Neurotransmitter

A neurotransmitter is a signaling molecule secreted by a

Structure of a typical chemical synapse
neuron to affect another cell across a synapse. The cell
receiving the signal, or target cell, may be another neuron, Neurotransmitter
but could also be a gland or muscle cell.[1] Neurotransmitter
transporter
Neurotransmitters are released from synaptic vesicles into Synaptic Axon
the synaptic cleft where they are able to interact with vesicle terminal
neurotransmitter receptors on the target cell. The Voltage-
neurotransmitter's effect on the target cell is determined by gated Ca++
the receptor it binds to. Many neurotransmitters are channel Synaptic
synthesized from simple and plentiful precursors such as Postsynaptic Receptor cleft
amino acids, which are readily available and often require a density Dendrite
small number of biosynthetic steps for conversion.

Neurotransmitters are essential to the function of complex neural systems. The exact number of unique neurotransmitters in
humans is unknown, but more than 100 have been identified.[2] Common neurotransmitters include glutamate, GABA,
acetylcholine, glycine and norepinephrine.

Mechanism and cycle

Synthesis

Neurotransmitters are generally synthesized in neurons and are made up of, or derived from, precursor molecules that are found
abundantly in the cell. Classes of neurotransmitters include amino acids, monoamines, and peptides. Monoamines are
synthesized by altering a single amino acid. For example, the precursor of serotonin is the amino acid tryptophan. Peptide
transmitters, or neuropeptides, are protein transmitters that often are released together with other transmitters to have a
modulatory effect.[3] Purine neurotransmitters, like ATP, are derived from nucleic acids. Other neurotransmitters are made up of
metabolic products like nitric oxide and carbon monoxide.

Examples

Amino Acid glycine, glutamate

Monoamines serotonin, epinephrine, dopamine

Peptides substance P, opioids

Purines ATP, GTP

Other nitric oxide, carbon monoxide

Storage

Neurotransmitters are generally stored in synaptic vesicles, clustered close to the cell
membrane at the axon terminal of the presynaptic neuron. However, some
neurotransmitters, like the metabolic gases carbon monoxide and nitric oxide, are
synthesized and released immediately following an action potential without ever being
stored in vesicles.[4] Synaptic vesicles containing
neurotransmitters

Release
Generally, a neurotransmitter is released at the presynaptic terminal in response to an electrical signal called an action potential in
the presynaptic neuron. However, low level 'baseline' release also occurs without electrical stimulation. Neurotransmitters are
released into and diffuse across the synaptic cleft, where they bind to specific receptors on the membrane of the postsynaptic
neuron.[5]

Receptor interaction

After being released into the synaptic cleft, neurotransmitters diffuse across the synapse where they are able to interact with
receptors on the target cell. The effect of the neurotransmitter is dependent on the identity of the target cell's receptors present at
the synapse. Depending on the receptor, binding of neurotransmitters may cause excitation, inhibition, or modulation of the
postsynaptic neuron. See below for more information.

Elimination

In order to avoid continuous activation of receptors on the post-synaptic or target cell,

neurotransmitters must be removed from the synaptic cleft.[6] Neurotransmitters are
removed through one of three mechanisms:

1. Diffusion – neurotransmitters drift out of the synaptic cleft, where they are
absorbed by glial cells. These glial cells, usually astrocytes, absorb the
excess neurotransmitters. In the glial cell, neurotransmitters are broken
down by enzymes or pumped back into
2. Enzyme degradation – proteins called enzymes break the
neurotransmitters down.
3. Reuptake – neurotransmitters are reabsorbed into the pre-synaptic neuron.
Transporters, or membrane transport proteins, pump neurotransmitters from
Acetylcholine is cleaved in the
the synaptic cleft back into axon terminals (the presynaptic neuron) where
they are stored for reuse. synaptic cleft into acetic acid and
choline
For example, acetylcholine is eliminated by having its acetyl group cleaved by the
enzyme acetylcholinesterase; the remaining choline is then taken in and recycled by the
pre-synaptic neuron to synthesize more acetylcholine.[7] Other neurotransmitters are able to diffuse away from their targeted
synaptic junctions and are eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very
specific degradation pathways at regulatory points, which may be targeted by the body's regulatory system or medication.
Cocaine blocks a dopamine transporter responsible for the reuptake of dopamine. Without the transporter, dopamine diffuses
much more slowly from the synaptic cleft and continues to activate the dopamine receptors on the target cell.[8]

Discovery
Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical.
However, through histological examinations by Ramón y Cajal, a 20 to 40  nm gap between neurons, known today as the
synaptic cleft, was discovered. The presence of such a gap suggested communication via chemical messengers traversing the
synaptic cleft, and in 1921 German pharmacologist Otto Loewi confirmed that neurons can communicate by releasing
chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate
of frogs by controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment,
Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations.
Furthermore, Otto Loewi is credited with discovering acetylcholine (ACh) – the first known neurotransmitter.[9]

Identification
There are four main criteria for identifying neurotransmitters:

1. The chemical must be synthesized in the neuron or otherwise be present in it.

2. When the neuron is active, the chemical must be released and produce a response in some targets.
3. The same response must be obtained when the chemical is experimentally placed on the target.
4. A mechanism must exist for removing the chemical from its site of activation after its work is done.
However, given advances in pharmacology, genetics, and chemical neuroanatomy, the term "neurotransmitter" can be applied to
chemicals that:

Carry messages between neurons via influence on the postsynaptic membrane.

Have little or no effect on membrane voltage, but have a common carrying function such as changing the
structure of the synapse.
Communicate by sending reverse-direction messages that affect the release or reuptake of transmitters.

The anatomical localization of neurotransmitters is typically determined using immunocytochemical techniques, which identify
the location of either the transmitter substances themselves or of the enzymes that are involved in their synthesis.
Immunocytochemical techniques have also revealed that many transmitters, particularly the neuropeptides, are co-localized, that
is, a neuron may release more than one transmitter from its synaptic terminal.[10] Various techniques and experiments such as
staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system.[11]

Actions
Neurons form elaborate networks through which nerve impulses – action potentials – travel. Each neuron has as many as
15,000 connections with neighboring neurons.

Neurons do not touch each other (except in the case of an electrical synapse through a gap junction); instead, neurons interact at
contact points called synapses: a junction within two nerve cells, consisting of a miniature gap within which impulses are carried
by a neurotransmitter. A neuron transports its information by way of a nerve impulse called an action potential. When an action
potential arrives at the synapse's presynaptic terminal button, it may stimulate the release of neurotransmitters. These
neurotransmitters are released into the synaptic cleft to bind onto the receptors of the postsynaptic membrane and influence
another cell, either in an inhibitory or excitatory way. The next neuron may be connected to many more neurons, and if the total
of excitatory influences minus inhibitory influences is great enough, it will also "fire". That is to say, it will create a new action
potential at its axon hillock, releasing neurotransmitters and passing on the information to yet another neighboring neuron.

Modulation

A neurotransmitter may have an excitatory, inhibitory or modulatory effect on the target cell. The effect is determined by the
receptors the neurotransmitter interacts with at the post-synaptic membrane. Neurotransmitter influences trans-membrane ion
flow either to increase (excitatory) or to decrease (inhibitory) the probability that the cell with which it comes in contact will
produce an action potential. Synapses containing receptors with excitatory effects are called Type I synapses, while Type II
synapses contain receptors with inhibitory effects.[12] Thus, despite the wide variety of synapses, they all convey messages of
only these two types. The two types are different appearance and are primarily located on different parts of the neurons under its
influence.[13] Receptors with modulatory effects are spread throughout all synaptic membranes and binding of neurotransmitters
sets in motion signaling cascades that help the cell regulate its function.[14] Binding of neurotransmitters to receptors with
modulatory effects can have many results. For example, it may result in an increase or decrease in sensitivity to future stimulus
by recruiting more or less receptors to the synaptic membrane.

Type I (excitatory) synapses are typically located on the shafts or the spines of dendrites, whereas type II (inhibitory) synapses
are typically located on a cell body. In addition, Type I synapses have round synaptic vesicles, whereas the vesicles of type II
synapses are flattened. The material on the presynaptic and post-synaptic membranes is denser in a Type I synapse than it is in a
type II, and the type I synaptic cleft is wider. Finally, the active zone on a Type I synapse is larger than that on a Type II
synapse.

The different locations of type I and type II synapses divide a neuron into two zones: an excitatory dendritic tree and an
inhibitory cell body. From an inhibitory perspective, excitation comes in over the dendrites and spreads to the axon hillock to
trigger an action potential. If the message is to be stopped, it is best stopped by applying inhibition on the cell body, close to the
axon hillock where the action potential originates. Another way to conceptualize excitatory–inhibitory interaction is to picture
excitation overcoming inhibition. If the cell body is normally in an inhibited state, the only way to generate an action potential at
the axon hillock is to reduce the cell body's inhibition. In this "open the gates" strategy, the excitatory message is like a
racehorse ready to run down the track, but first, the inhibitory starting gate must be removed.[15]

Neurotransmitter actions
As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a
neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical properties of the
receptors.

Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at
most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Modifiable synapses
are thought to be the main memory-storage elements in the brain. Excessive glutamate release can
overstimulate the brain and lead to excitotoxicity causing cell death resulting in seizures or strokes.[16]
Excitotoxicity has been implicated in certain chronic diseases including ischemic stroke, epilepsy, amyotrophic
lateral sclerosis, Alzheimer's disease, Huntington disease, and Parkinson's disease.[17]
GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many
sedative/tranquilizing drugs act by enhancing the effects of GABA.[18] Correspondingly, glycine is the inhibitory
transmitter in the spinal cord.
Acetylcholine was the first neurotransmitter discovered in the peripheral and central nervous systems. It
activates skeletal muscles in the somatic nervous system and may either excite or inhibit internal organs in the
autonomic system.[11] It is distinguished as the transmitter at the neuromuscular junction connecting motor
nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses.
Acetylcholine also operates in many regions of the brain, but using different types of receptors, including
nicotinic and muscarinic receptors.[19]
Dopamine has a number of important functions in the brain; this includes regulation of motor behavior,
pleasures related to motivation and also emotional arousal. It plays a critical role in the reward system;
Parkinson's disease has been linked to low levels of dopamine and schizophrenia has been linked to high
levels of dopamine.[20]
Serotonin is a monoamine neurotransmitter. Most is produced by and found in the intestine (approximately
90%), and the remainder in central nervous system neurons. It functions to regulate appetite, sleep, memory
and learning, temperature, mood, behaviour, muscle contraction, and function of the cardiovascular system and
endocrine system. It is speculated to have a role in depression, as some depressed patients are seen to have
lower concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.[21]
Norepinephrine which is synthesized in the central nervous system and sympathetic nerves, modulates the
responses of the autonomic nervous system, the sleep patterns, focus and alertness. It is synthesized from
tyrosine.
Epinephrine which is also synthesized from tyrosine is released in the adrenal glands and the brainstem. It
plays a role in sleep, with one's ability to become and stay alert, and the fight-or-flight response.

Types
There are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides, and monoamines is
sufficient for some classification purposes.[22]

Major neurotransmitters:

Amino acids: glutamate,[23] aspartate, D-serine, gamma-Aminobutyric acid (GABA),[nb 1] glycine

Gasotransmitters: nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S)
Monoamines:
Catecholamines: dopamine (DA), norepinephrine (noradrenaline, NE), epinephrine (adrenaline)
Indolamines: serotonin (5-HT, SER), melatonin
histamine
Trace amines: phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine, octopamine,
tryptamine, etc.
Peptides: oxytocin, somatostatin, substance P, cocaine and amphetamine regulated transcript, opioid
peptides[24]
Purines: adenosine triphosphate (ATP), adenosine
Others: acetylcholine (ACh), anandamide, etc.

In addition, over 100 neuroactive peptides have been found, and new ones are discovered regularly.[25][26] Many of these are
co-released along with a small-molecule transmitter. Nevertheless, in some cases, a peptide is the primary transmitter at a
synapse. Beta-Endorphin is a relatively well-known example of a peptide neurotransmitter because it engages in highly specific
interactions with opioid receptors in the central nervous system.
Single ions (such as synaptically released zinc) are also considered neurotransmitters by some,[27] as well as some gaseous
molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2 S).[28] The gases are produced in the
neural cytoplasm and are immediately diffused through the cell membrane into the extracellular fluid and into nearby cells to
stimulate production of second messengers. Soluble gas neurotransmitters are difficult to study, as they act rapidly and are
immediately broken down, existing for only a few seconds.

The most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain.[23] The
next most prevalent is gamma-Aminobutyric Acid, or GABA, which is inhibitory at more than 90% of the synapses that do not
use glutamate. Although other transmitters are used in fewer synapses, they may be very important functionally: the great
majority of psychoactive drugs exert their effects by altering the actions of some neurotransmitter systems, often acting through
transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamines exert their effects primarily on
the dopamine system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides, which, in
turn, regulate dopamine levels.

List of neurotransmitters, peptides, and gaseous signaling molecules

Neurotransmitters

Category Name Abbreviation Metabotropic Ionotropic

Small: Amino α2-Adrenergic receptors,

Arginine Arg, R NMDA receptors
acids (Arg) imidazoline receptors
Small: Amino
Aspartate Asp, D – NMDA receptors
acids

Small: Amino NMDA receptors, kainate

Glutamate Glu, E Metabotropic glutamate receptors
acids receptors, AMPARs

Small: Amino GABAA receptors, GABAA-

Gamma-aminobutyric acid GABA GABAB receptors
acids ρ receptors
Small: Amino NMDA receptors, glycine
Glycine Gly, G –
acids receptors

Small: Amino
D-serine Ser, S – NMDA receptors
acids

Small: Nicotinic acetylcholine

Acetylcholine ACh Muscarinic acetylcholine receptors
Acetylcholine receptors
Small:
Dopamine receptors, trace amine-
Monoamine Dopamine DA –
(Phe/Tyr) associated receptor 1[29][30]

Small:
Norepinephrine
Monoamine NE, NAd Adrenergic receptors –
(noradrenaline)
(Phe/Tyr)

Small:
Monoamine Epinephrine (adrenaline) Epi, Ad Adrenergic receptors –
(Phe/Tyr)

Small: Serotonin (5- Serotonin receptors (all except 5-

5-HT 5-HT3
Monoamine (Trp) hydroxytryptamine) HT3)

Small:
Histamine H Histamine receptors –
Monoamine (His)

Small: Trace Human trace amine-associated

Phenethylamine PEA –
amine (Phe) receptors: hTAAR1, hTAAR2

Small: Trace
N-methylphenethylamine NMPEA hTAAR1 –
amine (Phe)
Small: Trace
Tyramine TYR hTAAR1, hTAAR2 –
amine (Phe/Tyr)

Small: Trace
octopamine Oct hTAAR1 –
amine (Phe/Tyr)

Small: Trace
Synephrine Syn hTAAR1 –
amine (Phe/Tyr)
Small: Trace hTAAR1, various serotonin
Tryptamine –
amine (Trp) receptors

Small: Trace hTAAR1, various serotonin

N-methyltryptamine NMT –
amine (Trp) receptors

Lipid Anandamide AEA Cannabinoid receptors –

Lipid 2-Arachidonoylglycerol 2-AG Cannabinoid receptors –

Lipid 2-Arachidonyl glyceryl ether 2-AGE Cannabinoid receptors –

Lipid N-Arachidonoyl dopamine NADA Cannabinoid receptors TRPV1

Lipid Virodhamine Cannabinoid receptors –
Small: Purine Adenosine Ado Adenosine receptors –
Small: Purine Adenosine triphosphate ATP P2Y receptors P2X receptors

Nicotinamide adenine
Small: Purine β-NAD P2Y receptors P2X receptors
dinucleotide
 Neuropeptides
Category Name Abbreviation Metabotropic Ionotropic

Bombesin-like
Bombesin BBR1-2-3 –
peptides

Bombesin-like
Gastrin releasing peptide GRP – –
peptide
Bombesin-like
Neuromedin B NMB Neuromedin B receptor –
peptide

Bradykinins Bradykinin B1, B2 –

Calcitonin/CGRP
Calcitonin Calcitonin receptor –
family
Calcitonin/CGRP Calcitonin gene-related
CGRP CALCRL –
family peptide

Corticotropin- Corticotropin-releasing
CRH CRHR1 –
releasing factors hormone

Corticotropin-
Urocortin CRHR1 –
releasing factors
Galanins Galanin GALR1, GALR2, GALR3 –

Galanins Galanin-like peptide GALR1, GALR2, GALR3 –

Gastrins Gastrin Cholecystokinin B receptor –

Gastrins Cholecystokinin CCK Cholecystokinin receptors –

Granins Chromogranin A ChgA – –

Melanocortins Adrenocorticotropic hormone ACTH ACTH receptor –

Melanocortins Proopiomelanocortin POMC Melanocortin 4 receptor –

Melanocyte-stimulating
Melanocortins MSH Melanocortin receptors –
hormones
Neurohypophyseals Vasopressin AVP Vasopressin receptors –

Neurohypophyseals Oxytocin OT Oxytocin receptor –

Neurohypophyseals Neurophysin I – –
Neurohypophyseals Neurophysin II – –

Neurohypophyseals Copeptin – –

Neuromedins Neuromedin U NmU NmUR1, NmUR2 –

Neuropeptide B/W Neuropeptide B NPB NPBW1, NPBW2 –

Neuropeptide B/W Neuropeptide S NPS Neuropeptide S receptors –

Neuropeptide Y Neuropeptide Y NY Neuropeptide Y receptors –

Neuropeptide Y Pancreatic polypeptide PP – –

Neuropeptide Y Peptide YY PYY – –

Opioids Enkephalins δ-Opioid receptor –

Opioids Dynorphins κ-Opioid receptor –

Opioids Neoendorphins κ-Opioid receptor –

Opioids Endorphins μ-Opioid receptors –

Opioids Endomorphins μ-Opioid receptors –

Opioids Morphine μ-Opioid receptors –

Opioids Nociceptin/orphanin FQ N/OFQ Nociceptin receptors –

Orexins Orexin A OX-A Orexin receptors –

Orexins Orexin B OX-B Orexin receptors –

Parathyroid Parathyroid hormone-related

PTHrP – –
hormone family protein
 RFamides Kisspeptin KiSS GPR54 –
RFamides Neuropeptide FF NPFF NPFF1, NPFF2 –

RFamides Prolactin-releasing peptide PrRP PrRPR –

Pyroglutamylated RFamide
RFamides QRFP GPR103 –
peptide
Secretins Secretin Secretin receptor –

Secretins Motilin Motilin receptor –

Secretins Glucagon Glucagon receptor –

Secretins Glucagon-like peptide-1 GLP-1 Glucagon-like peptide 1 receptor –

Secretins Glucagon-like peptide-2 GLP-2 Glucagon-like peptide 2 receptor –

Vasoactive intestinal peptide

Secretins Vasoactive intestinal peptide VIP –
receptors
Growth hormone–releasing Growth hormone–releasing
Secretins GHRH –
hormone hormone receptor

Pituitary adenylate cyclase-

Secretins PACAP ADCYAP1R1 –
activating peptide

Somatostatins Somatostatin Somatostatin receptors –

Tachykinins Neurokinin A – –

Tachykinins Neurokinin B – –

Tachykinins Substance P – –
Tachykinins Neuropeptide K – –

Other Agouti-related peptide AgRP Melanocortin receptor –

Metabotropic glutamate receptor 3

Other N-Acetylaspartylglutamate NAAG –
(mGluR3)

Cocaine- and amphetamine- Unknown Gi/Go-coupled

Other CART –
regulated transcript receptor[31]
Gonadotropin-releasing
Other GnRH GnRHR –
hormone
Thyrotropin-releasing
Other TRH TRHR –
hormone

Melanin-concentrating
Other MCH MCHR 1,2 –
hormone

Gasotransmitters
Category Name Abbreviation Metabotropic Ionotropic

Gaseous
signaling Nitric oxide NO Soluble guanylyl cyclase –
molecule
Gaseous
Heme bound to potassium
signaling Carbon monoxide CO –
channels
molecule

Gaseous
signaling Hydrogen sulfide H2S – –
molecule

Brain neurotransmitter systems

Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of the system affects
large volumes of the brain, called volume transmission. Major neurotransmitter systems include the noradrenaline
(norepinephrine) system, the dopamine system, the serotonin system, and the cholinergic system, among others. Trace amines
have a modulatory effect on neurotransmission in monoamine pathways (i.e., dopamine, norepinephrine, and serotonin
pathways) throughout the brain via signaling through trace amine-associated receptor  1.[32][33] A brief comparison of these
systems follows:
 Neurotransmitter systems in the brain
Regulated cognitive processes and
System Pathway origin and projections
behaviors

Noradrenergic pathways:

Locus coeruleus (LC) projections

LC → Amygdala and Hippocampus

anxiety
LC → Brain stem and Spinal cord
arousal (wakefulness)
LC → Cerebellum
circadian rhythm
LC → Cerebral cortex
Noradrenaline cognitive control and working memory
LC → Hypothalamus (co-regulated by dopamine)
system
[34][35][36][37][38][39] LC → Tectum feeding and energy homeostasis
LC → Thalamus medullary control of respiration
LC → Ventral tegmental area negative emotional memory
nociception (perception of pain)
Lateral tegmental field (LTF) projections
reward (minor role)
LTF → Brain stem and Spinal cord
LTF → Olfactory bulb

Dopaminergic pathways:

Ventral tegmental area (VTA) projections

VTA → Amygdala
VTA → Cingulate cortex
VTA → Hippocampus
VTA → Ventral striatum (Mesolimbic
pathway)
VTA → Olfactory bulb arousal (wakefulness)
VTA → Prefrontal cortex (Mesocortical aversion
pathway) cognitive control and working memory
(co-regulated by norepinephrine)
Nigrostriatal pathway emotion and mood
Dopamine system
[36][37][38][40][41][42] motivation (motivational salience)
Substantia nigra pars compacta → Dorsal
striatum motor function and control
positive reinforcement
Tuberoinfundibular pathway reward (primary mediator)
sexual arousal, orgasm, and refractory
Arcuate nucleus → Median eminence period (via neuroendocrine regulation)

Hypothalamospinal projection

Hypothalamus → Spinal cord

Incertohypothalamic pathway

Zona incerta → Hypothalamus

Histaminergic pathways:

Tuberomammillary nucleus (TMN) projections

TMN → Cerebral cortex arousal (wakefulness)

Histamine system TMN → Hippocampus feeding and energy homeostasis
[37][38][43]
TMN → Neostriatum learning
TMN → Nucleus accumbens memory
TMN → Amygdala
TMN → Hypothalamus

Serotonin system Serotonergic pathways:

[34][36][37][38][44][45][46] arousal (wakefulness)
Caudal nuclei (CN): body temperature regulation
Raphe magnus, raphe pallidus, and raphe emotion and mood, potentially including
aggression
obscurus
feeding and energy homeostasis
 Caudal projections reward (minor role)
sensory perception
CN → Cerebral cortex
CN → Thalamus
CN → Caudate-putamen and nucleus
accumbens
CN → Substantia nigra and ventral
tegmental area
CN → Cerebellum
CN → Spinal cord

Rostral nuclei (RN):

Nucleus linearis, dorsal raphe, medial
raphe, and raphe pontis

Rostral projections

RN → Amygdala
RN → Cingulate cortex
RN → Hippocampus
RN → Hypothalamus
RN → Neocortex
RN → Septum
RN → Thalamus
RN → Ventral tegmental area

Cholinergic pathways:

Forebrain cholinergic nuclei (FCN):

Nucleus basalis of Meynert, medial septal
nucleus, and diagonal band

Forebrain nuclei projections

FCN → Hippocampus
FCN → Cerebral cortex
FCN → Limbic cortex and sensory cortex arousal (wakefulness)
emotion and mood
Acetylcholine Striatal tonically active cholinergic neurons learning
system (TAN) motor function
[34][36][37][38][47]
motivation (motivational salience)
TAN → Medium spiny neuron
short-term memory
reward (minor role)
Brainstem cholinergic nuclei (BCN):
Pedunculopontine nucleus, laterodorsal
tegmentum, medial habenula, and
parabigeminal nucleus

Brainstem nuclei projections

BCN → Ventral tegmental area

BCN → Thalamus

Adrenergic pathways:

Rostral ventrolateral medulla (RVLM) projections medullary control of respiration

Adrenaline system sympathetic nervous system
[48][49] RVLM → Spinal cord feeding and energy homeostasis
RVLM → Brain stem arousal
RVLM → Hypothalamus stress

Drug effects
Understanding the effects of drugs on neurotransmitters comprises a significant portion of research initiatives in the field of
neuroscience. Most neuroscientists involved in this field of research believe that such efforts may further advance our
understanding of the circuits responsible for various neurological diseases and disorders, as well as ways to effectively treat and
someday possibly prevent or cure such illnesses.[50]

Drugs can influence behavior by altering neurotransmitter activity. For instance, drugs can decrease the rate of synthesis of
neurotransmitters by affecting the synthetic enzyme(s) for that neurotransmitter. When neurotransmitter syntheses are blocked,
the amount of neurotransmitters available for release becomes substantially lower, resulting in a decrease in neurotransmitter
activity. Some drugs block or stimulate the release of specific neurotransmitters. Alternatively, drugs can prevent
neurotransmitter storage in synaptic vesicles by causing the synaptic vesicle membranes to leak. Drugs that prevent a
neurotransmitter from binding to its receptor are called receptor antagonists. For example, drugs used to treat patients with
schizophrenia such as haloperidol, chlorpromazine, and clozapine are antagonists at receptors in the brain for dopamine. Other
drugs act by binding to a receptor and mimicking the normal neurotransmitter. Such drugs are called receptor agonists. An
example of a receptor agonist is morphine, an opiate that mimics effects of the endogenous neurotransmitter β-endorphin to
relieve pain. Other drugs interfere with the deactivation of a neurotransmitter after it has been released, thereby prolonging the
action of a neurotransmitter. This can be accomplished by blocking re-uptake or inhibiting degradative enzymes. Lastly, drugs
can also prevent an action potential from occurring, blocking neuronal activity throughout the central and peripheral nervous
system. Drugs such as tetrodotoxin that block neural activity are typically lethal.

Drugs targeting the neurotransmitter of major systems affect the whole system, which can explain the complexity of action of
some drugs. Cocaine, for example, blocks the re-uptake of dopamine back into the presynaptic neuron, leaving the
neurotransmitter molecules in the synaptic gap for an extended period of time. Since the dopamine remains in the synapse
longer, the neurotransmitter continues to bind to the receptors on the postsynaptic neuron, eliciting a pleasurable emotional
response. Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses, which leads to
the downregulation of some post-synaptic receptors. After the effects of the drug wear off, an individual can become depressed
due to decreased probability of the neurotransmitter binding to a receptor. Fluoxetine is a selective serotonin re-uptake inhibitor
(SSRI), which blocks re-uptake of serotonin by the presynaptic cell which increases the amount of serotonin present at the
synapse and furthermore allows it to remain there longer, providing potential for the effect of naturally released serotonin.[51]
AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpine prevents dopamine storage within
vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels.
 Drug-Neurotransmitter Interactions[52]
Drug Interacts with: Receptor Interaction: Type Effects
Blocks Acetylcholine
release in PNS

Botulinum Toxin (Botox) Acetylcholine – Antagonist Prevents muscle

contractions

Promotes acetylcholine
release in PNS

Black Widow Spider Venom Acetylcholine – Agonist Stimulates muscle

contractions

Interferes with
acetylcholinerase activity

Increases effects of
Neostigmine Acetylcholine – – ACh at receptors

Used to treat
myasthenia gravis

Increases ACh activity

Increases attention
Nicotine Acetylcholine Nicotinic (skeletal muscle) Agonist
Reinforcing effects

Decreases activity at
d-tubocurarine Acetylcholine Nicotinic (skeletal muscle) Antagonist
receptor site

Decreases ACh activity

Curare Acetylcholine Nicotinic (skeletal muscle) Antagonist Prevents muscle

contractions

Increases ACh activity

Muscarinic (heart and
Muscarine Acetylcholine Agonist
smooth muscle) Toxic

Blocks pupil constriction

Muscarinic (heart and Blocks saliva

Atropine Acetylcholine Antagonist
smooth muscle)
production

Treats motion sickness

Muscarinic (heart and
Scopolamine (Hyoscine) Acetylcholine Antagonist and postoperative nausea
smooth muscle)
and vomiting

Inactivates tyrosine
AMPT Dopamine/norepinephrine – – hydroxylase and inhibits
dopamine production

Prevents storage of
dopamine and other
monoamines in synaptic
vesicles
Reserpine Dopamine – –
Causes sedation and
depression

Apomorphine Dopamine D2 Receptor (presynaptic Antagonist Low dose: blocks

autoreceptors/postsynaptic (low autoreceptors
receptors) dose)/Direct
 agonist High dose: stimulates
(high dose)
postsynaptic receptors

Releases dopamine,
noradrenaline, and
Indirect serotonin
Amphetamine Dopamine/norepinephrine –
agonist
Blocks reuptake[32][33]

Releases dopamine and

noradrenaline
Methamphetamine Dopamine/norepinephrine – –
Blocks reuptake

Blocks reuptake

Enhances attention
Methylphenidate Dopamine – –
and impulse control in
ADHD

Blocks reuptake into

presynapse

Blocks voltage-
dependent sodium
Indirect channels
Cocaine Dopamine –
Agonist
Can be used as a
topical anesthetic (eye
drops)

Inhibits MAO-B

Deprenyl Dopamine – Agonist Prevents destruction

of dopamine

Blocks D2 receptors

Chlorpromazine Dopamine D2 Receptors Antagonist Alleviates

hallucinations

Results in Parkinson like

MPTP Dopamine – –
symptoms

Disrupts serotonin
synthesis by blocking the
PCPA Serotonin (5-HT) – Antagonist
activity of tryptophan
hydroxylase
Reduces side effects of
chemotherapy and radiation

Ondansetron Serotonin (5-HT) 5-HT3 receptors Antagonist Reduces nausea and

vomiting

Partial Treats symptoms of

Buspirone Serotonin (5-HT) 5-HT1A receptors
Agonist anxiety and depression

Fluoxetine Serotonin (5-HT) supports 5-HT reuptake SSRI Inhibits reuptake of

serotonin

Treats depression,
some anxiety
disorders, and
 OCD[51] Common
examples: Prozac and
Sarafem

Causes release of
serotonin

Inhibits reuptake of
Fenfluramine Serotonin (5-HT) – – serotonin

Used as an appetite
suppressant

Produces visual perception

distortions
Post-synaptic 5-HT2A Direct
Lysergic acid diethylamide Serotonin (5-HT) Stimulates 5-HT2A
receptors Agonist
receptors in forebrain

Stimulates release of
serotonin and
norepinephrine and inhibits
Methylenedioxymethamphetamine Serotonin (5-HT)/ the reuptake
– –
(MDMA) norepinphrine
Causes excitatory and
hallucinogenic effects

Causes severe muscle

Strychnine Glycine – Antagonist
spasms[53]
Crosses blood brain barrier
Diphenhydramine Histamine
to cause drowsiness

Produces analgesia and

sedation

Cannabinoid (CB) Increases appetite

Tetrahydrocannabinol (THC) Endocannabinoids Agonist
receptors
Cognitive effects

Suppresses appetite

Cannabinoid (CB)
Rimonabant Endocannabinoids
receptors
Antagonist Used in smoking
cessation

Inhibits FAAH

Used in research to
MAFP Endocannabinoids – –
increase cannabinoid
system activity

Blocks cannabinoid
reuptake

AM1172 Endocannabinoids – – Used in research to

increase cannabinoid
system activity

Cannabinoid (CB) Reduce nausea and

Anandamide (endogenous) – receptors; 5-HT3 receptors –
vomiting

Caffeine Adenosine Adenosine receptors Antagonist Blocks adenosine

receptors
 Increases
wakefulness

Blocks PCP binding site

Prevents calcium ions

Indirect
PCP Glutamate NMDA receptor
Antagonist
from entering neurons

Impairs learning

Blocks glutamate binding

site on NMDA receptor

AP5 Glutamate NMDA receptor Antagonist Impairs synaptic

plasticity and certain
forms of learning

Used as anesthesia

Induces trance-like
Ketamine Glutamate NMDA receptor Antagonist
state, helps with pain
relief and sedation

Used in research to study

NMDA receptor
NMDA Glutamate NMDA receptor Agonist
Ionotropic receptor

Used in research to study

AMPA receptor
AMPA Glutamate AMPA receptor Agonist
Ionotropic receptor

Inhibits GABA synthesis

Allyglycine GABA – –
Causes seizures

Muscimol GABA GABA receptor Agonist Causes sedation

Bicuculine GABA GABA receptor Antagonist Causes Seizures

Anxiolytic, sedation,
GABAA receptor Indirect
Benzodiazepines GABA memory impairment,
agonists
muscle relaxation
Sedation, memory
GABAA receptor Indirect
Barbiturates GABA impairment, muscle
agonists
relaxation

Sedation, memory
Indirect
Alcohol GABA GABA receptor impairment, muscle
agonist
relaxation

GABAA receptor Indirect

Picrotoxin GABA High doses cause seizures
antagonist
GABA transporter
antagonist

Increase availability of
Tiagabine GABA – Antagonist GABA

Reduces the
likelihood of seizures

Blocks MAO-A to treat

Moclobemide Norepinephrine – Agonist
depression
 Blocks alpha-2
autoreceptors

alpha-2 adrenergic Used to study

Idazoxan Norepinephrine Agonist
autoreceptors
norepinephrine
system

Inhibits activity of
dopamine beta-hydroxylase
which blocks the
production of
norepinephrine

Fusaric acid Norepinephrine – – Used to study

norepinephrine
system without
affecting dopamine
system

Opiates (Opium, morphine, Analgesia, sedation, and

heroin, and oxycodone)
Opioids Opioid receptor[54] Agonists
reinforcing effects
Reverses opiate
intoxication or overdose
Naloxone Opioids – Antagonist
symptoms (i.e. problems
with breathing)

Agonists

An agonist is a chemical capable of binding to a receptor, such as a neurotransmitter receptor, and initiating the same reaction
typically produced by the binding of the endogenous substance.[55] An agonist of a neurotransmitter will thus initiate the same
receptor response as the transmitter. In neurons, an agonist drug may activate neurotransmitter receptors either directly or
indirectly. Direct-binding agonists can be further characterized as full agonists, partial agonists, inverse agonists.[56][57]

Direct agonists act similar to a neurotransmitter by binding directly to its associated receptor site(s), which may be located on the
presynaptic neuron or postsynaptic neuron, or both.[58] Typically, neurotransmitter receptors are located on the postsynaptic
neuron, while neurotransmitter autoreceptors are located on the presynaptic neuron, as is the case for monoamine
neurotransmitters;[32] in some cases, a neurotransmitter utilizes retrograde neurotransmission, a type of feedback signaling in
neurons where the neurotransmitter is released postsynaptically and binds to target receptors located on the presynaptic
neuron.[59][note 1] Nicotine, a compound found in tobacco, is a direct agonist of most nicotinic acetylcholine receptors, mainly
located in cholinergic neurons.[54] Opiates, such as morphine, heroin, hydrocodone, oxycodone, codeine, and methadone, are
μ-opioid receptor agonists; this action mediates their euphoriant and pain relieving properties.[54]

Indirect agonists increase the binding of neurotransmitters at their target receptors by stimulating the release or preventing the
reuptake of neurotransmitters.[58] Some indirect agonists trigger neurotransmitter release and prevent neurotransmitter reuptake.
Amphetamine, for example, is an indirect agonist of postsynaptic dopamine, norepinephrine, and serotonin receptors in each
their respective neurons;[32][33] it produces both neurotransmitter release into the presynaptic neuron and subsequently the
synaptic cleft and prevents their reuptake from the synaptic cleft by activating TAAR1, a presynaptic G protein-coupled
receptor, and binding to a site on VMAT2, a type of monoamine transporter located on synaptic vesicles within monoamine
neurons.[32][33]

Antagonists

An antagonist is a chemical that acts within the body to reduce the physiological activity of another chemical substance (as an
opiate); especially one that opposes the action on the nervous system of a drug or a substance occurring naturally in the body by
combining with and blocking its nervous receptor.[60]

There are two main types of antagonist: direct-acting Antagonist and indirect-acting Antagonists:

1. Direct-acting antagonist- which takes up space present on receptors which are otherwise taken up by
neurotransmitters themselves. This results in neurotransmitters being blocked from binding to the receptors.
The most common is called Atropine.
 2. Indirect-acting antagonist- drugs that inhibit the release/production of neurotransmitters (e.g., Reserpine).

Drug antagonists

An antagonist drug is one that attaches (or binds) to a site called a receptor without activating that receptor to produce a
biological response. It is therefore said to have no intrinsic activity. An antagonist may also be called a receptor "blocker"
because they block the effect of an agonist at the site. The pharmacological effects of an antagonist, therefore, result in
preventing the corresponding receptor site's agonists (e.g., drugs, hormones, neurotransmitters) from binding to and activating it.
Antagonists may be "competitive" or "irreversible".

A competitive antagonist competes with an agonist for binding to the receptor. As the concentration of antagonist increases, the
binding of the agonist is progressively inhibited, resulting in a decrease in the physiological response. High concentration of an
antagonist can completely inhibit the response. This inhibition can be reversed, however, by an increase of the concentration of
the agonist, since the agonist and antagonist compete for binding to the receptor. Competitive antagonists, therefore, can be
characterized as shifting the dose–response relationship for the agonist to the right. In the presence of a competitive antagonist, it
takes an increased concentration of the agonist to produce the same response observed in the absence of the antagonist.

An irreversible antagonist binds so strongly to the receptor as to render the receptor unavailable for binding to the agonist.
Irreversible antagonists may even form covalent chemical bonds with the receptor. In either case, if the concentration of the
irreversible antagonist is high enough, the number of unbound receptors remaining for agonist binding may be so low that even
high concentrations of the agonist do not produce the maximum biological response.[61]

Precursors

While intake of Biosynthetic pathways for catecholamines and trace amines in the human
brain[62][63][64]
neurotransmitter precursors
does increase AADC PNMT
neurotransmitter synthesis,
evidence is mixed as to
L -Phenylalanine Phenethylamine N-Methylphenethylamine
whether neurotransmitter
release and postsynaptic AAAH
receptor firing is increased.
Even with increased PNMT
neurotransmitter release, it is AADC N-Methyltyramine
unclear whether this will
result in a long-term increase L -Tyrosine p-Tyramine DBH
in neurotransmitter signal
strength, since the nervous AAAH brain minor
CYP2D6 pathway p-Octopamine
system can adapt to changes
such as increased PNMT
neurotransmitter synthesis AADC
and may therefore maintain primary
pathway
constant firing.[65] Some L -DOPA Dopamine
neurotransmitters may have a
role in depression and there DBH COMT Synephrine
is some evidence to suggest
that intake of precursors of
these neurotransmitters may PNMT
be useful in the treatment of
mild and moderate Epinephrine Norepinephrine 3-Methoxytyramine
depression.[65][66] In humans, catecholamines and phenethylaminergic trace amines are derived from the amino
acid L-phenylalanine.

Catecholamine and
trace amine precursors

L -DOPA, a precursor of dopamine that crosses the blood–brain barrier, is used in the treatment of Parkinson's disease. For
depressed patients where low activity of the neurotransmitter norepinephrine is implicated, there is only little evidence for
benefit of neurotransmitter precursor administration. L-phenylalanine and L-tyrosine are both precursors for dopamine,
norepinephrine, and epinephrine. These conversions require vitamin B6, vitamin C, and S-adenosylmethionine. A few studies
suggest potential antidepressant effects of L-phenylalanine and L-tyrosine, but there is much room for further research in this
area.[65]

Serotonin precursors

Administration of L-tryptophan, a precursor for serotonin, is seen to double the production of serotonin in the brain. It is
significantly more effective than a placebo in the treatment of mild and moderate depression.[65] This conversion requires
vitamin C.[21] 5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is more effective than a placebo.[65]

Diseases and disorders

Diseases and disorders may also affect specific neurotransmitter systems. The following are disorders involved in either an
increase, decrease, or imbalance of certain neurotransmitters.

Dopamine:

For example, problems in producing dopamine (mainly in the substantia nigra) can result in Parkinson's disease, a disorder that
affects a person's ability to move as they want to, resulting in stiffness, tremors or shaking, and other symptoms. Some studies
suggest that having too little or too much dopamine or problems using dopamine in the thinking and feeling regions of the brain
may play a role in disorders like schizophrenia or attention deficit hyperactivity disorder (ADHD). Dopamine is also involved in
addiction and drug use, as most recreational drugs cause an influx of dopamine in the brain (especially opioid and
methamphetamines) that produces a pleasurable feeling, which is why users constantly crave drugs.

Serotonin:

Similarly, after some research suggested that drugs that block the recycling, or reuptake, of serotonin seemed to help some
people diagnosed with depression, it was theorized that people with depression might have lower-than-normal serotonin levels.
Though widely popularized, this theory was not borne out in subsequent research.[67] Therefore, selective serotonin reuptake
inhibitors (SSRIs) are used to increase the amounts of serotonin in synapses.

Glutamate:

Furthermore, problems with producing or using glutamate have been suggestively and tentatively linked to many mental
disorders, including autism, obsessive–compulsive disorder (OCD), schizophrenia, and depression.[68] Having too much
glutamate has been linked to neurological diseases such as Parkinson's disease, multiple sclerosis, Alzheimer's disease, stroke,
and ALS (amyotrophic lateral sclerosis).[69]

Neurotransmitter imbalance
Generally, there are no scientifically established "norms" for appropriate levels or
"balances" of different neurotransmitters. It is in most cases pragmatically impossible to
even measure levels of neurotransmitters in a brain or body at any distinct moments in
time. Neurotransmitters regulate each other's release, and weak consistent imbalances in
this mutual regulation were linked to temperament in healthy people.[70][71][72][73][74]
Strong imbalances or disruptions to neurotransmitter systems have been associated with
many diseases and mental disorders. These include Parkinson's, depression, insomnia, CAPON Binds Nitric Oxide
Attention Deficit Hyperactivity Disorder (ADHD), anxiety, memory loss, dramatic Synthase, Regulating NMDA
changes in weight and addictions. Chronic physical or emotional stress can be a Receptor–Mediated Glutamate
contributor to neurotransmitter system changes. Genetics also plays a role in Neurotransmission
neurotransmitter activities. Apart from recreational use, medications that directly and
indirectly interact with one or more transmitter or its receptor are commonly prescribed
for psychiatric and psychological issues. Notably, drugs interacting with serotonin and norepinephrine are prescribed to patients
with problems such as depression and anxiety—though the notion that there is much solid medical evidence to support such
interventions has been widely criticized.[75] Studies shown that dopamine imbalance has an influence on multiple sclerosis and
other neurological disorders.[76]

See also
Medicine portal

BK channel#Cellular level Neurotransmission

Kiss-and-run fusion Neurotransmitter analog
Natural neuroactive substance Neurotransmitter release
Neuroendocrine Neural pathway
Neuroendocrinology Neuromodulation
Neuropsychopharmacology False neurotransmitter

Notes
1. In the central nervous system, anandamide other endocannabinoids utilize retrograde neurotransmission,
since their release is postsynaptic, while their target receptor, cannabinoid receptor 1 (CB1), is presynaptic.[59]
The cannabis plant contains Δ9-tetrahydrocannabinol, which is a direct agonist at CB1.[59]

1. GABA is a non-proteinogenic amino acid

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s://pubmed.ncbi.nlm.nih.gov/21272013). "VMAT2 is the CNS vesicular transporter for not only the biogenic
amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ...
[Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for
storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC)."
34. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines,
Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for
Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 155. ISBN 9780071481274. "Different
subregions of the VTA receive glutamatergic inputs from the prefrontal cortex, orexinergic inputs from the lateral
hypothalamus, cholinergic and also glutamatergic and GABAergic inputs from the laterodorsal tegmental
nucleus and pedunculopontine nucleus, noradrenergic inputs from the locus ceruleus, serotonergic inputs from
the raphe nuclei, and GABAergic inputs from the nucleus accumbens and ventral pallidum."
35. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines,
Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for
Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 145, 156–157. ISBN 9780071481274.
"Descending NE fibers modulate afferent pain signals. ... The locus ceruleus (LC), which is located on the floor
of the fourth ventricle in the rostral pons, contains more than 50% of all noradrenergic neurons in the brain; it
innervates both the forebrain (eg, it provides virtually all the NE to the cerebral cortex) and regions of the
brainstem and spinal cord. ... The other noradrenergic neurons in the brain occur in loose collections of cells in
the brainstem, including the lateral tegmental regions. These neurons project largely within the brainstem and
spinal cord. NE, along with 5HT, ACh, histamine, and orexin, is a critical regulator of the sleep-wake cycle and
of levels of arousal. ... LC firing may also increase anxiety ...Stimulation of β-adrenergic receptors in the
amygdala results in enhanced memory for stimuli encoded under strong negative emotion ... Epinephrine
occurs in only a small number of central neurons, all located in the medulla. Epinephrine is involved in visceral
functions, such as control of respiration."
36. Rang HP (2003). Pharmacology. Edinburgh: Churchill Livingstone. pp. 474 for noradrenaline system, page
476 for dopamine system, page 480 for serotonin system and page 483 for cholinergic system. ISBN 978-0-
443-07145-4.
37. Iwańczuk W, Guźniczak P (2015). "Neurophysiological foundations of sleep, arousal, awareness and
consciousness phenomena. Part 1" (https://doi.org/10.5603%2FAIT.2015.0015). Anaesthesiology Intensive
Therapy. 47 (2): 162–7. doi:10.5603/AIT.2015.0015 (https://doi.org/10.5603%2FAIT.2015.0015).
PMID 25940332 (https://pubmed.ncbi.nlm.nih.gov/25940332). "The ascending reticular activating system
(ARAS) is responsible for a sustained wakefulness state. ... The thalamic projection is dominated by
cholinergic neurons originating from the pedunculopontine tegmental nucleus of pons and midbrain (PPT) and
laterodorsal tegmental nucleus of pons and midbrain (LDT) nuclei [17, 18]. The hypothalamic projection
involves noradrenergic neurons of the locus coeruleus (LC) and serotoninergic neurons of the dorsal and
median raphe nuclei (DR), which pass through the lateral hypothalamus and reach axons of the histaminergic
tubero-mamillary nucleus (TMN), together forming a pathway extending into the forebrain, cortex and
hippocampus. Cortical arousal also takes advantage of dopaminergic neurons of the substantia nigra (SN),
ventral tegmenti area (VTA) and the periaqueductal grey area (PAG). Fewer cholinergic neurons of the pons
and midbrain send projections to the forebrain along the ventral pathway, bypassing the thalamus [19, 20]."
38. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 12: Sleep and Arousal". In Sydor A, Brown RY (eds.).
Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-
Hill Medical. p. 295. ISBN 9780071481274. "The ARAS is a complex structure consisting of several different
circuits including the four monoaminergic pathways ... The norepinephrine pathway originates from the locus
ceruleus (LC) and related brainstem nuclei; the serotonergic neurons originate from the raphe nuclei within the
brainstem as well; the dopaminergic neurons originate in ventral tegmental area (VTA); and the histaminergic
pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As
discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell
bodies. Norepinephrine, serotonin, dopamine, and histamine have complex modulatory functions and, in
general, promote wakefulness. The PT in the brain stem is also an important component of the ARAS. Activity
of PT cholinergic neurons (REM-on cells) promotes REM sleep. During waking, REM-on cells are inhibited by
a subset of ARAS norepinephrine and serotonin neurons called REM-off cells."
39. Rinaman L (February 2011). "Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine,
cognitive, and behavioral functions" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3043801). American
Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 300 (2): R222-35.
doi:10.1152/ajpregu.00556.2010 (https://doi.org/10.1152%2Fajpregu.00556.2010). PMC 3043801 (https://ww
w.ncbi.nlm.nih.gov/pmc/articles/PMC3043801). PMID 20962208 (https://pubmed.ncbi.nlm.nih.gov/20962208).
40. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines,
Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for
Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147–148, 154–157.
ISBN 9780071481274. "Neurons from the SNc densely innervate the dorsal striatum where they play a critical
role in the learning and execution of motor programs. Neurons from the VTA innervate the ventral striatum
(nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and
cingulate cortex. VTA DA neurons play a critical role in motivation, reward-related behavior, attention, and
multiple forms of memory. ... Thus, acting in diverse terminal fields, dopamine confers motivational salience
("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value
placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple
forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining
this reward in the future (nucleus accumbens core region and dorsal striatum). ... DA has multiple actions in the
prefrontal cortex. It promotes the "cognitive control" of behavior: the selection and successful monitoring of
behavior to facilitate attainment of chosen goals. Aspects of cognitive control in which DA plays a role include
working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent
behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome
distractions. ... Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA
to regulate cognitive control. ..."
41. Calipari ES, Bagot RC, Purushothaman I, Davidson TJ, Yorgason JT, Peña CJ, et al. (March 2016). "In vivo
imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward" (https://www.ncb
i.nlm.nih.gov/pmc/articles/PMC4791010). Proceedings of the National Academy of Sciences of the United
States of America. 113 (10): 2726–31. Bibcode:2016PNAS..113.2726C (https://ui.adsabs.harvard.edu/abs/201
6PNAS..113.2726C). doi:10.1073/pnas.1521238113 (https://doi.org/10.1073%2Fpnas.1521238113).
PMC 4791010 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791010). PMID 26831103 (https://pubmed.ncb
i.nlm.nih.gov/26831103). "Previous work has demonstrated that optogenetically stimulating D1 MSNs
promotes reward, whereas stimulating D2 MSNs produces aversion."
42. Ikemoto S (November 2010). "Brain reward circuitry beyond the mesolimbic dopamine system: a
neurobiological theory" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894302). Neuroscience and
Biobehavioral Reviews. 35 (2): 129–50. doi:10.1016/j.neubiorev.2010.02.001 (https://doi.org/10.1016%2Fj.neu
biorev.2010.02.001). PMC 2894302 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894302).
PMID 20149820 (https://pubmed.ncbi.nlm.nih.gov/20149820). "Recent studies on intracranial self-
administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the
mesolimbic dopamine structures–the posterior ventral tegmental area, medial shell nucleus accumbens and
medial olfactory tubercle. ... In the 1970s it was recognized that the olfactory tubercle contains a striatal
component, which is filled with GABAergic medium spiny neurons receiving glutamatergic inputs form cortical
regions and dopaminergic inputs from the VTA and projecting to the ventral pallidum just like the nucleus
accumbens"
Figure 3: The ventral striatum and self-administration of amphetamine (https://www.ncbi.nlm.nih.gov/pmc/article
s/PMC2894302/figure/F3/)
43. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines,
Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for
Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 175–176. ISBN 9780071481274. "Within
the brain, histamine is synthesized exclusively by neurons with their cell bodies in the tuberomammillary
nucleus (TMN) that lies within the posterior hypothalamus. There are approximately 64000 histaminergic
neurons per side in humans. These cells project throughout the brain and spinal cord. Areas that receive
especially dense projections include the cerebral cortex, hippocampus, neostriatum, nucleus accumbens,
amygdala, and hypothalamus.  ... While the best characterized function of the histamine system in the brain is
regulation of sleep and arousal, histamine is also involved in learning and memory ...It also appears that
histamine is involved in the regulation of feeding and energy balance."
44. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines,
Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for
Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 158–160. ISBN 9780071481274. "[The]
dorsal raphe preferentially innervates the cerebral cortex, thalamus, striatal regions (caudate-putamen and
nucleus accumbens), and dopaminergic nuclei of the midbrain (eg, the substantia nigra and ventral tegmental
area), while the median raphe innervates the hippocampus, septum, and other structures of the limbic
forebrain. ... it is clear that 5HT influences sleep, arousal, attention, processing of sensory information in the
cerebral cortex, and important aspects of emotion (likely including aggression) and mood regulation. ...The
rostral nuclei, which include the nucleus linearis, dorsal raphe, medial raphe, and raphe pontis, innervate most
of the brain, including the cerebellum. The caudal nuclei, which comprise the raphe magnus, raphe pallidus,
and raphe obscuris, have more limited projections that terminate in the cerebellum, brainstem, and spinal
cord."
45. Nestler EJ. "Brain Reward Pathways" (http://neuroscience.mssm.edu/nestler/brainRewardpathways.html).
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47. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines,
Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for
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External links
Purves, Dale; Augustine, George J.; Fitzpatrick, David; Katz, Lawrence C.; LaMantia, Anthony-Samuel;
McNamara, James O.; Williams, S. Mark (2001). "Chapter 6. Neurotransmitters". What Defines a
Neurotransmitter? (https://www.ncbi.nlm.nih.gov/books/NBK10957/). Neuroscience (2nd ed.). Sunderland
(MA): Sinauer Associates. ISBN 0-87893-742-0.
Holz, Ronald W.; Fisher, Stephen K. (1999). "Chapter 10. Synaptic Transmission and Cellular Signaling: An
Overview". In Siegel, George J; Agranoff, Bernard W; Albers, R Wayne; Fisher, Stephen K; Uhler, Michael D
(eds.). Synaptic Transmission (https://www.ncbi.nlm.nih.gov/books/NBK27911/). Basic Neurochemistry:
Molecular, Cellular and Medical Aspects (6th ed.). Philadelphia: Lippincott-Raven. ISBN 0-397-51820-X.
Neurotransmitters and Neuroactive Peptides at Neuroscience for Kids website (http://faculty.washington.edu/ch
udler/chnt1.html)

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