Monoamine releasing agent

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Amphetamine, the prototypical monoamine releasing agent, which acts on norepinephrine and dopamine. Racemic amphetamine 2.svg
Amphetamine, the prototypical monoamine releasing agent, which acts on norepinephrine and dopamine.

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.

Contents

Types of MRAs

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

MRAs must be distinguished from monoamine reuptake inhibitors and monoaminergic activity enhancers, which work via distinct mechanisms.

Endogenous MRAs

A number of endogenous compounds are known to act as MRAs. [1] [2] [3] [4] These include the monoamine neurotransmitters dopamine (an NDRA), [1] norepinephrine (an NDRA), [1] and serotonin (an SRA) themselves, [1] as well as the trace amines phenethylamine (an NDRA), [4] [5] [6] [7] tryptamine (an SDRA or imbalanced SNDRA), [2] [3] and tyramine (an NDRA). [1] Synthetic MRAs are substantially based on structural modification of these endogenous compounds, most prominently including the substituted phenethylamines and substituted tryptamines. [1] [8] [9] [2] [10] [11] [12]

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). [13] 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).

In spite of findings that TAAR1 activation by amphetamines can reverse the monoamine transporters and mediate monoamine release however, [13] [14] [15] [16] major literature reviews on monoamine releasing agents by experts like Richard B. Rothman and David J. Heal state that the nature of monoamine transport reversal is not well understood and/or do not mention TAAR1 activation. [17] [18] [19] [20] Moreover, amphetamines continue to produce psychostimulant-like effects and induction of dopamine and norepinephrine release in TAAR1 knockout mice. [13] [21] [22] [23] [24] In fact, TAAR1 knockout mice are supersensitive to the effects of amphetamines and TAAR1 activation appears to inhibit the striatal dopaminergic effects of psychostimulants. [13] [22] [21] [23] [24] Additionally, many substrate-type MRAs that do not bind to and/or activate the (human) TAAR1 are known, including most cathinones, ephedrine, 4-methylamphetamine, and 4-methylaminorex derivatives, among others. [25] [26] [27] [28]

Dopamine reuptake inhibitors (DRIs) have been grouped into two types, typical or conventional DRIs like cocaine, WIN-35428 (β-CFT), and methylphenidate that produce potent psychostimulant, euphoric, and reinforcing effects, and atypical DRIs like vanoxerine (GBR-12909), modafinil, benztropine, and bupropion, which do not produce such effects or have greatly reduced such effects. [20] [18] [4] [29] It has been proposed that typical DRIs may not actually be acting primarily as DRIs but rather as dopamine releasing agents (DRAs) via mechanisms distinct from conventional substrate-type DRAs like amphetamines. [20] A variety of different pieces of evidence support this hypothesis and help to explain otherwise confusing findings. [20] Under this model, typical cocaine-like DRIs have been referred to with the new label of dopamine transporter (DAT) "inverse agonists" to distinguish them from conventional substrate-type DRAs. [20] An alternative theory is that typical DRIs and atypical DRIs stabilize the DAT in different conformations, with typical DRIs resulting in an outward-facing open conformation that results in differing pharmacological effects from those of atypical DRIs. [18] [4] [29] [30]

Some MRAs, like the amphetamines amphetamine and methamphetamine, as well as trace amines like phenethylamine, tryptamine, and tyramine, are additionally monoaminergic activity enhancers (MAEs). [31] [32] [5] That is, they induce the action potential-mediated release of monoamine neurotransmitters (in contrast to MRAs, which induced uncontrolled monoamine release independent of neuronal firing). [31] [32] [5] They are usually active as MAEs at much lower concentrations than those at which they induce monoamine release. [31] [32] [5] The MAE actions of MAEs may be mediated by TAAR1 agonism, which has likewise been implicated in monoamine-releasing actions. [33] [34] MAEs without concomitant potent monoamine-releasing actions, like selegiline (L-deprenyl), phenylpropylaminopentane (PPAP), and benzofuranylpropylaminopentane (BPAP), have been developed. [31] [32]

Effects and uses

MRAs can have a wide variety of effects depending upon their selectivity for inducing release of different monoamine neurotransmitters.

Selective SRAs 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. [35] [36] Less selective SRAs that also stimulate the release of dopamine, such as methylenedioxymethamphetamine (MDMA), are described as more pleasant, elevating mood and increasing energy and sociability. [37] SRAs have been used as appetite suppressants and as entactogens. They have also been proposed for use as more effective antidepressants and anxiolytics than selective serotonin reuptake inhibitors (SSRIs) owing to the fact that they can produce much larger increases in serotonin levels in comparison. [38]

DRAs, usually non-selective for both norepinephrine and dopamine, have psychostimulant effects, causing an increase in energy, motivation, elevated mood, and euphoria. [39] Other variables can significantly affect the subjective effects, such as infusion rate (increasing positive effects of DRAs) and psychological expectancy effects. [40] They are used in the treatment of attention deficit hyperactivity disorder (ADHD), as appetite suppressants, wakefulness-promoting agents, to improve motivation, and are drugs of recreational use and misuse.

Selective NRAs are minimally psychoactive, but as demonstrated by ephedrine, may be distinguished from placebo, and may trends towards liking. [41] They may also be performance-enhancing, [42] in contrast to reboxetine which is solely a norepinephrine reuptake inhibitor. [43] [44] In addition to their central effects, NRAs produce peripheral sympathomimetic effects like increased heart rate, blood pressure, and force of heart contractions. They are used as nasal decongestants and bronchodilators, but have also seen use as wakefulness-promoting agents, appetite suppressants, and antihypotensive agents. They have additionally seen use as performance-enhancing drugs, for instance in sports.

Selectivity

MRAs act to varying extents on serotonin, norepinephrine, and dopamine. Some induce the release of all three neurotransmitters to a similar degree, like methylenedioxymethamphetamine (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 of dopamine, respectively) and MBDB is a fairly balanced SNRA but a weak releaser of dopamine (~6- and 10-fold lower of dopamine than of 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. [45] Several selective SDRAs, including tryptamine, (+)-α-ethyltryptamine (αET), 5-chloro-αMT, and 5-fluoro-αET, are known. [3] [46] However, besides their serotonin release, these compounds additionally act as non-selective serotonin receptor agonists, including of the serotonin 5-HT2A receptor (with accompanying hallucinogenic effects), and some of them are known to act as monoamine oxidase inhibitors. [3] [46]

Neurotoxicity

Some MRAs have been found to act as monoaminergic neurotoxins and hence to produce long-lasting damage to monoaminergic neurons. [47] [48] Examples include dopaminergic neurotoxicity with amphetamine and methamphetamine and serotonergic neurotoxicity with methylenedioxymethamphetamine (MDMA). [47] [48] Amphetamine may produce significant dopaminergic neurotoxicity even at therapeutic doses. [49] [50] [51] [52] [53] [54] However, clinical doses of amphetamine producing neurotoxicity is controversial and disputed. [55] [49] [51] In contrast to amphetamines, monoamine reuptake inhibitors like methylphenidate lack apparent neurotoxic effects. [49]

Analogues of MDMA with retained MRA activity but reduced or no serotonergic neurotoxicity, like 5,6-methylenedioxy-2-aminoindane (MDAI) and 5-iodo-2-aminoindane (5-IAI), have been developed. [56] [57] Certain drugs have been found to block the neurotoxicity of MRAs in animals. [48] For instance, the selective MAO-B inhibitor selegiline has been found to prevent the serotonergic neurotoxicity of MDMA in rodents. [48]

Activity profiles

Activity profiles of MRAs (EC50, nM) [8] [9]
Compound 5-HT Tooltip Serotonin NE Tooltip Norepinephrine DA Tooltip DopamineTypeClassRef
2C-E >100000>100000>100000IA Phenethylamine [58]
2C-I >100000>100000>100000IAPhenethylamine [58]
3-Chloromethcathinone NDND46.8NDCathinone [4]
3-Fluoroamphetamine 193716.124.2NDRA Amphetamine [59]
3-Methylamphetamine 21818.333.3NDRAAmphetamine [59]
4-Fluoroamphetamine 730–93928.0–3751.5–200NDRAAmphetamine [59] [58]
cis-4-Methylaminorex 53.24.81.7NDRA Aminorex [60]
4-Methylamphetamine 53.422.244.1SNDRAAmphetamine [59]
4-Methylphenethylamine NDND271NDPhenethylamine [4]
4-Methylthiomethamphetamine 21NDNDNDAmphetamine [61]
4,4'-Dimethylaminorex NDNDNDSNDRAAminorexND
   ''cis''-4,4'-Dimethylaminorex 17.7–18.511.8–26.98.6–10.9SNDRAAminorex [60] [62]
   ''trans''-4,4'-Dimethylaminorex 59.931.624.4SNDRAAminorex [62]
5-(2-Aminopropyl)indole 28–104.813.3–7912.9–173SNDRAAmphetamine [46] [63]
   (''R'')-5-(2-Aminopropyl)indole 177811062SNRAAmphetamine [46]
   (''S'')-5-(2-Aminopropyl)indole NDNDNDSNDRAAmphetamineND
5-Chloro-αMT 16343454SDRA Tryptamine [3] [46]
5-Fluoro-αET 36.65334150SDRATryptamine [3]
5-Fluoro-αMT 1912632SNDRATryptamine [46]
5-MeO-αMT 46089001500SNDRATryptamine [58]
5-MeO-DMT >100000>100000>100000IATryptamine [58]
6-(2-Aminopropyl)indole 19.925.6164.0SNDRAAmphetamine [63]
α-Ethyltryptamine 23.2640232SDRATryptamine [3]
α-Methyltryptamine 21.7–6879–11278.6–180SNDRATryptamine [58] [3]
Amfepramone (diethylpropion) >10000>10000>10000PD Cathinone [64]
Aminorex 193–41415.1–26.49.1–49.4SNDRAAminorex [1] [60]
Amphetamine NDNDNDNDRAAmphetamineND
   D-Amphetamine 698–17656.6–7.25.8–24.8NDRAAmphetamine [1] [65]
   L-Amphetamine NDNDNDNRAAmphetamineND
β-Ketophenethylamine NDND208NDPhenethylamine [4]
BDB 1805402,300NDRAAmphetamine [58]
Benzylpiperazine ≥605062–68175–600NDRA Arylpiperazine [58] [66] [9]
Bufotenin 30.5>10000>10000SRATryptamine [2]
Butylamphetamine NDNDIANDAmphetamine [4]
Cathinone NDNDNDNDRACathinoneND
   D-Cathinone NDNDNDNRACathinoneND
   L-Cathinone 236612.418.5NDRACathinone [67]
Chlorphentermine 30.9>100002650SRAAmphetamine [1]
DMPP 26561207SNRAArylpiperazine [61]
DMT 1144166>10000SRATryptamine [2]
Dopamine >1000066.286.9NDRAPhenethylamine [1]
DPT >100000>100000>100000IATryptamine [58] [2]
Ephedrine (racephedrine)NDNDNDNDRA Cathinol ND
   D-Ephedrine (ephedrine)>1000043.1–72.4236–1350NDRACathinol [1]
   L-Ephedrine >100002182104NRACathinol [1] [67]
Epinephrine NDNDNDNDRAPhenethylamineND
Ethcathinone 211899.3>1000NRACathinone [64]
Ethylamphetamine NDND296NDAmphetamine [4]
Fenfluramine 79.3–108739>10000SRAAmphetamine [1] [68] [69]
   D-Fenfluramine 51.7302>10000SNRAAmphetamine [1] [68]
   L-Fenfluramine 147>10000>10000SRAAmphetamine [68] [70]
MBDB 5403300>100000SNRAAmphetamine [58]
mCPP 28–38.1≥140063000SRAArylpiperazine [58] [70] [71]
MDA 160108190SNDRAAmphetamine [69]
   (''R'')-MDA 310290900SNDRAAmphetamine [69]
   (''S'')-MDA 1005098SNDRAAmphetamine [69]
MDEA 472608622SNDRAAmphetamine [61]
   (''R'')-MDEA 52651507SNDRAAmphetamine [61]
   (''S'')-MDEA 465RIRISRAAmphetamine [61]
MDMA 49.6–7254.1–11051.2–278SNDRAAmphetamine [1] [72] [63] [69]
  (''R'')-MDMA 3405603700SNDRAAmphetamine [69]
   (''S'')-MDMA 74136142SNDRAAmphetamine [69]
MDMAR NDNDNDSNDRAAminorexND
   ''cis''-MDMAR 43.914.810.2SNDRAAminorex [62]
   ''trans''-MDMAR 73.438.936.2SNDRAAminorex [62]
Mephedrone 118.3–12258–62.749.1–51SNDRACathinone [72] [65]
Methamnetamine 133410SNDRAAmphetamine [61]
Methamphetamine NDNDNDNDRAAmphetamineND
   D-Methamphetamine 736–1291.712.3–13.88.5–24.5NDRAAmphetamine [1] [72]
   L-Methamphetamine 464028.5416NRAAmphetamine [1]
Methcathinone NDNDNDNDRACathinoneND
   D-Methcathinone NDNDNDNRACathinoneND
   L-Methcathinone 177213.114.8NDRACathinone [67]
Methylone 234–242.1140–152.3117–133.0SNDRACathinone [72] [65]
Naphthylisopropylamine 3.411.112.6SNDRAAmphetamine [73]
Norephedrine (phenylpropanolamine)NDNDNDNDRACathinolND
   D-Norephedrine >1000042.1302NDRACathinol [67]
   L-Norephedrine >100001371371NRACathinol [67]
Norepinephrine >10000164869NDRAPhenethylamine [1]
Norfenfluramine 104168–1701900–1925SNRAAmphetamine [68] [69]
Norpropylhexedrine NDNDNDNDRACyclohexethylamineND
Norpseudoephedrine NDNDNDNDRACathinolND
   D-Norpseudoephedrine (cathine)>1000015.068.3NDRACathinol [67]
   L-Norpseudoephedrine >1000030.1294NDRACathinol [67]
oMPP 17539.1296–542SNDRAArylpiperazine [74] [4]
PAL-738 236558SNDRA Phenylmorpholine [61]
Phendimetrazine >100000>10000>10000PDPhenylmorpholine [75]
Phenethylamine NDND39.5NDRAPhenethylamine [4]
Phenmetrazine 776550.4131NDRAPhenylmorpholine [75]
Phentermine 351139.4262NDRAAmphetamine [1]
Phenylalaninol NDNDNDNDAmphetamineND
   D-Phenylalaninol >100001061355NRAAmphetamine [74]
   L-Phenylalaninol NDNDNDNDAmphetamineND
Phenylisobutylamine NDND225NDAmphetamine [4]
pMPP 3200150011000SNRAArylpiperazine [58]
pNPP 43>10000>10000SRAArylpiperazine [61]
Propylamphetamine NDNDRI (1013)NDAmphetamine [4]
Propylhexedrine NDNDNDNDRACyclohexethylamineND
Pseudoephedrine (racemic pseudoephedrine)NDNDNDNDRACathinolND
   D-Pseudoephedrine >1000040929125NDRACathinol [67]
   L-Pseudoephedrine (pseudoephedrine)>100002241988NRACathinol [67]
Pseudophenmetrazine >10000514RINRAPhenylmorpholine [75]
Psilocin 561>10000>10000SRATryptamine [61] [2]
Serotonin 44.4>10000>10000SRATryptamine [1]
TFMCPP 33>10000>10000SRAArylpiperazine [61]
TFMPP 121ND>10000SRAArylpiperazine [66]
Trimethoxyamphetamine 16000>100000>100000IAAmphetamine [58]
Tryptamine 32.6716164SDRATryptamine [2] [3]
Tyramine 277540.6119NDRAPhenethylamine [1]
Notes: The smaller the value, the more strongly the substance releases the neurotransmitter.

See also

Related Research Articles

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Tryptamine</span> Metabolite of the amino acid tryptophan

Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon. The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others.

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

<span class="mw-page-title-main">Levmetamfetamine</span> Topical nasal decongestant

Levmetamfetamine, also known as l-desoxyephedrine or levomethamphetamine, and commonly sold under the brand name Vicks VapoInhaler among others, is an optical isomer of methamphetamine primarily used as a topical nasal decongestant. It is used to treat nasal congestion from allergies and the common cold. It was first used medically as decongestant beginning in 1958 and has been used for such purposes, primarily in the United States, since then.

<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.

<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

Naphthylaminopropane (PAL-287) is an experimental drug under investigation as of 2007 for the treatment of alcohol and stimulant addiction.

<span class="mw-page-title-main">Benzofuranylpropylaminopentane</span> Chemical compound

(–)-Benzofuranylpropylaminopentane is an experimental drug related to selegiline which acts as a monoaminergic activity enhancer (MAE). It is orally active in animals.

<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

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.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective and robust DRAs are currently known. On the other hand, many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known. Serotonin–dopamine releasing agents (SDRAs), for instance 5-chloro-αMT, are much more rare and are not selective for dopamine release but have also been developed. Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). These drugs are frequently used for recreational purposes and encountered as drugs of abuse. Selective DRAs, as well as NDRAs, have medical applications in the treatment of attention deficit hyperactivity disorder (ADHD).

<span class="mw-page-title-main">Norepinephrine–dopamine reuptake inhibitor</span> Drug that inhibits the reuptake of norepinephrine and dopamine

A norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson's disease. The drug acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.

<span class="mw-page-title-main">3-Methylamphetamine</span> Stimulant drug of the amphetamine class

3-Methylamphetamine is a stimulant drug from the amphetamine family. It is self-administered by mice to a similar extent to 4-fluoroamphetamine and has comparable properties as a monoamine releaser, although with a more balanced release of all three monoamines, as opposed to the more dopamine/noradrenaline selective fluoro analogues.

<span class="mw-page-title-main">3-Fluoroamphetamine</span> Stimulant drug that acts as an amphetamine

3-Fluoroamphetamine is a stimulant drug from the amphetamine family which acts as a monoamine releaser with similar potency to methamphetamine but more selectivity for dopamine and norepinephrine release over serotonin. It is self-administered by mice to a similar extent to related drugs such as 4-fluoroamphetamine and 3-methylamphetamine.

<span class="mw-page-title-main">Substituted cathinone</span> Class of chemical compounds

Substituted cathinones, which include some stimulants and entactogens, are derivatives of cathinone. They feature a phenethylamine core with an alkyl group attached to the alpha carbon, and a ketone group attached to the beta carbon, along with additional substitutions. Cathinone occurs naturally in the plant khat whose leaves are chewed as a recreational drug.

<span class="mw-page-title-main">Serotonin–dopamine reuptake inhibitor</span> Class of drug

A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

<span class="mw-page-title-main">Pseudophenmetrazine</span> Chemical compound

Pseudophenmetrazine is a psychostimulant compound of the morpholine class. It is the N-demethylated and cis-configured analogue of phendimetrazine as well as the cis-configured stereoisomer of phenmetrazine. In addition, along with phenmetrazine, it is believed to be one of the active metabolites of phendimetrazine, which itself is inactive and behaves merely as a prodrug. Relative to phenmetrazine, pseudophenmetrazine is of fairly low potency, acting as a modest releasing agent of norepinephrine (EC50 = 514 nM), while its (+)-enantiomer is a weak releaser of dopamine (EC50 = 1,457 nM) whereas its (−)-enantiomer is a weak reuptake inhibitor of dopamine (Ki = 2,691 nM); together as a racemic mixture with the two enantiomers combined, pseudophenmetrazine behaves overall more as a dopamine reuptake inhibitor (Ki = 2,630 nM), possibly due to the (+)-enantiomer blocking the uptake of the (−)-enantiomer into dopaminergic neurons and thus preventing it from inducing dopamine release. Neither enantiomer has any significant effect on serotonin reuptake or release (both Ki = >10,000 nM and EC50 = >10,000 nM, respectively).

<span class="mw-page-title-main">Monoaminergic activity enhancer</span> Class of compounds in the nervous system

Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of compounds that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system. MAEs are distinct from monoamine releasing agents (MRAs) like amphetamine and fenfluramine in that they do not induce the release of monoamines from synaptic vesicles but rather potentiate only nerve impulse propagation-mediated monoamine release. That is, MAEs increase the amounts of monoamine neurotransmitters released by neurons per electrical impulse.

<span class="mw-page-title-main">Substituted β-hydroxyamphetamine</span> Class of compounds based upon the β-hydroxyamphetamine structure

Substituted β-hydroxyamphetamines, also known as substituted phenylisopropanolamines, substituted phenylpropanolamines, substituted norephedrines, or substituted cathinols, are derivatives of β-hydroxyamphetamine with one or more chemical substituents. They are substituted phenethylamines, phenylethanolamines (β-hydroxyphenethylamines), and amphetamines (α-methylphenethylamines), and are closely related to but distinct from the substituted cathinones (β-ketoamphetamines). Examples of β-hydroxyamphetamines include the β-hydroxyamphetamine stereoisomers phenylpropanolamine and cathine and the stereospecific N-methylated β-hydroxyamphetamine derivatives ephedrine and pseudoephedrine, among many others.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID   11071707. S2CID   15573624.
  2. 1 2 3 4 5 6 7 8 Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB (October 2014). "Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes". Psychopharmacology. 231 (21): 4135–4144. doi:10.1007/s00213-014-3557-7. PMC   4194234 . PMID   24800892.
  3. 1 2 3 4 5 6 7 8 9 Blough BE, Landavazo A, Partilla JS, Decker AM, Page KM, Baumann MH, et al. (October 2014). "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorganic & Medicinal Chemistry Letters. 24 (19): 4754–4758. doi:10.1016/j.bmcl.2014.07.062. PMC   4211607 . PMID   25193229.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC   4297708 . PMID   25548026.
  5. 1 2 3 4 Knoll J, Miklya I, Knoll B, Markó R, Rácz D (1996). "Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain". Life Sciences. 58 (23): 2101–2114. doi:10.1016/0024-3205(96)00204-4. PMID   8649195.
  6. ↑ Nakamura M, Ishii A, Nakahara D (May 1998). "Characterization of beta-phenylethylamine-induced monoamine release in rat nucleus accumbens: a microdialysis study". European Journal of Pharmacology. 349 (2–3): 163–169. doi:10.1016/s0014-2999(98)00191-5. PMID   9671094.
  7. ↑ Zsilla G, Hegyi DE, Baranyi M, Vizi ES (October 2018). "3,4-Methylenedioxymethamphetamine, mephedrone, and β-phenylethylamine release dopamine from the cytoplasm by means of transporters and keep the concentration high and constant by blocking reuptake". European Journal of Pharmacology. 837: 72–80. doi:10.1016/j.ejphar.2018.08.037. PMID   30172789.
  8. 1 2 Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID   14612135.
  9. 1 2 3 Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID   17017961.
  10. ↑ Shulgin AT, Shulgin A (1991). Pihkal: A Chemical Love Story. Biography/science. Transform Press. ISBN   978-0-9630096-0-9 . Retrieved 18 August 2024.
  11. ↑ Shulgin AT, Shulgin A (1997). Tihkal: The Continuation. Transform Press. ISBN   978-0-9630096-9-2 . Retrieved 18 August 2024.
  12. ↑ Shulgin A, Manning T, Daley PF (2011). The Shulgin Index: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Transform Press. ISBN   978-0-9630096-3-0 . Retrieved 2024-08-18.
  13. 1 2 3 4 Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". Journal of Neurochemistry. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC   3005101 . PMID   21073468.
  14. ↑ Wu R, Liu J, Li JX (2022). "Trace amine-associated receptor 1 and drug abuse". Behavioral Pharmacology of Drug Abuse: Current Status. Adv Pharmacol. Vol. 93. pp. 373–401. doi:10.1016/bs.apha.2021.10.005. ISBN   978-0-323-91526-7. PMC   9826737 . PMID   35341572. It is reported that methamphetamine (METH) interacts with TAAR1 and subsequently inhibits DA uptake, enhance DA efflux and induces DAT internalization, and these effects are dependent on TAAR1 (Xie & Miller, 2009). For example, METH-induced inhibition of DA uptake was observed in TAAR1 and DAT cotransfected cells and WT mouse and monkey striatal synaptosomes but not in DAT-only transfected cells or in striatal synaptosomes of TAAR1-KO mice (Xie & Miller, 2009). TAAR1 activation was enhanced by co-expression of monoamine transporters and this effect could be blocked by monoamine transporter antagonists (Xie & Miller, 2007; Xie et al., 2007). Furthermore, DA activation of TAAR1 induced C-FOS-luciferase expression only in the presence of DAT (Xie et al., 2007).
  15. ↑ Xie Z, Miller GM (July 2009). "A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain". The Journal of Pharmacology and Experimental Therapeutics. 330 (1): 316–325. doi:10.1124/jpet.109.153775. PMC   2700171 . PMID   19364908.
  16. ↑ Lewin AH, Miller GM, Gilmour B (December 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorganic & Medicinal Chemistry. 19 (23): 7044–7048. doi:10.1016/j.bmc.2011.10.007. PMC   3236098 . PMID   22037049. While our data suggest a role for TAAR1 in eliciting amphetamine-like stimulant effects, it must be borne in mind that the observed in vivo effects are likely to result from interaction with both TAAR1 and monoamine transporters. Thus it has been shown that the selective TAAR1 agonist RO5166017 fully prevented psychostimulant-induced and persistent hyperdopaminergia-related hyperactivity in mice.42 This effect was found to be DAT-independent, since suppression of hyperactivity was observed in DAT-KO mice.42 The collected information leads us to conclude that TAAR1 is a stereoselective binding site for amphetamine and that TAAR1 activation by amphetamine and its congeners may contribute to the stimulant properties of this class of compounds.
  17. ↑ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC   4297708 . PMID   25548026. Converging lines of evidence have solidified the notion that DA releasers are substrates of the transporter and once translocated, they reverse the normal direction of transporter flux to evoke release of endogenous neurotransmitters. The nature of this reversal is not well understood, but the entire process is primarily transporter-dependent and requires elevated intracellular sodium concentrations, phosphorylation of DAT, and possible involvement of transporter oligomers (Khoshbouei et al., 2003, 2004; Sitte and Freissmuth, 2010).
  18. 1 2 3 Schmitt KC, Rothman RB, Reith ME (July 2013). "Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates". The Journal of Pharmacology and Experimental Therapeutics. 346 (1): 2–10. doi:10.1124/jpet.111.191056. PMC   3684841 . PMID   23568856.
  19. ↑ Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC   3666194 . PMID   23539642.
  20. 1 2 3 4 5 Heal DJ, Gosden J, Smith SL (December 2014). "Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine". Neuropharmacology. 87: 19–40. doi:10.1016/j.neuropharm.2014.06.012. PMID   24953830.
  21. 1 2 Espinoza S, Gainetdinov RR (2014). "Neuronal Functions and Emerging Pharmacology of TAAR1". Taste and Smell. Topics in Medicinal Chemistry. Vol. 23. Cham: Springer International Publishing. pp. 175–194. doi:10.1007/7355_2014_78. ISBN   978-3-319-48925-4.
  22. 1 2 Liu J, Wu R, Li JX (March 2020). "TAAR1 and Psychostimulant Addiction". Cellular and Molecular Neurobiology. 40 (2): 229–238. doi:10.1007/s10571-020-00792-8. PMC   7845786 . PMID   31974906.
  23. 1 2 Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, et al. (March 2008). "Trace amine-associated receptor 1 modulates dopaminergic activity". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 948–956. doi:10.1124/jpet.107.132647. PMID   18083911.
  24. 1 2 Achat-Mendes C, Lynch LJ, Sullivan KA, Vallender EJ, Miller GM (April 2012). "Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1". Pharmacology, Biochemistry, and Behavior. 101 (2): 201–207. doi:10.1016/j.pbb.2011.10.025. PMC   3288391 . PMID   22079347.
  25. ↑ Kuropka P, Zawadzki M, Szpot P (May 2023). "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse". Hum Psychopharmacol. 38 (3): e2866. doi:10.1002/hup.2866. PMID   36866677. Another feature that distinguishes [substituted cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013).
  26. ↑ Simmler LD, Liechti ME (2018). "Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances". Handb Exp Pharmacol. 252: 143–164. doi:10.1007/164_2018_113. PMID   29633178. The activation of human TAAR1 might diminish the effects of psychostimulation and intoxication arising from 7-APB effects on monoamine transporters (see 4.1.3. for more details). Affinity to mouse and rat TAAR1 has been shown for many psychostimulants, but species differences are common (Simmler et al. 2016). For example, [5-(2-aminopropyl)indole (5-IT)] and [4-methylamphetamine (4-MA)] bind and activate TAAR1 in the nanomolar range, but do not activate human TAAR1.
  27. ↑ Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther. 357 (1): 134–144. doi:10.1124/jpet.115.229765. PMID   26791601.
  28. ↑ Rickli A, Kolaczynska K, Hoener MC, Liechti ME (May 2019). "Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR". Neurotoxicology. 72: 95–100. Bibcode:2019NeuTx..72...95R. doi:10.1016/j.neuro.2019.02.011. PMID   30776375.
  29. 1 2 Schmitt KC, Reith ME (2011). "The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors". PLOS ONE. 6 (10): e25790. Bibcode:2011PLoSO...625790S. doi: 10.1371/journal.pone.0025790 . PMC   3197159 . PMID   22043293.
  30. ↑ Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH (February 2021). "Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder". Current Opinion in Pharmacology. 56: 13–21. doi:10.1016/j.coph.2020.07.007. PMC   8247144 . PMID   32927246.
  31. 1 2 3 4 Shimazu S, Miklya I (May 2004). "Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 28 (3): 421–427. doi:10.1016/j.pnpbp.2003.11.016. PMID   15093948. S2CID   37564231.
  32. 1 2 3 4 Knoll J (August 2003). "Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives". Neurochemical Research. 28 (8): 1275–1297. doi:10.1023/a:1024224311289. PMID   12834268.
  33. ↑ Harsing LG, Knoll J, Miklya I (August 2022). "Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum". International Journal of Molecular Sciences. 23 (15): 8543. doi: 10.3390/ijms23158543 . PMC   9369307 . PMID   35955676.
  34. ↑ Harsing LG, Timar J, Miklya I (August 2023). "Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline". International Journal of Molecular Sciences. 24 (17): 13334. doi: 10.3390/ijms241713334 . PMC   10487936 . PMID   37686140.
  35. ↑ Brust JC (2004). Neurological Aspects of Substance Abuse. Butterworth-Heinemann. pp. 117–. ISBN   978-0-7506-7313-6.
  36. ↑ Competitive problems in the drug industry: hearings before Subcommittee on Monopoly and Anticompetitive Activities of the Select Committee on Small Business, United States Senate, Ninetieth Congress, first session. U.S. Government Printing Office. 1976. pp. 2–.
  37. ↑ Parrott AC, Stuart M (1 September 1997). "Ecstasy (MDMA), amphetamine, and LSD: comparative mood profiles in recreational polydrug users". Human Psychopharmacology: Clinical and Experimental. 12 (5): 501–504. CiteSeerX   10.1.1.515.2896 . doi:10.1002/(sici)1099-1077(199709/10)12:5<501::aid-hup913>3.3.co;2-m. ISSN   1099-1077.
  38. ↑ Scorza C, Silveira R, Nichols DE, Reyes-Parada M (July 1999). "Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action". Neuropharmacology. 38 (7): 1055–1061. doi:10.1016/s0028-3908(99)00023-4. PMID   10428424.
  39. ↑ Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, O'Malley SS (May 2013). "The drug effects questionnaire: psychometric support across three drug types". Psychopharmacology. 227 (1): 177–192. doi:10.1007/s00213-012-2954-z. PMC   3624068 . PMID   23271193.
  40. ↑ Nelson RA, Boyd SJ, Ziegelstein RC, Herning R, Cadet JL, Henningfield JE, et al. (March 2006). "Effect of rate of administration on subjective and physiological effects of intravenous cocaine in humans". Drug and Alcohol Dependence. 82 (1): 19–24. doi:10.1016/j.drugalcdep.2005.08.004. PMID   16144747.
  41. ↑ Berlin I, Warot D, Aymard G, Acquaviva E, Legrand M, Labarthe B, et al. (September 2001). "Pharmacodynamics and pharmacokinetics of single nasal (5 mg and 10 mg) and oral (50 mg) doses of ephedrine in healthy subjects". European Journal of Clinical Pharmacology. 57 (6–7): 447–455. doi:10.1007/s002280100317. PMID   11699608. S2CID   12410591.
  42. ↑ Powers ME (October 2001). "Ephedra and its application to sport performance: another concern for the athletic trainer?". Journal of Athletic Training. 36 (4): 420–424. PMC   155439 . PMID   16558668.
  43. ↑ Meeusen R, Watson P, Hasegawa H, Roelands B, Piacentini MF (1 January 2006). "Central fatigue: the serotonin hypothesis and beyond". Sports Medicine. 36 (10): 881–909. doi:10.2165/00007256-200636100-00006. PMID   17004850. S2CID   5178189.
  44. ↑ Roelands B, Meeusen R (March 2010). "Alterations in central fatigue by pharmacological manipulations of neurotransmitters in normal and high ambient temperature". Sports Medicine. 40 (3): 229–246. doi:10.2165/11533670-000000000-00000. PMID   20199121. S2CID   25717280.
  45. ↑ Rothman RB, Blough BE, Baumann MH (January 2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". The AAPS Journal. 9 (1): E1-10. doi:10.1208/aapsj0901001. PMC   2751297 . PMID   17408232.
  46. 1 2 3 4 5 6 Banks ML, Bauer CT, Blough BE, Rothman RB, Partilla JS, Baumann MH, et al. (June 2014). "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys". Experimental and Clinical Psychopharmacology. 22 (3): 274–284. doi:10.1037/a0036595. PMC   4067459 . PMID   24796848.
  47. 1 2 Kostrzewa RM (2022). "Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons". Handbook of Neurotoxicity. Cham: Springer International Publishing. pp. 159–198. doi:10.1007/978-3-031-15080-7_53. ISBN   978-3-031-15079-1.
  48. 1 2 3 4 Moratalla R, Khairnar A, Simola N, Granado N, García-Montes JR, Porceddu PF, et al. (August 2017). "Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms". Prog Neurobiol. 155: 149–170. doi:10.1016/j.pneurobio.2015.09.011. hdl:10261/156486. PMID   26455459.
  49. 1 2 3 Baumeister AA (2021). "Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson's Disease?" (PDF). Harv Rev Psychiatry. 29 (2): 142–158. doi:10.1097/HRP.0000000000000283. PMID   33560690. It has been suggested that the association between PD and ADHD may be explained, in part, by toxic effects of these drugs on DA neurons.241 [...] An important question is whether amphetamines, as they are used clinically to treat ADHD, are toxic to DA neurons. In most of the animal and human studies cited above, stimulant exposure levels are high relative to clinical doses, and dosing regimens (as stimulants) rarely mimic the manner in which these drugs are used clinically. The study by Ricaurte and colleagues248 is an exception. In that study, baboons orally self-administered a racemic (3:1 d/l) amphetamine mixture twice daily in increasing doses ranging from 2.5 to 20 mg/day for four weeks. Plasma amphetamine concentrations, measured at one-week intervals, were comparable to those observed in children taking amphetamine for ADHD. Two to four weeks after cessation of amphetamine treatment, multiple markers of striatal DA function were decreased, including DA and DAT. In another group of animals (squirrel monkeys), d/l amphetamine blood concentration was titrated to clinically comparable levels for four weeks by administering varying doses of amphetamine by orogastric gavage. These animals also had decreased markers of striatal DA function assessed two weeks after cessation of amphetamine.
  50. ↑ Asser A, Taba P (2015). "Psychostimulants and movement disorders". Front Neurol. 6: 75. doi: 10.3389/fneur.2015.00075 . PMC   4403511 . PMID   25941511. Amphetamine treatment similar to that used for ADHD has been demonstrated to produce brain dopaminergic neurotoxicity in primates, causing the damage of dopaminergic nerve endings in the striatum that may also occur in other disorders with long-term amphetamine treatment (57).
  51. 1 2 Advokat C (July 2007). "Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD". J Atten Disord. 11 (1): 8–16. doi:10.1177/1087054706295605. PMID   17606768.
  52. ↑ Berman SM, Kuczenski R, McCracken JT, London ED (February 2009). "Potential adverse effects of amphetamine treatment on brain and behavior: a review". Mol Psychiatry. 14 (2): 123–142. doi:10.1038/mp.2008.90. PMC   2670101 . PMID   18698321. Though the paradigm used by Ricaurte et al. 53 arguably still incorporates amphetamine exposure at a level above much clinical use,14,55 it raises important unanswered questions. Is there a threshold of amphetamine exposure above which persistent changes in the dopamine system are induced? [...]
  53. ↑ Ricaurte GA, Mechan AO, Yuan J, Hatzidimitriou G, Xie T, Mayne AH, et al. (October 2005). "Amphetamine treatment similar to that used in the treatment of adult attention-deficit/hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult nonhuman primates". J Pharmacol Exp Ther. 315 (1): 91–98. doi:10.1124/jpet.105.087916. PMID   16014752.
  54. ↑ Courtney KE, Ray LA (2016). "Clinical neuroscience of amphetamine-type stimulants: From basic science to treatment development". Prog Brain Res. 223: 295–310. doi:10.1016/bs.pbr.2015.07.010. PMID   26806782. Repeated exposure to moderate to high levels of methamphetamine has been related to neurotoxic effects on the dopaminergic and serotonergic systems, leading to potentially irreversible loss of nerve terminals and/or neuron cell bodies (Cho and Melega, 2002). Preclinical evidence suggests that d-amphetamine, even when administered at commonly prescribed therapeutic doses, also results in toxicity to brain dopaminergic axon terminals (Ricaurte et al., 2005).
  55. ↑ Gerlach M, Grünblatt E, Lange KW (June 2013). "Is the treatment with psychostimulants in children and adolescents with attention deficit hyperactivity disorder harmful for the dopaminergic system?". Atten Defic Hyperact Disord. 5 (2): 71–81. doi:10.1007/s12402-013-0105-y. PMID   23605387.
  56. ↑ Oeri HE (May 2021). "Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy". J Psychopharmacol. 35 (5): 512–536. doi:10.1177/0269881120920420. PMC   8155739 . PMID   32909493.
  57. ↑ Pinterova N, Horsley RR, Palenicek T (2017). "Synthetic Aminoindanes: A Summary of Existing Knowledge". Front Psychiatry. 8: 236. doi: 10.3389/fpsyt.2017.00236 . PMC   5698283 . PMID   29204127.
  58. 1 2 3 4 5 6 7 8 9 10 11 12 13 Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". European Journal of Pharmacology. 559 (2–3): 132–137. doi:10.1016/j.ejphar.2006.11.075. PMID   17223101.
  59. 1 2 3 4 Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (May 2005). "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs". The Journal of Pharmacology and Experimental Therapeutics. 313 (2): 848–854. doi:10.1124/jpet.104.080101. PMID   15677348. S2CID   12135483.
  60. 1 2 3 Brandt SD, Baumann MH, Partilla JS, Kavanagh PV, Power JD, Talbot B, et al. (2014). "Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')". Drug Testing and Analysis. 6 (7–8): 684–695. doi:10.1002/dta.1668. PMC   4128571 . PMID   24841869.
  61. 1 2 3 4 5 6 7 8 9 10 Rothman RB, Partilla JS, Baumann MH, Lightfoot-Siordia C, Blough BE (April 2012). "Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters". The Journal of Pharmacology and Experimental Therapeutics. 341 (1): 251–262. doi:10.1124/jpet.111.188946. PMC   3364510 . PMID   22271821.
  62. 1 2 3 4 McLaughlin G, Morris N, Kavanagh PV, Power JD, Twamley B, O'Brien J, et al. (July 2015). "Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR)". Drug Testing and Analysis. 7 (7): 555–564. doi:10.1002/dta.1732. PMC   5331736 . PMID   25331619.
  63. 1 2 3 Marusich JA, Antonazzo KR, Blough BE, Brandt SD, Kavanagh PV, Partilla JS, et al. (February 2016). "The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue". Neuropharmacology. 101: 68–75. doi:10.1016/j.neuropharm.2015.09.004. PMC   4681602 . PMID   26362361.
  64. 1 2 Yu H, Rothman RB, Dersch CM, Partilla JS, Rice KC (December 2000). "Uptake and release effects of diethylpropion and its metabolites with biogenic amine transporters". Bioorganic & Medicinal Chemistry. 8 (12): 2689–2692. doi:10.1016/s0968-0896(00)00210-8. PMID   11131159.
  65. 1 2 3 Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, et al. (March 2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC   3572453 . PMID   23072836.
  66. 1 2 Baumann MH, Clark RD, Budzynski AG, Partilla JS, Blough BE, Rothman RB (March 2005). "N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy')". Neuropsychopharmacology. 30 (3): 550–560. doi: 10.1038/sj.npp.1300585 . PMID   15496938.
  67. 1 2 3 4 5 6 7 8 9 Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, et al. (October 2003). "In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates". The Journal of Pharmacology and Experimental Therapeutics. 307 (1): 138–145. doi:10.1124/jpet.103.053975. PMID   12954796. S2CID   19015584.
  68. 1 2 3 4 Rothman RB, Clark RD, Partilla JS, Baumann MH (June 2003). "(+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters". The Journal of Pharmacology and Experimental Therapeutics. 305 (3): 1191–1199. doi:10.1124/jpet.103.049684. PMID   12649307. S2CID   21164342.
  69. 1 2 3 4 5 6 7 8 Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, et al. (June 2003). "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology. 63 (6): 1223–1229. doi:10.1124/mol.63.6.1223. PMID   12761331. S2CID   839426.
  70. 1 2 Rothman RB, Baumann MH (July 2002). "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacology & Therapeutics. 95 (1): 73–88. doi:10.1016/s0163-7258(02)00234-6. PMID   12163129.
  71. ↑ Rothman RB, Baumann MH (April 2002). "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacology, Biochemistry, and Behavior. 71 (4): 825–836. doi:10.1016/s0091-3057(01)00669-4. PMID   11888573. S2CID   24296122.
  72. 1 2 3 4 Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC   3306880 . PMID   22169943.
  73. ↑ Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS, Mello NK, et al. (June 2005). "Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration". The Journal of Pharmacology and Experimental Therapeutics. 313 (3): 1361–1369. doi:10.1124/jpet.104.082503. PMID   15761112. S2CID   19802702.
  74. 1 2 Kohut SJ, Jacobs DS, Rothman RB, Partilla JS, Bergman J, Blough BE (December 2017). "Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys". Psychopharmacology. 234 (23–24): 3455–3465. doi:10.1007/s00213-017-4731-5. PMC   5747253 . PMID   28889212.
  75. 1 2 3 Rothman RB, Katsnelson M, Vu N, Partilla JS, Dersch CM, Blough BE, et al. (June 2002). "Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain". European Journal of Pharmacology. 447 (1): 51–57. doi:10.1016/s0014-2999(02)01830-7. PMID   12106802.

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