Neurotransmitter

NEUROTRANSMITTER
Neuroscience of Clinical Psychiatry, The: The Pathophysiology of Behavior and Mental Illness, 1st Edition
A neurotransmitter is technically defined by meeting three criteria:

1. The substance must be stored in the presynaptic neuron. 2. It must be released with depolarization of the presynaptic neuron induced by the influx of Ca2+. 3. The substance must bind with a specific receptor on the postsynaptic neuron
CLASSIFICATION OF NEUROTRANSMITTER
1. The classic neurotransmitters:
1. Amino acids:
1. 2. Glutamate GABA and Glycine Catecholamines
1. 2. 3. Dopamine Norepineprhine Epinephrine Serotonin Melatonin Histamine
2.
Monoamines
1.
2.
Indoleamines
1. 2. 3.
3.
Acetylcholine
2. Neuropeptides. 3. Unconventional neurotransmitters

1. 2. Gases : Nitric oxide (NO) Endocannabinoids
Neuropeptides
Neuropeptides Gut-brain peptides Example
Pituitary peptides
Hypothalamic releasing peptides
Opioid peptides
Other peptides
Substance P Cholecystokinin Galanin Adrenocorticotropic hormone (ACTH) Luteinizing hormone (LH) Oxytocin Vasopressin Corticotropin-releasing factor (CRF) Gonadotropin-releasing hormone (GnRH) Thyroidtropin-releasing hormone (TRH) Somatostatin Endorphin Enkephalins
Angiotensin Bradykinin
Unconventional neurotransmitters
1. Gases 2. Endocannabinoids
Catecholamines are synthesized from the essential amino acid tyrosine that must be obtained from the diet. Note that L-dopa is synthesized into DA. This shows why L-dopa can be given as a treatment for Parkinson's disease. The trick is to allow the synthesis in the CNS, but inhibit the enzyme dopa decarboxylase in the periphery so that the patient is not too nauseated.
The synthesis of catecholamines from tyrosine.
The relative size of -A : the amino acids -B : two of the amines -C : neuropeptide
Glutamate
This is the major workhorse of the brain, with glutamate neurons making up more than half of the excitatory neurons. Without glutamate the brain does not get started or keep running. Glutamate and another excitatory transmitter aspartate are nonessential amino acids that do not cross the blood-brain barrier. Consequently, glutamate must be synthesized in the brain from glucose and other precursors. Glial cells assist in the reuptake, degradation, and resupply of glutamate for neurons. Disorders:
Too much glutamate (as in stroke) is toxic to the nerve cells glutamatergic dysregulation may be present in patients with schizophrenia
GABA and Glycine

GABA is the major inhibitory transmitter in the brain and is used by approximately 25% of the cortical neurons. Glycine is the other inhibitory amino acid, but is less common. GABA puts the brakes on the brain: not enough GABA and one can have seizures. The GABA neurons are primarily the interneurons in the gray matter providing local constraint over cortical circuitry.
Dopamine (DA)
There are 3 dopaminergic system in the brain: 1. Nigrostriatal system or Mesostriatal system :
From Substantia nigra to striatum (nucleus Caudatus and Putamen)Parkinson disease
2. Mesolimbocortical DA system:
1. Mesolimbic : from ventral tegmental area (VTA) to nucleus accumbens, amygdala, and hippocampus. 2. Mesocortical : from VTA to prefrontal cortex
3. Tuberoinfundibular DA system :
From Arcuate nucleus to hypophysis inhibit synthesis and release of prolactin. antipsychotic medications that block the DA receptor can cause an increase in prolactin (hyperprolactinemia)
Dopamine (cont.)
The branches to the nucleus accumbens are involved with reward and substance abuse. The branches to the prefrontal cortex are involved with attention and cognition, and seem to be impaired in patients with attention deficit hyperactivity disorder (ADHD). Some speculate that problems with the mesolimbic system cause the positive symptoms of schizophrenia whereas negative symptoms are caused by impairment in the mesocortical system.
The dopaminergic system The substantia nigra forms the nigrostriatal pathways to the caudate and putamen. The ventral tegmental area projects to the nucleus accumbens and cortex. The arcuate nucleus of the hypothalamus projects to the tuberoinfundibular area of the hypothalamus Neuroscience of Clinical Psychiatry, The:
The Pathophysiology of Behavior and Mental Illness, 1st Edition
Norepinephrine (NE)
NE neurons contain an additional enzyme in their terminals that converts DA to NE. Approximately 50% of the NE neurons are located in the locus coeruleus. There are approximately 12,000 neurons in each nucleus. The remainder of the NE neurons is found in loose clusters in the medullary reticular formation . Plays an important role in anxiety and depression.
Norepinephrine (cont.)
The NE neurons play an important role in alertness. The firing of the locus coeruleus increases along a spectrum from drowsy to alert, with the lowest found when we sleep and the highest when we are hypervigilant. The noradrenergic neurons are important in handling danger. In a threatening situation, the locus coeruleus is active as are the sympathetic neurons of the autonomic nervous system (ANS) where the peripheral noradrenergic neurons are found.
The noradrenergic system. With projections to almost every area of the brain and spinal cord, the NE system plays an important role in alertness and anxiety.
Epinephrine
The epinephrine (or adrenaline) neurons are few and play a minor role in the CNS. Most of the epinephrine in the body is produced in the adrenal medulla and excreted with sympathetic stimulation. Therefore, epinephrine plays a much greater role outside of the brain as a hormone, than within as a neurotransmitter
Serotonin synthesis
Serotonin (5-hydroxytryptamine)
Serotonin is found in many parts of the body outside of the CNS, such as platelets and mast cells. Only approximately 1% to 2% of the body's serotonin in located in the brain. The most closely associated neurotransmitter with modern neuropsychopharmacology. Serotonin is synthesized from tryptophan that must be obtained in the diet . In the pineal gland there are two additional enzymes that convert serotonin to melatonin. The serotonin neurons are relatively few in number (approximately 200,000) and reside in the raphe nuclei in the brain stem. As with NE, the serotonin neurons project to virtually all areas of the brain. Plays an important role in depression and anxiety, and also in the sleep-wake cycle.
The serotonergic system The cluster of Raphe nuclei along the brainstem has projections to most of the brain and spinal cord. These neurons play an important roll in mood, anxiety, and with the sleep-wake cycle Neuroscience of Clinical Psychiatry, The:
The Pathophysiology of Behavior and Mental Illness, 1st Edition
Histamine
Histamine in the brain is involved in arousal and attention. Most of the cell bodies start in the tuberomammilary nucleus of the posterior hypothalamus, with sparse but widespread projects to all regions of the brain and spinal cord. When animals are alert, the histamine neurons are active. Histamine neurons are quiet when animals are sleeping. More recently, there has been increased interest in activating the histamine neurons as a treatment for fatigue. Modafinil, the only agent in the class, indirectly activates the histamine neurons and has been used successfully as a treatment for narcolepsy, excessive sleepiness, and ADHD.
Acetylcholine
Acetylcholine (ACh) was the first neurotransmitter identified (1920) ACh is a small molecule transmitter but it is not an amino acid nor a monoamine. ACh plays a prominent role :
in the peripheral autonomic nervous system (ANS) at the neuromuscular junction.
In the CNS arises from cell bodies in the brain stem and forebrain with prominent projects to the cortex and hippocampus. Projections to the hippocampus are involved with learning and memory and are disrupted in Alzheimer's disease. ACh, unlike the catecholamines and indoleamines, is also synthesized in interneurons in the CNS. In the striatum, the ACh neurons balance the dopaminergic input from the substantia nigra to coordinate extrapyramidal motor control. Disruption of this balance with DA-blocking antipsychotic agents can result in extrapyramidal side effects. The anticholinergic agents are administered to restore the ACh/DA balance and allow normal movement.
Neuropeptides
The neuropeptides are small chains of amino acids but larger than the classic neurotransmitters. Peptides are synthesized in nerve cells and have effects on behaviors such as learning, attachment, mood, and anxiety. Some have important endocrine functions in the body, such as the regulation of reproduction, growth, water intake, salt metabolism, temperature control. The formation, release, and inactivation of the neuropeptides differ from that of the monoamines. Peptides must be transcribed from mRNA on the ribosomes of the endoplasmic reticulum. Initially the peptide is a large propeptide precursor, which is cleaved into an active neuropeptide as it is moved from the Golgi apparatus into large dense core vesicles that are stored at the terminal bud of the neuron. Unlike the monoamines, neuropeptides are not recycled by the neuron, but are rather broken down by degradative enzymes (peptidases) on the receptor membrane.
Neuropeptides
Neuropeptides Gut-brain peptides Example
Pituitary peptides
Hypothalamic releasing peptides
Opioid peptides
Other peptides
Substance P Cholecystokinin Galanin Adrenocorticotropic hormone (ACTH) Luteinizing hormone (LH) Oxytocin Vasopressin Corticotropin-releasing factor (CRF) Gonadotropin-releasing hormone (GnRH) Thyroidtropin-releasing hormone (TRH) Somatostatin Endorphin Enkephalins
Angiotensin Bradykinin
Unconventional Neurotransmitters
Nitric oxide (NO) :
most commonly associated with erectile dysfunction, is a gas that is formed in glutamate neurons when arginine is converted into citrulline and NO. NO has the ability to diffuse (without obstruction) out of the originating cell, through the extracellular medium and into any neighboring cell that it meets. NO converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (GMP) that acts as a second messenger. Cells containing the NO synthase (the enzyme that creates NO) constitute only approximately 1% of neuronal cells in the brain, but reach out so extensively that nearly every cell in the brain may encounter NO. NO may be involved with aggression and sexual behavior, as well as migraine headaches. NO may restrain aggressive and sexual behavior. It is worth noting that the medications for erectile dysfunction have not been associated with any adverse effects on mental function. This may be due to the inability of these medications in their current form to cross the blood-brain barrier.
Unconventional Neurotransmitters (cont.)

Endocannabinoids:
The cannabinoid receptor (CB1) is widely expressed throughout the brain on presynaptic terminals. The effect of activating CB1 receptors results in inhibition of that neuron and in a simple way explains the calming effect of marijuana. Blocking the CB1 receptor can inhibit appetite. Rimonabant, a potent and selective blocker (antagonist) of the CB1 receptor, has been shown in clinical studies to facilitate weight loss.

Neurotransmitter

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NEUROTRANSMITTER

A neurotransmitter is technically defined by meeting three criteria:

2. Neuropeptides. 3. Unconventional neurotransmitters

Hypothalamic releasing peptides

The synthesis of catecholamines from tyrosine.

GABA and Glycine

Hypothalamic releasing peptides

Unconventional Neurotransmitters (cont.)

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