in higher doses some hallucinogenic effects have been reported. Less selective serotonergic agents that stimulate an efflux in dopamine, such as MDMA are described as more pleasant, increasing energy, sociability and elevating mood. Dopamine releasing agents, usually selective for both norepinephrine and dopamine have psychostimulant effect, causing an increase in energy, and elevated mood. Other variables can significantly affect the subjective effects, such as infusion rate(increasing positive effects of cocaine), and expectancy. Selectively noradrenergic drugs are minimally psychoactive, but as demonstrated by ephedrine may be distinguished from placebo, and trends towards liking. They may also be ergogenic, in contrast to reboxetine which is solely a reuptake inhibitor.

Selectivity

MRAs act to varying extents on serotonin, norepinephrine, and dopamine. Some induce the release of all three neurotransmitters to a similar degree, like MDMA, while others are more selective. As examples, amphetamine and methamphetamine are NDRAs but only very weak releasers of serotonin (~60- and 30-fold less than dopamine, respectively) and MBDB is a fairly balanced SNRA but a weak releaser of dopamine (~6- and 10-fold lower for dopamine than norepinephrine or serotonin, respectively). Even more selective include agents like fenfluramine, a selective SRA, and ephedrine, a selective NRA. The differences in selectivity of these agents is the result of different affinities as substrates for the monoamine transporters, and thus differing ability to gain access into monoaminergic neurons and induce monoamine neurotransmitter release via the TAAR1 and VMAT2 proteins.

As of present, no selective DRAs are known. This is because it has proven extremely difficult to separate DAT affinity from NET affinity and retain releasing efficacy at the same time. Several selective SDRAs are known however, though these compounds also act as non-selective serotonin receptor agonists.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Monoamine_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 are Dopaminergic Pathways?

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Introduction

Dopaminergic pathways (dopamine pathways, dopaminergic projections) in the human brain are involved in both physiological and behavioural processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. Each pathway is a set of projection neurons, consisting of individual dopaminergic neurons.

The four major dopaminergic pathways are the mesolimbic pathway, the mesocortical pathway, the nigrostriatal pathway, and the tuberoinfundibular pathway. The mesolimbic pathway and the mesocortical pathway form the mesocorticolimbic system. Two other dopaminergic pathways to be considered are the hypothalamospinal tract and the incertohypothalamic pathway.

Parkinson’s disease, attention deficit hyperactivity disorder (ADHD), substance use disorders (addiction), and restless legs syndrome (RLS) can be attributed to dysfunction in specific dopaminergic pathways.

The dopamine neurons of the dopaminergic pathways synthesize and release the neurotransmitter dopamine. Enzymes tyrosine hydroxylase and dopa decarboxylase are required for dopamine synthesis. These enzymes are both produced in the cell bodies of dopamine neurons. Dopamine is stored in the cytoplasm and vesicles in axon terminals. Dopamine release from vesicles is triggered by action potential propagation-induced membrane depolarisation. The axons of dopamine neurons extend the entire length of their designated pathway.

Pathways

Major

Six of the dopaminergic pathways are listed in the table below.

Pathway NameDescriptionAssociated ProcessesAssociated Disorders
Mesocorticolimbic
system (Mesolimbic
pathway)		1. The mesolimbic pathway transmits dopamine from the ventral tegmental area (VTA), which is located in the midbrain, to the ventral striatum, which includes both the nucleus accumbens and olfactory tubercle.
2. The “meso” prefix in the word “mesolimbic” refers to the midbrain, or “middle brain”, since “meso” means “middle” in Greek.		1. Reward-related cognition
a. Incentive salience (“wanting”)
b. Pleasure (“liking”) response from certain stimuli
c. Positive reinforcement
2. Aversion-related cognition		1. ADHD
2. Addiction
3. Schizophrenia
Mesocorticolimbic
system (Mesocortical
pathway)		1. The mesocortical pathway transmits dopamine from the VTA to the prefrontal cortex.
2. The “meso” prefix in “mesocortical” refers to the VTA, which is located in the midbrain, and “cortical” refers to the cortex.		1. Executive functions1. ADHD
2. Addiction
3. Schizophrenia
Nigrostriatal pathway1. The nigrostriatal pathway transmits dopaminergic neurons from the zona compacta of the substantia nigra to the caudate nucleus and putamen.
2. The substantia nigra is located in the midbrain, while both the caudate nucleus and putamen are located in the dorsal striatum.		1. Motor function
2. Reward-related cognition
3. Associative learning		1. Addiction
2. Chorea
3. Huntington’s disease
4. Schizophrenia
5. ADHD
6. Tourette’s Syndrome
7. Parkinson’s disease
Tuberoinfundibular pathway1. The tuberoinfundibular pathway transmits dopamine from the hypothalamus to the pituitary gland.
2. This pathway controls the secretion of certain hormones, including prolactin, from the pituitary gland.
3. “Infundibular” in the word “tuberoinfundibular” refers to the cup or infundibulum, out of which the pituitary gland develops.		1. Regulation of prolactin secretion1. Hyperprolactinaemia
Hypothalamospinal tract1. This pathway influences locomotor networks in the brainstem and spinal cord.1. Motor function1. Restless leg syndrome
Incertohypothalamic pathway1. This pathway from the zona incerta influences the hypothalamus and locomotor centres in the brainstem.1. Visceral and sensorimotor activities1. Tremor

Minor

  • Hypothalamospinal
    • Hypothalamus → Spinal cord
  • Incertohypothalamic
    • Zona incerta → Hypothalamus
    • Zona incerta → Brainstem VTA → Amygdala (mesoamygdaloid pathway)
  • VTA → Hippocampus
  • VTA → Cingulate cortex
  • VTA → Olfactory bulb
  • SNc → Subthalamic nucleus

Function

Mesocorticolimbic system

The mesocorticolimbic system (mesocorticolimbic circuit) refers to both the mesocortical and mesolimbic pathways. Both pathways originate at the ventral tegmental area (VTA). Through separate connections to the prefrontal cortex (mesocortical) and ventral striatum (mesolimbic), the mesocorticolimbic projection has a significant role in learning, motivation, reward, memory and movement. Dopamine receptor subtypes, D1 and D2 have been shown to have complementary functions in the mesocorticolimbic projection, facilitating learning in response to both positive and negative feedback. Both pathways of the mesocorticolimbic system are associated with ADHD, schizophrenia and addiction.

Mesocortical Pathway

The mesocortical pathway projects from the ventral tegmental area to the prefrontal cortex (VTA → Prefrontal cortex). This pathway is involved in cognition and the regulation of executive functions (e.g. attention, working memory, inhibitory control, planning, etc.) Dysregulation of the neurons in this pathway has been connected to ADHD.

Mesolimbic Pathway

Referred to as the reward pathway, mesolimbic pathway projects from the ventral tegmental area to the ventral striatum ( VTA → Ventral striatum (nucleus accumbens and olfactory tubercle). When a reward is anticipated, the firing rate of dopamine neurons in the mesolimbic pathway increases. The mesolimbic pathway is involved with incentive salience, motivation, reinforcement learning, fear and other cognitive processes. In animal studies, depletion of dopamine in this pathway, or lesions at its site of origin, decrease the extent to which an animal is willing to go to obtain a reward (e.g. the number of lever presses for nicotine or time searching for food). Research is ongoing to determine the role of the mesolimbic pathway in the perception of pleasure.

Nigrostriatal Pathway

The nigrostriatal pathway is involved in behaviours relating to movement and motivation. The transmission of dopaminergic neurons to the dorsal striatum particularly plays a role in reward and motivation while movement is influenced by the transmission of dopaminergic neurons to the substantia nigra. The nigrostriatal pathway is associated with conditions such as Huntington’s disease, Parkinson’s disease, ADHD, Schizophrenia, and Tourette’s Syndrome. Huntington’s disease, Parkinson’s disease, and Tourette’s Syndrome are conditions affected by motor functioning while schizophrenia and ADHD are affected by reward and motivation functioning. This pathway also regulates associated learning such as classical conditioning and operant conditioning.

Tuberoinfundibular Pathway

The tuberoinfundibular pathway transmits dopamine the hypothalamus to the pituitary gland. This pathway also regulates the secretion of prolactin from the pituitary gland, which is responsible for breast milk production in females. Hyperprolactinemia is an associated condition caused by an excessive amount of prolactin production that is common in pregnant women.

Cortico-Basal Ganglia-Thalamo-Cortical Loop

The dopaminergic pathways that project from the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) into the striatum (i.e. the nigrostriatal and mesolimbic pathways, respectively) form one component of a sequence of pathways known as the cortico-basal ganglia-thalamo-cortical loop. The nigrostriatal component of the loop consists of the SNc, giving rise to both inhibitory and excitatory pathways that run from the striatum into the globus pallidus, before carrying on to the thalamus, or into the subthalamic nucleus before heading into the thalamus. The dopaminergic neurons in this circuit increase the magnitude of phasic firing in response to positive reward error, that is when the reward exceeds the expected reward. These neurons do not decrease phasic firing during a negative reward prediction (less reward than expected), leading to hypothesis that serotonergic, rather than dopaminergic neurons encode reward loss (source?). Dopamine phasic activity also increases during cues that signal negative events, however dopaminergic neuron stimulation still induces place preference, indicating its main role in evaluating a positive stimulus. From these findings, two hypotheses have developed, as to the role of the basal ganglia and nigrostiatal dopamine circuits in action selection. The first model suggests a “critic” which encodes value, and an actor which encodes responses to stimuli based on perceived value. However, the second model proposes that the actions do not originate in the basal ganglia, and instead originate in the cortex and are selected by the basal ganglia. This model proposes that the direct pathway controls appropriate behaviour and the indirect suppresses actions not suitable for the situation. This model proposes that tonic dopaminergic firing increases the activity of the direct pathway, causing a bias towards executing actions faster.

These models of the basal ganglia are thought to be relevant to the study of OCD, ADHD, Tourette syndrome, Parkinson’s disease, schizophrenia, and addiction. For example, Parkinson’s disease is hypothesized to be a result of excessive inhibitory pathway activity, which explains the slow movement and cognitive deficits, while Tourettes is proposed to be a result of excessive excitatory activity resulting in the tics characteristic of Tourettes.

Regulation

The ventral tegmental area and substantia nigra pars compacta receive inputs from other neurotransmitters systems, including glutaminergic inputs, GABAergic inputs, cholinergic inputs, and inputs from other monoaminergic nuclei. The VTA contains 5-HT1A receptors that exert a biphasic effects on firing, with low doses of 5-HT1A receptor agonists eliciting an increase in firing rate, and higher doses suppressing activity. The 5-HT2A receptors expressed on dopaminergic neurons increase activity, while 5-HT2C receptors elicit a decrease in activity. The mesolimbic pathway, which projects from the VTA to the nucleus accumbens, is also regulated by muscarinic acetylcholine receptors. In particular, the activation of muscarinic acetylcholine receptor M2 and muscarinic acetylcholine receptor M4 inhibits dopamine release, while muscarinic acetylcholine receptor M1 activation increases dopamine release. GABAergic inputs from the striatum decrease dopaminergic neuronal activity, and glutaminergic inputs from many cortical and subcortical areas increase the firing rate of dopaminergic neurons. Endocannabinoids also appear to have a modulatory effect on dopamine release from neurons that project out of the VTA and SNc. Noradrenergic inputs deriving from the locus coeruleus have excitatory and inhibitory effects on the dopaminergic neurons that project out of the VTA and SNc. The excitatory orexinergic inputs to the VTA originate in the lateral hypothalamus and may regulate the baseline firing of VTA dopaminergic neurons.

Inputs to the Ventral Tegmental Area (VTA) and Substantia Nigra Pars Compacta (SNc)

NeurotransmitterOriginType of Connection
Glutamate1. pedunculopontine nucleus
2. subthalamic nucleus
3. laterodorsal tegmental nucleus
4. stria terminalis
5. superior colliculus
6. lateral hypothalamus
7. preoptic area
8. periaqueductal gray
9. raphe nuclei		1. Excitatory projections into the VTA and SNc
GABA1. rostromedial tegmental nucleus
2. striatum
3. local GABAergic inputs		1. Inhibitory projections into the VTA and SNc
Serotonin1. raphe nuclei1. Modulatory effect, depending on receptor subtype
2. Produces a biphasic effect on VTA neurons
Norepineprhine1. locus coeruleus
2. other noradrenergic nuclei		1. Modulatory effect, depending on receptor subtype
2. The excitatory and inhibitory effects of the LC on the VTA and SNc are time-dependent
Endocannabinoids1. VTA dopamine neurons[note 1 & 2]
2. SNc dopamine neurons[note 1 & 2]		1. Excitatory effect on dopaminergic neurons from inhibiting GABAergic inputs
2. Inhibitory effect on dopaminergic neurons from inhibiting glutamatergic inputs
3. May interact with orexins via CB1–OX1 receptor heterodimers to regulate neuronal firing
Acetylcholine1. pedunculopontine nucleus
2. laterodorsal tegmental nuclei		1. Modulatory effect, depending on receptor subtype
Orexin1. lateral hypothalamus1. Excitatory effect on dopaminergic neurons via signalling through orexin receptors (OX1 and OX2)
2. Increases both tonic and phasic firing of dopaminergic neurons in the VTA
3. May interact with endocannabinoids via CB1–OX1 receptor heterodimers to regulate neuronal firing

Notes

  1. At a chemical synapse, neurotransmitters are normally released from the presynaptic axon terminal and signal through receptors that are located on the dendrites of the postsynaptic neuron; however, in retrograde neurotransmission, the dendrites of the postsynaptic neuron release neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron.
  2. Endocannabinoids signal between neurons through retrograde neurotransmission at synapses; consequently, the dopaminergic neurons that project out of the VTA and SNc release endocannabinoids from their dendrites onto the axon terminals of their inhibitory GABAergic and excitatory glutamatergic inputs to inhibit their effects on dopamine neuronal firing.

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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.

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What is a Serotonin-Norepinephrine-Dopamine Releasing Agent?

Published on by Andrew Marshall1 Comment

Introduction

A serotonin–norepinephrine–dopamine releasing agent (SNDRA), also known as a triple releasing agent (TRA), is a type of drug which induces the release of serotonin, norepinephrine/epinephrine, and dopamine in the brain and body. SNDRAs produce euphoriant, entactogen, and psychostimulant effects, and are almost exclusively encountered as recreational drugs.

A closely related type of drug is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI).

Stahl uses the term “Trimonoaminergic Modulators” (TMM) in his work.

Examples of SNDRAs

Examples of SNDRAs include specific amphetamines such as MDMA, MDA, 4-methylamphetamine, methamphetamine (in high doses), certain substituted benzofurans such as 5-APB and 6-APB, naphthylisopropylamine; cathinones such as mephedrone and methylone; tryptamines such as αMT and αET; along with agents of other chemical classes such as 4,4′-DMAR, and 5-IAI. αET and αMT are of special notability among SNDRAs in that those tryptamines were once used as pharmaceutical drugs, specifically as antidepressants, but were withdrawn shortly after introduction in the 1960s due to problems with toxicity and recreational use. Such tryptamines were originally thought to act as monoamine oxidase inhibitors (MAOIs) before the signature monoamine-releasing actions were elucidated. Many years after being withdrawn, αET was also determined to produce serotonergic neurotoxicity, similarly to MDMA and various other SNDRAs; the same is very likely true for αMT as well, although it has not specifically been assessed.

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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)

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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))

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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.

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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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