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Monoamine neurotransmitter
Monoamine neurotransmitter
Monoamine neurotransmitter
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Dopamine
Norepinephrine
Serotonin

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 are derived from aromatic amino acids like phenylalanine, tyrosine, and tryptophan by the action of aromatic amino acid decarboxylase enzymes. They are deactivated in the body by the enzymes known as monoamine oxidases which clip off the amine group.

Monoaminergic systems, i.e., the networks of neurons that use monoamine neurotransmitters, are involved in the regulation of processes such as emotion, arousal, and certain types of memory. It has also been found that monoamine neurotransmitters play an important role in the secretion and production of neurotrophin-3 by astrocytes, a chemical which maintains neuron integrity and provides neurons with trophic support.[1]

Drugs used to increase or reduce the effect of monoamine neurotransmitters are used to treat patients with psychiatric and neurological disorders, including depression, anxiety, schizophrenia and Parkinson's disease.[2]

Examples

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Biosynthetic pathways for catecholamines and trace amines in the human brain[3][4][5]
Graphic of catecholamine and trace amine biosynthesis
The image above contains clickable links
Phenethylaminergic trace amines and the catecholamines are derivatives of L-phenylalanine.
Part of this section is transcluded from Trace amine. (edit | history)
Classical monoamines
Trace amines

Specific transporter proteins called monoamine transporters that transport monoamines in or out of a cell exist. These are the dopamine transporter (DAT), serotonin transporter (SERT), and the norepinephrine transporter (NET) in the outer cell membrane and the vesicular monoamine transporter (VMAT1 and VMAT2) in the membrane of intracellular vesicles.[citation needed]

After release into the synaptic cleft, monoamine neurotransmitter action is ended by reuptake into the presynaptic terminal. There, they can be repackaged into synaptic vesicles or degraded by the enzyme monoamine oxidase (MAO), which is a target of monoamine oxidase inhibitors, a class of antidepressants.[citation needed]

Evolution

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A phylogenetic tree showing how a number of monoamine receptors are related to each other.

Monoamine neurotransmitter systems occur in virtually all vertebrates, where the evolvability of these systems has served to promote the adaptability of vertebrate species to different environments.[12][13]

A recent computational investigation of genetic origins shows that the earliest development of monoamines occurred 650 million years ago and that the appearance of these chemicals, necessary for active or participatory awareness and engagement with the environment, coincides with the emergence of bilaterian or "mirror" body in the midst of (or perhaps in some sense catalytic of?) the Cambrian Explosion.[14]

See also

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References

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Monoamine neurotransmitter

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Monoamine neurotransmitters are a class of biogenic amine signaling molecules that act as chemical messengers within the nervous system, distinguished by their structure featuring a single amine group (-NH₂) connected to an aromatic ring via a two-carbon chain. Derived primarily from aromatic amino acids through enzymatic processes, they include catecholamines such as dopamine and norepinephrine (synthesized from tyrosine), indolamines like serotonin (derived from tryptophan), and the imidazoleamine histamine (from histidine). These compounds are synthesized in specific neuronal populations, stored in synaptic vesicles via transporters like the vesicular monoamine transporter 2 (VMAT2), and released into synapses to bind G-protein-coupled receptors, thereby modulating neuronal excitability and circuit activity. The functions of monoamine neurotransmitters are diverse and integral to brain physiology, influencing processes ranging from and to autonomic regulation. , primarily acting in mesolimbic and nigrostriatal pathways, governs reward motivation, motor control, and executive functions, with deficiencies linked to conditions like . Norepinephrine, released from the , enhances , , and the stress response, contributing to vigilance and adaptive behaviors during "fight-or-flight" scenarios. Serotonin, originating from , stabilizes mood, regulates sleep-wake cycles, , and gastrointestinal , and its dysregulation is central to affective disorders such as depression. , produced in the , promotes , modulates allergic responses, and influences learning and . Imbalances in monoamine underlie numerous neuropsychiatric and neurological disorders, making these systems key targets for pharmacological interventions. For instance, selective serotonin reuptake inhibitors (SSRIs) elevate synaptic serotonin to alleviate depression symptoms, while agonists treat Parkinson's by compensating for nigral cell loss. Ongoing research continues to elucidate their interactions with , the gut-brain axis, and other systems, highlighting their role in orchestrating complex behaviors and emotional states.

Overview and Classification

Definition

Monoamine neurotransmitters are a class of biogenic amines that function as chemical messengers in the , enabling interneuronal communication through synaptic transmission. These compounds are derived from single aromatic —tyrosine (for catecholamines), (for serotonin), or (for )—each featuring a single group (-NH₂) that imparts their characteristic biochemical properties. Their core structure consists of an aromatic ring attached to an side chain, generally following the Ar-CH₂-CH₂-NH₂ (where Ar represents the aromatic ring), with minor variations such as additional hydroxyl groups in catecholamines like or the ring in serotonin. This structural configuration allows monoamines to be stored in synaptic vesicles and released via in response to action potentials, distinguishing their in neural signaling. Unlike neurotransmitters (e.g., glutamate or GABA), which are unmodified acting primarily as fast ionotropic signals, or neurotransmitters formed by chains of that often serve modulatory roles, monoamines are small organic molecules that typically engage G-protein-coupled receptors for slower, modulatory effects on postsynaptic excitability. Gaseous neurotransmitters like , by contrast, are non-stored diffusible signals without vesicular release. This positions monoamines as a unique subclass emphasizing vesicular storage and targeted synaptic release for . The identification of monoamine neurotransmitters began in the early with the isolation of adrenaline (epinephrine) from adrenal glands in 1901 by Jokichi Takamine, initially recognized for its hormonal effects but later linked to neural functions. Noradrenaline (norepinephrine) was established as a key neurotransmitter in the by Ulf von Euler in 1946 through extraction from adrenergic nerves, providing foundational evidence for their role in chemical synaptic transmission.

Types and Examples

Monoamine neurotransmitters are broadly classified into catecholamines and , with frequently grouped alongside them due to its similar and function, despite deriving from a different precursor. Catecholamines, derived from , encompass (DA; 3,4-dihydroxyphenethylamine), norepinephrine (NE; also known as noradrenaline, 4-(2-amino-1-hydroxyethyl)benzene-1,2-diol), and epinephrine (E; also known as adrenaline, 4-[(1R)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol). is primarily synthesized by dopaminergic neurons in the of the . Norepinephrine is mainly produced by noradrenergic neurons in the of the . Epinephrine, while predominantly functioning as a from the , is synthesized in limited sites, including sparse neuronal groups expressing phenylethanolamine N-methyltransferase. Indolamines, derived from , are represented by serotonin (5-HT; 5-hydroxytryptamine, 3-(2-aminoethyl)-1H-indol-5-ol), which is primarily synthesized in serotonergic neurons of the spanning the . (2-(1H-imidazol-4-yl)ethanamine), derived from , is classified as a monoamine and synthesized exclusively by histaminergic neurons in the of the posterior .

Biosynthesis and Metabolism

Synthesis Pathways

Monoamine neurotransmitters are synthesized from specific precursors through enzymatic pathways primarily occurring in the neuronal . The catecholamines (, norepinephrine, and epinephrine) derive from L-tyrosine, serotonin from L-tryptophan, and from L-histidine. These pathways involve rate-limiting steps and , with subsequent modifications for certain monoamines. The biosynthesis of dopamine begins with L-tyrosine, which is hydroxylated to L-3,4-dihydroxyphenylalanine (L-DOPA) by the enzyme tyrosine hydroxylase (TH), the rate-limiting step requiring tetrahydrobiopterin (BH4) as a cofactor. L-DOPA is then decarboxylated to dopamine by aromatic L-amino acid decarboxylase (AADC), also known as DOPA decarboxylase, which uses pyridoxal phosphate (vitamin B6) as a cofactor. TH activity is tightly regulated by phosphorylation via calcium- and cAMP-dependent kinases, as well as by feedback inhibition from catecholamines and transcriptional control. Norepinephrine synthesis extends from dopamine, where dopamine β-hydroxylase (DBH) converts to norepinephrine in a reaction dependent on ascorbic acid () and as cofactors. This occurs within synaptic vesicles due to DBH localization. Epinephrine is further produced from norepinephrine by phenylethanolamine N-methyltransferase (PNMT), which transfers a using S-adenosylmethionine as a cofactor; PNMT expression is induced by glucocorticoids in the . Serotonin (5-hydroxytryptamine) is synthesized from , which crosses the blood-brain barrier via the large neutral transporter and is hydroxylated to 5-hydroxytryptophan (5-HTP) by (TPH), the rate-limiting enzyme also requiring BH4. 5-HTP is then decarboxylated to serotonin by AADC, utilizing . TPH regulation depends on availability from diet and , with TPH2 isoform predominant in the . Histamine biosynthesis involves the decarboxylation of L-histidine to by (HDC), a pyridoxal phosphate-dependent enzyme. This single-step pathway occurs in histaminergic neurons of the , with HDC regulation less understood but influenced by neuronal activity. Following synthesis, monoamines are packaged into synaptic vesicles by vesicular monoamine transporters (VMAT1 and VMAT2), proton-dependent antiporters that sequester cytosolic monoamines using a vesicle proton gradient established by . VMAT2 predominates in the , ensuring storage and protection from degradation.

Degradation Mechanisms

The degradation of monoamine neurotransmitters primarily occurs after their into presynaptic neurons via specific transporters for catecholamines and serotonin, which serves as the initial step in terminating synaptic signaling and preparing the molecules for enzymatic breakdown. The (NET), (DAT), and (SERT) facilitate this reuptake; NET primarily handles norepinephrine, DAT targets dopamine, and SERT manages serotonin, thereby concentrating the monoamines intracellularly for subsequent . A key in intraneuronal degradation is (MAO), a flavin-containing bound to the outer mitochondrial membrane that catalyzes the oxidative of monoamines, producing corresponding aldehydes, , and as byproducts. MAO exists in two isoforms: MAO-A, which exhibits higher affinity for serotonin and norepinephrine, and MAO-B, which preferentially metabolizes phenylethylamine and, to a lesser extent in humans, . This isoform-specific substrate selectivity helps regulate the turnover rates of different monoamines, with MAO activity preventing excessive accumulation that could lead to from reactive intermediates. In parallel, (COMT) contributes to the degradation of catecholamines such as and norepinephrine through extraneuronal , adding a to one of the hydroxyl groups on the ring using S-adenosylmethionine as the methyl donor. Unlike the intraneuronal MAO, COMT is predominantly expressed in non-neuronal tissues and glial cells, acting on extracellular or reuptake-resistant catecholamines to form methylated metabolites like 3-methoxytyramine from . This process complements MAO by providing an alternative catabolic route, particularly in peripheral tissues. The aldehydes generated by MAO, such as 3,4-dihydroxyphenylacetaldehyde (DOPAL) from , are further metabolized by (ALDH) enzymes to less reactive carboxylic acids, mitigating potential cellular damage from these toxic intermediates. ALDH, including isoforms like ALDH1A1 (cytosolic) and (mitochondrial), catalyzes this NAD(P)+-dependent oxidation, converting DOPAL to 3,4-dihydroxyphenylacetic acid (DOPAC) in neurons. Impaired ALDH function can lead to aldehyde buildup, contributing to . For , termination of signaling occurs primarily through diffusion and low-affinity uptake via organic cation transporters (e.g., OCT3), rather than high-affinity , followed by intracellular degradation mainly by histamine N-methyltransferase (HNMT), which methylates to N-tele-methylhistamine using S-adenosylmethionine. This metabolite is then oxidized by MAO-B to N-methylimidazoleacetic acid. Extracellularly, (DAO) can oxidize to imidazole-4-acetaldehyde, which is further processed to imidazole-4-acetic acid. These pathways regulate histaminergic tone in the CNS, with HNMT predominant in the . The major end metabolites of these degradation pathways include homovanillic acid (HVA) from (via sequential MAO, ALDH, and COMT action), (5-HIAA) from serotonin (primarily via MAO and ALDH), (VMA) from norepinephrine (involving MAO, ALDH, and COMT), and N-methylimidazoleacetic acid from . These metabolites are often measured in or as biomarkers of monoamine turnover, reflecting the overall balance of synthesis and degradation in the .

Physiological Functions

Roles in the Central Nervous System

Monoamine neurotransmitters play critical roles in modulating various functions within the (CNS), influencing regions involved in emotion, cognition, and behavior. These molecules, including , serotonin, norepinephrine, and , are synthesized from precursors and released from specific neuronal clusters to exert widespread effects through diffuse projections. Dopamine, originating primarily from the ventral tegmental area (VTA) and , operates via distinct pathways in the CNS. The projects to the and is central to reward processing and , facilitating behaviors associated with pleasure and . The , extending to the dorsal , regulates by modulating circuits, ensuring coordinated movement and habit formation. Additionally, the innervates the , supporting such as , , and decision-making. Serotonin, produced in the of the , exerts influence through extensive projections to limbic structures like the and hippocampus. These connections are essential for mood regulation, promoting emotional stability and inhibiting impulsive responses. Serotonergic neurons also contribute to the orchestration of sleep-wake cycles by modulating states across cortical and subcortical regions. Furthermore, serotonin impacts control via hypothalamic pathways, balancing signals and to influence feeding behavior. Norepinephrine, synthesized in the (LC), provides broad innervation to the and , enhancing overall CNS vigilance. LC projections to the cortex and drive and , optimizing and task-oriented focus during demanding situations. This system is also pivotal in the stress response, amplifying sympathetic activation to mobilize resources for threat detection and adaptive coping. Histamine neurons, located exclusively in the (TMN) of the posterior , promote through projections to the cortex, , and other arousal centers. TMN activity peaks during alert states, suppressing sleep-promoting circuits to maintain consciousness. further synchronizes circadian rhythms by interacting with the , aligning daily physiological cycles with environmental cues. Beyond individual actions, monoamines interact to fine-tune excitatory-inhibitory balance in the CNS, particularly by modulating glutamate and GABA transmission. For instance, serotonin and norepinephrine can enhance or suppress excitability in cortical networks, while influences in striatal circuits, collectively stabilizing neural activity for .

Roles in the Peripheral Nervous System

Monoamine neurotransmitters exert significant influence in the peripheral nervous system (PNS), primarily through the autonomic and enteric nervous systems, where they modulate visceral functions such as cardiovascular , gastrointestinal , and immune responses. Unlike their roles in the , peripheral monoamines often act as both neurotransmitters and hormones, released from neurons, chromaffin cells, and non-neuronal sources to maintain . Norepinephrine serves as the primary neurotransmitter of postganglionic sympathetic neurons, facilitating the "fight-or-flight" response by binding to adrenergic receptors on target organs. It induces in arterioles of the skin, abdominal viscera, and kidneys via alpha-1 receptors, redirecting blood flow to skeletal muscles and vital organs. Additionally, norepinephrine increases and contractility through beta-1 receptors on cardiac tissue, enhancing overall during stress. Epinephrine, released from the in response to sympathetic preganglionic stimulation, amplifies these effects systemically; it promotes in the liver and further elevates via beta-2 receptors, preparing the body for acute physical demands. Dopamine functions peripherally in the renal and gastrointestinal systems, acting as a local modulator rather than a direct sympathetic transmitter. In the kidneys, dopamine synthesized in cells activates D1-like receptors to increase renal blood flow and promote by reducing and enhancing sodium excretion, thereby supporting . In the , dopamine regulates gastrointestinal motility through D2 receptors in the , inhibiting and secretion to fine-tune digestive processes. Serotonin, predominantly produced in the periphery, plays a crucial role in and gut function. Approximately 95% of the body's serotonin is synthesized by enterochromaffin cells in the intestinal mucosa, where it stimulates 5-HT3 and 5-HT4 receptors to enhance gut , intestinal , and colonic tone, facilitating and absorption. In the vascular system, serotonin stored in platelet granules is released during injury to promote platelet aggregation via 5-HT2A receptors, aiding clot formation and at injury sites. Histamine, while not exclusively neuronal in the PNS, is released from mast cells and enterochromaffin-like cells to mediate local responses. It stimulates secretion by binding to H2 receptors on parietal cells in the , increasing cyclic AMP to activate proton pumps and support . In allergic contexts, from degranulated mast cells acts on H1 receptors to induce , increased , and contraction in peripheral tissues, contributing to inflammatory defense mechanisms. In the , monoamines like norepinephrine and epinephrine are central to sympathetic activation, promoting excitatory responses such as arousal and energy mobilization, whereas serotonin and predominate in the , which interfaces with parasympathetic inputs to modulate inhibitory and propulsive gut activities. This division underscores their selective contributions to sympathetic versus parasympathetic balance in peripheral regulation.

Receptors and Signaling

Receptor Types

Monoamine neurotransmitters interact with a variety of receptor subtypes, primarily belonging to the G-protein-coupled receptor (GPCR) superfamily, with one exception being the 5-HT3 serotonin receptor. These receptors are classified based on their pharmacological properties, signaling mechanisms, and anatomical distributions, enabling diverse physiological responses. The main families correspond to , serotonin (5-HT), norepinephrine/epinephrine (adrenergic), and . Dopamine receptors are divided into two main subfamilies: D1-like (D1 and D5) and D2-like (D2, D3, and D4). The D1-like receptors couple to Gs proteins, leading to excitatory effects via increased cyclic AMP (cAMP) production, and are predominantly postsynaptic. In contrast, D2-like receptors couple to Gi/o proteins, resulting in inhibitory effects through decreased cAMP, and often function as presynaptic autoreceptors to regulate dopamine release. These subtypes are highly expressed in the (CNS), particularly in the and , with D1-like receptors more abundant in direct pathway medium spiny neurons and D2-like in indirect pathways. Serotonin receptors comprise seven families (5-HT1 through 5-HT7), with most being GPCRs, except for the , which is a permeable to cations like sodium and calcium. The 5-HT1 family (subtypes 5-HT1A, 1B, 1D, 1E, 1F) generally couples to Gi/o proteins for inhibitory signaling; for instance, the acts as a presynaptic in to inhibit serotonin release, while postsynaptic 5-HT1A modulates anxiety-related behaviors. The 5-HT2 family (2A, 2B, 2C) couples to Gq/11 for excitatory activation, with 5-HT2A being a key target for hallucinogenic effects due to its role in cortical pyramidal neurons. Other families include 5-HT4, 5-HT6, and 5-HT7 (Gs-coupled, excitatory) and 5-HT3 (ionotropic, excitatory). Serotonin receptors are distributed across both CNS (e.g., hippocampus, cortex) and (PNS), including gastrointestinal and cardiovascular tissues. Adrenergic receptors, activated by norepinephrine and epinephrine, are classified into alpha and beta subfamilies. Alpha-1 receptors (subtypes α1A, α1B, α1D) couple to Gq proteins, mediating excitatory responses via calcium mobilization, and are primarily postsynaptic in vascular smooth muscle. Alpha-2 receptors (α2A, α2B, α2C) couple to Gi/o for inhibitory effects, often presynaptic to inhibit norepinephrine release. Beta receptors (β1, β2, β3) couple to Gs proteins for stimulatory cAMP elevation; β1 predominates in cardiac tissue, β2 in bronchial and vascular smooth muscle, and β3 in adipose tissue. These receptors are widespread in the PNS, particularly in sympathetic nervous system targets like heart and blood vessels, with significant CNS expression in areas such as the locus coeruleus. Histamine receptors include four subtypes, all GPCRs. The H1 receptor couples to for excitatory signaling, playing a central role in allergic responses and contraction, and is postsynaptic in endothelial and neuronal cells. H2 couples to Gs for cAMP increase, primarily in gastric parietal cells to stimulate acid secretion. H3 receptors couple to Gi/o for inhibition, functioning mainly as presynaptic autoreceptors in the CNS to regulate , , and serotonin release. H4 receptors also couple to Gi/o, mediating immune responses in and mast cells. are expressed in both CNS (e.g., H3 in ) and PNS (e.g., H1 in and gut), with H1 and H2 more peripheral and H3/H4 bridging central and immune functions.
NeurotransmitterReceptor Subfamily/SubtypesG-Protein CouplingKey Distribution Notes
DopamineD1-like (D1, D5)Gs (excitatory)Postsynaptic, mainly CNS ()
D2-like (D2, D3, D4)Gi/o (inhibitory)Presynaptic s, CNS ()
Serotonin (5-HT)5-HT1 (A/B/D/E/F)Gi/o (inhibitory)Presynaptic (5-HT1A , CNS raphe), postsynaptic CNS/PNS
5-HT2 (A/B/C)Gq/11 (excitatory)Postsynaptic, CNS cortex, PNS GI tract
5-HT3Postsynaptic, CNS/PNS (, gut)
5-HT4/6/7Gs (excitatory)Postsynaptic, CNS hippocampus, PNS heart
Norepinephrine/Epinephrine (Adrenergic)α1 (A/B/D)Gq (excitatory)Postsynaptic, PNS vascular
α2 (A/B/C)Gi/o (inhibitory)Presynaptic, PNS sympathetic nerves, CNS
β (1/2/3)Gs (stimulatory)Postsynaptic, PNS heart (β1), lungs (β2), CNS/PNS
H1Gq (excitatory)Postsynaptic, PNS ( sites), CNS ()
H2Gs (stimulatory)Postsynaptic, PNS
H3Gi/o (inhibitory)Presynaptic , CNS ()
H4Gi/o (inhibitory)Presynaptic/immune cells, PNS (), low CNS

Signal Transduction Pathways

Monoamine neurotransmitters primarily exert their effects through binding to G-protein-coupled receptors (GPCRs), which constitute the majority of monoamine receptors and initiate diverse intracellular signaling cascades via heterotrimeric G proteins. Upon ligand binding, the receptor undergoes a conformational change that promotes GDP-GTP exchange on the Gα subunit, leading to dissociation of the Gα and Gβγ subunits and activation of downstream effectors. The specific G protein subtype determines the signaling pathway: Gs-coupled receptors stimulate adenylyl cyclase to increase cyclic AMP (cAMP) levels, as seen in β-adrenergic and dopamine D1 receptors; Gi/o-coupled receptors inhibit adenylyl cyclase to decrease cAMP, exemplified by α2-adrenergic, dopamine D2, and serotonin 5-HT1 receptors; and Gq/11-coupled receptors activate phospholipase C (PLC) to generate inositol trisphosphate (IP3) and diacylglycerol (DAG), as in α1-adrenergic, serotonin 5-HT2, and histamine H1 receptors. Second messengers produced by these pathways propagate the signal intracellularly. Elevated cAMP activates (PKA), which phosphorylates target proteins to modulate , activity, and neuronal excitability. IP3 triggers calcium release from stores, while DAG recruits and activates (PKC), which in turn phosphorylates substrates involved in cytoskeletal reorganization and . Although most monoamine receptors are metabotropic GPCRs mediating slower, modulatory effects, an exception is the serotonin , an ionotropic that permits rapid influx of Na⁺ and Ca²⁺ (and efflux of K⁺) upon serotonin binding, facilitating fast excitatory postsynaptic potentials in the central and peripheral nervous systems. Presynaptic autoreceptors provide feedback regulation of monoamine release, typically via Gi/o-coupled mechanisms that inhibit neurotransmitter synthesis and exocytosis. For instance, dopamine D2 autoreceptors on dopaminergic terminals suppress dopamine release by reducing cAMP and opening potassium channels via Gβγ subunits. Prolonged agonist exposure leads to receptor desensitization, primarily through phosphorylation by G-protein-coupled receptor kinases (GRKs), such as GRK2 and GRK6 for dopamine receptors, which uncouples the receptor from G proteins. Phosphorylated receptors then recruit β-arrestins, which sterically hinder further G protein interaction and promote clathrin-mediated internalization, reducing surface receptor density and allowing for potential recycling or degradation to restore signaling sensitivity.

Clinical and Pharmacological Aspects

Associated Disorders

Dysregulation of monoamine neurotransmitters is implicated in several neurological and psychiatric disorders, where imbalances in dopamine, serotonin, norepinephrine, and contribute to pathological symptoms. In , the progressive degeneration of dopaminergic neurons in the results in significant depletion, which underlies motor impairments such as bradykinesia and rigidity. This loss disrupts the , leading to reduced availability in the . The monoamine hypothesis of depression and anxiety posits that deficits in serotonin and norepinephrine levels play a central role in the of these mood disorders. Low serotonergic activity is associated with depressive symptoms, while norepinephrine imbalances contribute to heightened and anxiety states. In , hyperactivity of transmission in the is a key feature, particularly linked to positive symptoms like hallucinations and delusions. Attention-deficit/hyperactivity disorder (ADHD) involves dysregulation of norepinephrine and in the , impairing such as attention and impulse control. Migraines are influenced by serotonin fluctuations, which modulate vascular tone and pain signaling, and histamine release, which can trigger neurogenic and attacks. In allergic reactions, acts as a primary mediator, promoting and itching, while serotonin contributes to platelet aggregation and in certain responses. (CSF) levels of monoamine metabolites, such as homovanillic acid (HVA) for and 5-hydroxyindoleacetic acid (5-HIAA) for serotonin, serve as biomarkers for assessing monoamine turnover in these disorders, with reduced levels often correlating with disease severity.

Therapeutic Interventions

Therapeutic interventions for disorders involving monoamine neurotransmitter dysregulation primarily rely on pharmacological agents that enhance synaptic availability or modulate receptor activity of serotonin, norepinephrine, and . These drugs target key regulatory steps in monoamine transmission, offering symptomatic relief in conditions such as depression, anxiety, , , and attention-deficit/hyperactivity disorder (ADHD). By increasing monoamine levels or altering their signaling, these interventions restore balance in dysregulated neural circuits, though their efficacy varies by disorder and individual factors. Reuptake inhibitors form a of treatment by blocking presynaptic transporters, thereby prolonging monoamine presence in the synaptic cleft. Selective serotonin reuptake inhibitors (SSRIs), such as , selectively antagonize the (SERT), elevating extracellular serotonin levels to alleviate symptoms of and anxiety. Serotonin-norepinephrine reuptake inhibitors (SNRIs) like inhibit both SERT and the (NET), providing dual enhancement of serotonergic and noradrenergic transmission for broader antidepressant effects in . For dopaminergic systems, (DAT) blockers such as inhibit DAT , increasing synaptic to improve and reduce impulsivity in ADHD. Monoamine oxidase (MAO) inhibitors target the degradative enzyme MAO, preventing breakdown of monoamines in neurons and glia to sustain their levels. Tranylcypromine, an irreversible non-selective MAOI, inhibits both MAO-A and MAO-B isoforms, boosting , , and availability for use in or depression. In contrast, selectively and irreversibly inhibits MAO-B, primarily preserving in the , making it a key adjunct in therapy to mitigate motor symptoms. Direct receptor modulation via agonists and antagonists addresses specific monoamine receptor subtypes. (levodopa), a direct precursor to , is decarboxylated in the to replenish depleted dopamine stores in , effectively reducing bradykinesia and rigidity despite peripheral side effects. D2 receptor antagonists like the haloperidol block postsynaptic D2 receptors in mesolimbic pathways, attenuating positive symptoms of by dampening excessive dopaminergic signaling. For noradrenergic modulation, beta-adrenergic receptor blockers such as propranolol antagonize β1 and β2 receptors, reducing peripheral and central effects of norepinephrine release to manage anxiety disorders and performance-related tremors. Release enhancers promote efflux of monoamines from presynaptic vesicles into the and . Amphetamines, including , induce reversal of the (VMAT-2), displacing stored monoamines like and norepinephrine for rapid release, which underlies their use in ADHD and but also contributes to abuse liability. A critical risk of these interventions, particularly when combining multiple serotonergic agents, is , a potentially fatal condition arising from excessive monoamine activity. This manifests as autonomic hyperactivity (e.g., , ), neuromuscular excitation (e.g., , ), and mental status changes (e.g., agitation, confusion), often triggered by interactions between SSRIs, SNRIs, MAOIs, or amphetamines. Careful monitoring and dose adjustments are essential to mitigate such adverse effects while optimizing therapeutic benefits.

Evolutionary Perspectives

Origins and Conservation

Monoamine synthesis enzymes, such as aromatic L-amino acid decarboxylases, have ancient origins predating multicellular life, appearing in and protists where they facilitate metabolic processes and rather than . In , these enzymes contribute to the production of biogenic amines involved in stress responses and cellular , while in unicellular protists like , decarboxylases synthesize monoamines that regulate , , and ciliary activity. These non-neuronal roles, which emerged over a billion years ago, indicate that monoamine-related biochemistry initially served fundamental cellular functions long before the . The core monoaminergic system, encompassing genes for synthesis, modulation, and reception, represents a bilaterian that arose in the common of bilaterians approximately 600–650 million years ago during the Cryogenian-Ediacaran transition. In early , such as planarians (flatworms), serotonin plays a pivotal role in locomotion and regenerative processes, highlighting its precursor functions in basic behavioral modulation within simple nervous systems. Similarly, in insects like contributes to reward-related learning and motivational behaviors, though often intertwined with signaling, demonstrating the system's adaptation for adaptive responses in more complex invertebrate neural circuits. These invertebrate systems exhibit conserved biosynthetic pathways, underscoring the stability of monoamine machinery across bilaterian phyla. In vertebrates, monoamine systems emerged with the chordate lineage, as evidenced by catecholamine pathways in basal vertebrates like lampreys, where they mediate , locomotion, and stress responses—functions that parallel those in higher vertebrates. Key evolutionary expansions occurred through events involving hydroxylases (e.g., and ), which diverged early in metazoan evolution around 500–600 million years ago, enabling specialized monoamine production from precursors like and . This duplication, observed in amphioxus and conserved in vertebrates, facilitated the diversification of catecholamine and indolamine pathways while maintaining high sequence similarity across phyla. Overall, the profound conservation of these pathways from to vertebrates reflects their fundamental role in neural modulation, with non-synaptic, non-neuronal functions persisting as vestiges of their pre-metazoan origins.

Comparative Neurobiology

In , monoamine systems exhibit specialized adaptations that parallel yet diverge from counterparts. In arthropods, functions as the primary analog to norepinephrine, serving as a neuromodulator in fight-or-flight responses, , and learning. For instance, in like , neurons innervate widespread circuits to enhance arousal and sensory-motor integration, with its biosynthetic pathway evolving alongside and norepinephrine in early bilaterians. , another key monoamine, acts as the neurotransmitter in insect visual systems; in honeybees, it is released by photoreceptors to transmit photic signals to postsynaptic elements in the lamina and medulla, enabling color and motion processing essential for foraging and navigation. These systems highlight monoamines' conserved role in sensory and behavioral modulation, albeit with phylum-specific transmitters replacing some ones. In basal vertebrates such as and amphibians, monoaminergic projections are generally simpler and more diffuse than in amniotes, originating from fewer, less segregated nuclei with broad innervations to the telencephalon, , and . For example, serotonergic and noradrenergic fibers in like show centralized raphe and locus coeruleus-like clusters that project bilaterally but lack the compartmentalized organization seen in mammals. Serotonin notably influences in these groups; in the fighting fish Betta splendens, elevation of serotonin via activation reduces conspecific , mirroring inhibitory effects observed across vertebrates and underscoring its role in social behavior regulation. This simpler architecture supports fundamental adaptive responses, such as stress coping and reproductive behaviors, with monoamines integrating environmental cues in less complex neural networks. Across vertebrates, certain monoamine structures remain highly conserved, while others show clade-specific expansions. The , the principal noradrenergic nucleus, is present in , amphibians, reptiles, birds, and mammals, providing diffuse projections to regions for and ; in non-mammalian forms like amphibians and , it comprises a comparable cluster of neurons with similar ascending and descending pathways, though with reduced cell numbers and less laminar specificity. In contrast, the dopamine-mediated mesolimbic reward system, homologous across all vertebrate classes, exhibits expansion in mammals relative to birds and reptiles; early vertebrates like and amphibians possess core components including projections to , but mammals display amplified innervation to expanded cortical areas, enhancing reward-driven learning and . Reptiles and birds retain intermediate complexity, with conserved striatal targets but limited prefrontal integration compared to mammalian elaborations. Human monoaminergic systems reflect further evolutionary specialization, particularly in the , where enlarged and noradrenergic innervation supports advanced . , culminating in humans, introduced denser deep-layer projections from groups (A8/A9) to granular prefrontal areas, exceeding densities in other mammals like or even non-human such as macaques; this bilaminar fiber pattern and presence of cortical interneurons enable fine-tuned like and . Experimental studies in model organisms provide mechanistic insights into these comparative roles. In the Caenorhabditis elegans, serotonin modulates egg-laying via the hermaphrodite-specific neuron (); mutants lacking serotonin synthesis, such as tph-1 knockouts, exhibit prolonged pharyngeal pumping at the expense of egg release, demonstrating serotonin's necessity for switching between alternative behavioral states and highlighting its conserved neuromodulatory function in reproductive circuits. Similar genetic approaches in vertebrates, like serotonergic knockouts in fish, reinforce monoamines' cross-phyla importance in , though with increasing complexity in projection patterns up the phylogenetic scale.

References

  1. https://www.mdpi.com/2076-3417/9/21/4719
  2. https://www.ncbi.nlm.nih.gov/books/NBK539894/
  3. https://www.nature.com/articles/s41467-024-51960-z
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