Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

s that enhance the

action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...

-evoked

release Release may refer to: * Art release, the public distribution of an artistic production, such as a film, album, or song * Legal release, a legal instrument * News release, a communication directed at the news media * Release (ISUP), a code to i ...

monoamine neurotransmitter 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. All monoamines ...

s in the

nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...

. MAEs are distinct from

monoamine releasing agent A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrati ...

s (MRAs) like

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

and

fenfluramine Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treat ...

in that they do not induce the release of monoamines from

synaptic vesicle In a neuron, synaptic vesicles (or neurotransmitter vesicles) store various neurotransmitters that are exocytosis, released at the chemical synapse, synapse. The release is regulated by a voltage-dependent calcium channel. Vesicle (biology), Ves ...

s 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. MAEs have been shown to significantly enhance nerve impulse-mediated

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

release in the

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra a ...

, and

olfactory tubercle The olfactory tubercle (OT), also known as the tuberculum olfactorium, is a multi-sensory processing center that is contained within the olfactory cortex and ventral striatum and plays a role in reward cognition. The OT has also been shown to ...

;

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

release from the

locus coeruleus The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system in the reticular ...

; and/or

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

release from the

raphe nucleus The raphe nuclei (, "seam") are a moderate-size cluster of nuclei found in the brain stem. They have 5-HT1 receptors which are coupled with Gi/Go-protein-inhibiting adenyl cyclase. They function as autoreceptors in the brain and decrease the r ...

rodent studies Rodents have been employed in biomedical experimentation from the 1650s. Rodent studies up to the early 19th century were mainly physiological or toxicological. The first rodent behavioral study was carried out in 1822, a purely observational st ...

. Some MAEs are selective for effects on some of these neurotransmitters but not on others. The maximal impacts of MAEs on brain monoamine levels are more modest than with monoamine releasing agents like

and

monoamine reuptake inhibitor 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 monoamin ...

s like

methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...

. MAEs have a peculiar and characteristic

bimodal In statistics, a multimodal distribution is a probability distribution with more than one mode (i.e., more than one local peak of the distribution). These appear as distinct peaks (local maxima) in the probability density function, as shown ...

concentration–response relationship, with two bell-shaped curves of MAE activity across tested concentration ranges. Hence, there is a restricted concentration range for optimal

pharmacodynamic Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...

activity.

Endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

MAEs include certain

trace amine 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 ...

s like

β-phenylethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine ...

and

tryptamine 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 (third aromatic atom, with the firs ...

, while

synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

MAEs include certain

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace ami ...

and

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

s like

selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

, phenylpropylaminopentane (PPAP), benzofuranylpropylaminopentane (BPAP), and indolylpropylaminopentane (IPAP). Although this was originally not known, the actions of MAEs may be mediated by

agonism Agonism (from Greek 'struggle') is a political and social theory that emphasizes the potentially positive aspects of certain forms of conflict. It accepts a permanent place for such conflict in the political sphere, but seeks to show how indivi ...

of the

trace amine-associated receptor 1 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 a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is p ...

(TAAR1).

Antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.EPPTB (a known TAAR1 antagonist), 3-F-BPAP, and

rasagiline Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advan ...

, have been identified.

Endogenous monoaminergic activity enhancers

A few

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

MAEs have been identified, including the

(PEA),

tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the bl ...

, and

. At a concentration of 16μM (1.6 × 10⁻⁵ M), β-phenylethylamine has been shown to act as a MAE for norepinephrine (2.6-fold increase), dopamine (1.3-fold increase), and serotonin (2.3-fold increase) in the rat

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

''. Conversely, tryptamine has been found to act as a MAE for serotonin (3.6-fold increase) at a concentration of 1.3μM (1.3 × 10⁻⁶ M) and as a MAE for norepinephrine (1.9-fold increase) and dopamine (1.3-fold increase) at a concentration of 13μΜ (1.3 × 10⁻⁵ M) in the rat brainstem ''in vitro''. It is apparent that tryptamine at a concentration of 1.3μΜ is a much more effective MAE of serotonin than is β-phenylethylamine at a concentration of 16μM. Hence, tryptamine is a substantially more potent MAE of serotonin than β-phenylethylamine, whereas β-phenylethylamine is a slightly more potent MAE of norepinephrine than tryptamine. It has been suggested that these selectivities may indicate the existence of multiple MAE

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

s for these compounds. Tyramine has been shown to act as a MAE of norepinephrine, dopamine, and serotonin in the rat brainstem ''in vitro'' similarly to β-phenylethylamine. β-Phenylethylamine and tyramine additionally act as potent

s of norepinephrine and dopamine at higher concentrations. The MAE and monoamine releasing agent actions of these compounds are mechanistically distinct and they have been referred to as "mixed-acting" monoaminergic potentiators. The

MAE benzofuranylpropylaminopentane (BPAP) has been found to be far more potent as a MAE and to exert MAE and related effects at much lower concentrations than known endogenous MAEs like β-phenylethylamine and tryptamine. For example, BPAP has been found to have peak effects at a concentration of 10⁻¹⁴M (

femtomolar Molar concentration (also called molarity, amount concentration or substance concentration) is the number of moles of solute per liter of solution. Specifically, It is a measure of the concentration of a chemical species, in particular, of a solu ...

picomolar Molar concentration (also called molarity, amount concentration or substance concentration) is the number of moles of solute per liter of solution. Specifically, It is a measure of the concentration of a chemical species, in particular, of a solu ...

range). It has been hypothesized that the very high potency of BPAP may foreshadow the existence of much more potent endogenous MAEs than currently known compounds like β-phenylethylamine and tryptamine that have yet to be identified and may be the true key endogenous mediators for this system.

Monoaminergic activity enhancing drugs

β-Phenylethylamine, tryptamine, and tyramine when administered to animals are ineffective as MAEs ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' due to very rapid breakdown by

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...

(MAO). However,

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...

s (MAOIs), specifically

MAO-B Monoamine oxidase B (MAO-B) is an enzyme that in humans is encoded by the ''MAOB'' gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. It catalyze ...

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

s like

, can dramatically potentiate β-phenylethylamine by inhibiting its metabolism and thereby allow for it to produce significant

effects. Tyramine, unlike β-phenylethylamine and tryptamine, is unable to cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

, which additionally limits its capacity for centrally mediated effects.

Selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

(L-deprenyl) (a phenylethylamine derivative) is used as an

antiparkinsonian agent In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutr ...

and

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

and exhibits CAE effects independent of its

monoamine oxidase inhibition Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especia ...

. It has been shown to enhance both impulse-evoked norepinephrine and dopamine release. Selegiline shows a bimodal concentration–response relationship in terms of its CAE actions for dopamine activity in the striatum. Besides enhancing catecholaminergic activity, it has additionally been found to decrease serotonergic activity. Selegiline's metabolite desmethylselegiline has also been found to be active as a CAE. Aside from selegiline and its metabolites, D-deprenyl is a CAE, with slightly lower potency than selegiline. By extension to selegiline and D-deprenyl, the

racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

form, deprenyl, is a CAE. A

halogenated In chemistry, halogenation is a chemical reaction which introduces one or more halogens into a chemical compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, drugs ...

analogue of deprenyl, 4-fluorodeprenyl, has been found to act as a CAE as well. The

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

(both

levoamphetamine Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination drug, combination with dextroam ...

and

dextroamphetamine Dextroamphetamine (international nonproprietary name, INN: dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narc ...

) and

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

(both

levomethamphetamine Levomethamphetamine (International Nonproprietary Name, INN: levmetamfetamine) is an optical isomer of methamphetamine primarily used as a Topical decongestant, topical nasal decongestant. Levomethamphetamine is used to treat nasal congestion f ...

and

dextromethamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational or performance-enhancing drug and less commonly as a second-line treatment for attention deficit hyperactivity di ...

) are CAEs like selegiline, but these drugs are also potent

s and these actions overshadow the former activities. Levomethamphetamine, levoamphetamine, and dextroamphetamine are all similarly potent as CAEs and compared to selegiline, but are substantially more potent as CAEs than dextromethamphetamine. Besides acting as CAEs, levomethamphetamine and dextromethamphetamine diminish serotonergic activity, similarly to selegiline, whereas levoamphetamine and dextroamphetamine do not do so. Phenylpropylaminopentane (PPAP) is a CAE for norepinephrine and dopamine that was derived from selegiline and is a phenethylamine derivative. In contrast to selegiline, it lacks monoamine oxidase inhibition and hence is much more selective in its actions. Indolylpropylaminopentane (IPAP) is a MAE for serotonin, norepinephrine, and dopamine that was derived from PPAP and is a tryptamine derivative. It shows some selectivity for serotonin, with its maximal impact on this neurotransmitter occurring at 10-fold lower concentrations than for norepinephrine or dopamine. Benzofuranylpropylaminopentane (BPAP) is a MAE for serotonin, norepinephrine, and dopamine that was derived from PPAP and is related to tryptamine. It is about 130times more potent in its MAE actions than selegiline. Similarly to selegiline, BPAP shows a bimodal concentration–response relationship in its MAE effects. In contrast to selegiline,

and its metabolite (''R'')-1-aminoindan do not have MAE actions. Similarly, SU-11739 (AGN-1133; J-508), the ''N''-

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...

ated analogue of rasagiline and a closer analogue of selegiline, does not have MAE actions.

Mechanism of action

The

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

of MAEs, for instance the trace amines, may be explained by their shared affinities for the

(TAAR1). Trace amines like β-phenylethylamine and tyramine bind to the TAAR1 with high affinity, whereas the affinities of other monoamines like

octopamine Octopamine (OA), also known as ''para''-octopamine and norsynephrine among synonyms, is an organic chemical closely related to norepinephrine, and synthesized biologically by a homologous pathway. Octopamine is often considered the major "fig ...

, dopamine, and serotonin for this receptor are much lower. In addition, recent findings have suggested that known

MAEs like BPAP and selegiline may exert their effects via TAAR1 activation. This was evidenced by the TAAR1 antagonist EPPTB reversing their MAE effects, among other findings. However, in an older study of

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

, no non-MAO binding of

radiolabel A radioactive tracer, radiotracer, or radioactive label is a synthetic derivative of a natural compound in which one or more atoms have been replaced by a radionuclide (a radioactive atom). By virtue of its radioactive decay, it can be used to exp ...

ed selegiline was detected in the brain, suggesting that this agent might not act directly via a

macromolecular A macromolecule is a "molecule of high relative molecular mass, the structure of which essentially comprises the multiple repetition of units derived, actually or conceptually, from molecules of low relative molecular mass." Polymers are physi ...

target in terms of its MAE effects. MAEs require

transport Transport (in British English) or transportation (in American English) is the intentional Motion, movement of humans, animals, and cargo, goods from one location to another. Mode of transport, Modes of transport include aviation, air, land tr ...

into

monoaminergic Monoaminergic means "working on monoamine neurotransmitters", which include serotonin, dopamine, norepinephrine, epinephrine, and histamine. A monoaminergic, or monoaminergic drug, is a chemical, which functions to directly modulate the seroton ...

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s by

monoamine transporter Monoamine transporters (MATs) are proteins that function as integral Cell membrane, plasma-membrane Neurotransmitter transporter, transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are se ...

s (MATs) like the

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

(DAT). Hence, they must be

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

s of these transporters in order to exert their MAE effects. This may be due to the fact that the TAAR1 is located

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

ly within neurons. Transport by MATs into monoaminergic neurons is similarly required for the releasing effects of

s (MRAs) like

. The TAAR1 may also be involved in the releasing effects of MRAs as with MAEs. It has been proposed that there may be two distinct

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

s on the TAAR1, one for MAEs and one for MRAs. MAEs are thought to induce action potential-dependent vesicular monoamine release via TAAR1 activation, whereas MRAs are thought to induce impulse-independent non-vesicular monoamine release via TAAR1 activation. However, there are conflicting findings with regard to the involvement of TAAR1 activation in the monoamine-releasing actions of MRAs, such as TAAR1 activation and signaling inhibiting the psychostimulant and reinforcing effects of MRAs, MRAs continuing to induce monoamine release in TAAR1 knockout mice, and many MRAs, including most

cathinone Cathinone (; also known as β-ketoamphetamine) is a monoamine alkaloid found in the shrub ''Catha edulis'' (khat) and is chemically similar to ephedrine, cathine, methcathinone and other amphetamines. It is probably the main contributor to t ...

s, being inactive as agonists of the human TAAR1. As with MRAs like amphetamine and

s like

, single acute doses of MAEs rapidly increase brain monoamine levels. However, MAEs have more limited impacts on brain monoamine levels compared to MRAs and monoamine reuptake inhibitors. In an ''

'' rodent study, BPAP was found to maximally increase dopamine levels in the

by 44%, in the

by 118%, and in the

by 57%; norepinephrine levels in the

by 228%; and serotonin levels in the

by 166%. The maximal impacts of other MAEs like

on brain monoamine levels are similar. For comparison, the

norepinephrine–dopamine releasing agent A norepinephrine–dopamine releasing agent (NDRA) is a type of drug which induces the synapse, release of norepinephrine (and epinephrine) and dopamine in the body and/or brain. Many of these are amphetamine type stimulants. Examples Examples ...

amphetamine increases dopamine levels in the striatum by 700 to 1,500% of baseline and norepinephrine levels in the

prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...

by 400 to 450% of baseline. However, there appears to be no dose–effect

ceiling A ceiling is an overhead interior roof that covers the upper limits of a room. It is not generally considered a structural element, but a finished surface concealing the underside of the roof structure or the floor of a story above. Ceilings can ...

with this agent and it can maximally increase striatal dopamine levels by more than 5,000% of baseline at higher doses. Monoamine reuptake inhibitors including methylphenidate,

atomoxetine Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndr ...

bupropion Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant that is indicated in the treatment of major depressive disorder, seasonal affective disorder, and to support smo ...

, and

vanoxerine Vanoxerine is an investigational drug which is being evaluated for the treatment of heart arrhythmias and cocaine dependence. Vanoxerine is a piperazine derivative which has multiple pharmacological activities including acting as an dopamine re ...

(GBR-12909) also robustly increase brain monoamine levels in rodents, though the maximal impacts of these agents are much smaller (e.g., 5- to 10-fold lower) than those of releasers like amphetamine. MAEs like PPAP and BPAP have been found to increase locomotor activity, increase stereotyped behavior, facilitate

learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, Attitude (psychology), attitudes, and preferences. The ability to learn is possessed by humans, non-human animals, and ...

and retention, and produce

-like effects in rodent studies. In relation to these effects, they have been described as having

-like effects. The locomotor stimulant effect of BPAP has been shown to be dependent on enhancement of

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

signaling. In contrast to PPAP and BPAP, as well as in contrast to

s, selegiline does not appear to stimulate locomotor activity and lacks psychostimulant-like effects in rodents. Accordingly, selegiline has been reported to not activate the mesolimbic dopamine pathway in rodents.

Antagonists

Antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. For example, 3-F-BPAP, a

of BPAP, antagonizes the MAE actions of BPAP. However, it does not antagonize the MAE actions of selegiline or PPAP. EPPTB, a TAAR1 antagonist, has been found to reverse the MAE actions of both BPAP and selegiline. Likewise,

has been found to reverse the MAE actions of selegiline and has been proposed as a possible TAAR1 antagonist.

Monoaminergic activity enhancers versus other monoaminergic drugs

József Knoll, the developer of the MAEs, was interviewed by David Healy in 2000 about his work and about MAEs. In the interview, Healy asked Knoll the question of why MAEs should be preferred for increasing

signaling and enhancing

drive Drive or The Drive may refer to: Motoring * Driving, the act of controlling a vehicle * Road trip, a journey on roads Roadways Roadways called "drives" may include: * Driveway, a private road for local access to structures, abbreviated "drive" * ...

over other monoaminergic drugs, including

s such as

s, monoamine

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

s, and direct

monoamine receptor A monoamine receptor is a receptor for the monoamine neurotransmitters and/or trace amines, endogenous small-molecule signaling molecules with a monoamine structure. The monoamine receptors are almost all G protein-coupled receptors, with the se ...

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s. Knoll answered that other monoaminergic agents create an artificial, unphysiological, and abnormal situation in the brain that has substantial accompanying

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s and problems, for instance triggering of homeostatic compensation mechanisms. In contrast, Knoll maintained that MAEs simply augment normal and physiological monoaminergic signaling by increasing the amount of

released per

. He described this as very similar to how the brain situation-dependently regulates its own monoaminergic activity and stated that it is simply a matter of shifting the normal physiological range to allow for a higher level of activity and consequent behavioral performance. On the basis of these arguments, Knoll claimed that MAEs are theoretically better- tolerated,

safer Safer or SAFER may refer to: * FSO ''Safer'', a Yemeni floating oil storage and offloading vessel * Safer (surname) * Safar or safer, the second month of the Islamic calendar * As an acronym: ** SAFER, an initiative of the World Health Organizat ...

, and less tolerance-forming than other monoaminergic drugs.

Enhancer regulation system and age-related changes

An endogenous enhancer regulation system for

s has been proposed to exist in which so-called enhancer substances can potentiate the

-evoked release of

s in a variety of

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

areas. This has also been referred to as the "mesencephalic enhancer regulation" system to emphasize the key importance of dopaminergic neurons and their modulation of behavior in this system. However, enhancer-sensitive neurons are also present outside of the

mesencephalon The midbrain or mesencephalon is the uppermost portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum. It is functionally associated with vision, hearing, mo ...

(midbrain) and activity enhancers can affect

noradrenergic Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone, neurotransmitter and neuromodulator. The name "noradrenaline" (from L ...

and serotonergic neurons as well. Enhancer effects have even been observed in the

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...

. The enhancer regulation system has been theorized to play an important role in dynamically controlling innate and acquired drives and mediating age-related changes in goal-directed behavioral activity. The concept of this system was created and advanced by the developers of

, including József Knoll and Ildikó Miklya. Endogenous enhancer substances like

and

are known, but are of relatively low

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...

. The key endogenous actors in the enhancer regulation system have been hypothesized to be much more potent but have not been identified. Rodents are much more behaviorally and motivationally active in the late developmental phase of life (2months) than in the early post-developmental phase (4months). This has been specifically quantified with orienting-searching reflex activity induced by hunger. Male rats are

weaned Weaning is the process of gradually introducing an infant human or other mammal to what will be its adult diet while withdrawing the supply of its mother's milk. In the UK, weaning primarily refers to the introduction of solid foods at 6 mont ...

at about 3weeks of age and complete

sexual development Puberty is the process of physical changes through which a child's Human body, body matures into an adult body capable of sexual reproduction. It is initiated by hormone, hormonal signals from the Human brain, brain to the gonads: the ovary ...

by 2months of age. Subsequent research found that brain monoamine release is much higher during the developmental phase (4weeks of age) compared to prior to weaning (2weeks of age) or following sexual maturity (16–32weeks of age). This has included dopamine release in the

, and

; norepinephrine release in the

; and serotonin release in the

. Serotonin release was 6- to 7-fold higher at 4weeks of age compared to 2weeks of age, whereas dopamine and norepinephrine release in their respective areas was around 2-fold higher relative to pre-weaning and post-sexual maturity. In addition, monoamine release progressively declines with age going from 4weeks to 32weeks. The higher behavioral activity of rodents at 2months of age compared to before or after this age has been attributed to greater activity of the brain catecholaminergic system at this time. As previously described, brain monoamine release begins to rapidly decrease with sexual maturity in rodents. This suggests that

sex hormone Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...

s and the onset of their

production Production may refer to: Economics and business * Production (economics) * Production, the act of manufacturing goods * Production, in the outline of industrial organization, the act of making products (goods and services) * Production as a stat ...

may dampen brain monoamine release. Accordingly, brain monoamine release was found to be significantly higher in prepubertally castrated rats at 3months of age compared to non-castrated controls. In addition, treatment of 3-week-old prepubertal rats for 2weeks with

exogenous In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It is the opposite of endogeneity or endogeny, the fact of being influenced from within a system. Economics In an economic model, an ...

sex hormones, including the

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

or the

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

estrone Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...

, though not

progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

, significantly and rapidly reduced brain monoamine release relative to untreated controls. Similarly, sexual activity following sexual maturity substantially declines with age in both male rodents and humans. This is thought to be due to age-related decreased activity of the brain dopaminergic system. It is known that brain levels of phenethylamine, a known endogenous enhancer substance, decline with age. This may be due to progressively increased levels of

with age. Decreased levels of phenethylamine may contribute to reduced activation of the enhancer regulation system and reduced brain catecholamine release with age. However, the key endogenous actors of the enhancer regulation system have been theorized to be more potent than phenethylamine but have yet to be identified. It has been hypothesized that highly potent enhancer substances may exist that may be able to rapidly modulate the activity of brain catecholaminergic neurons by as much as 5- to 10-fold to quickly control time-dependent motivational states. However, such mediators remain speculative and have not been discovered or substantiated as of present. Rodent studies have found that exogenous MAEs like selegiline and BPAP augment brain monoamine release, slow monoaminergic neurodegeneration, and help to preserve behavioral activity with age. As an example, selegiline has been found to augment sexual performance and delay its age-related decline in rodents. It has been proposed that exogenous MAEs like selegiline might be able to modestly slow the age-related decay of brain monoamine release in humans, although such hypotheses have yet to be tested.

Medical use

is currently the only MAE without concomitant potent

actions that is available for medical use. It is also a selective

and is used in the treatment of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

and depression. According to József Knoll, one of the original developers of selegiline, the CAE effects of selegiline may be more important than MAO-B inhibition in terms of its effectiveness for Parkinson's disease. This is consistent with clinical findings that selegiline may be more effective in the treatment of Parkinson's disease than

. Selective MAEs have been proposed for potential medical use in the treatment of a variety of conditions. These include

psychiatric disorder A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

s like depression and

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD) as well as

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...

s like Parkinson's disease and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. There has also been theoretical interest in MAEs as potential antiaging agents that might help to oppose age-related catecholaminergic

neurodegeneration A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their cell death, death. Neurodegenerative diseases include amyotrophic lateral sc ...

and prolong lifespan, though such ideas have not been tested. Benzofuranylpropylaminopentane (BPAP) in particular has been proposed for potential clinical development. However, no other MAEs besides selegiline have been developed for medical use as of present.

Amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

, and likely other

substituted amphetamine Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...

s are MAEs, but their MAE effects are overshadowed and complicated by their concomitant potent

activities.

List of monoaminergic activity enhancers

Endogenous

Phenylethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine ...

Tryptamine 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 (third aromatic atom, with the firs ...

Tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the bl ...

Synthetic

* BPAP * PPAP * IPAP * MPAP * NPAP * Deprenyl **

(L-deprenyl) ** D-Deprenyl * Desmethylselegiline * 4-Fluorodeprenyl *

Dextroamphetamine Dextroamphetamine (international nonproprietary name, INN: dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narc ...

Levoamphetamine Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination drug, combination with dextroam ...

Methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

Dextromethamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational or performance-enhancing drug and less commonly as a second-line treatment for attention deficit hyperactivity di ...

Levomethamphetamine Levomethamphetamine (International Nonproprietary Name, INN: levmetamfetamine) is an optical isomer of methamphetamine primarily used as a Topical decongestant, topical nasal decongestant. Levomethamphetamine is used to treat nasal congestion f ...

Antagonists

* 3-F-BPAP * EPPTB *

Rasagiline Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advan ...

References

{{Monoaminergic activity enhancers Neurophysiology Selegiline Trace amines

Endogenous monoaminergic activity enhancers

Monoaminergic activity enhancing drugs

Mechanism of action

Antagonists

Monoaminergic activity enhancers versus other monoaminergic drugs

Enhancer regulation system and age-related changes

Medical use

List of monoaminergic activity enhancers

Endogenous

Synthetic

Antagonists

See also

References