NeurotransmittersMLS 2010

Introduction

• A chemical released from a nerve cell transmits an impulse from a nerve cell to another nerve, muscle, organ, or other tissue.

• Acetylcholine - First neurotransmitter to be discovered in 1921 by Otto Loewi, a German biologist who later wins the Nobel Prize for physiology or

medicine in 1936.

• Today over 100 NTs has been identified and characterized (Neuroscience, Purves 2009)

Types of NTIntroduction contd…

A. Structural classification a. Small molecules - mono amines, catecholamine ,amino acids,

purine derivatives and soluble gases(eg-NO).

b. large molecules - peptides.

B. Functional classification

a. Neurotransmitters vs. neuromodulators

b. Excitatory vs. Inhibitory

c. Conventional vs. unconventional

Types of NT-Small moleculesIntroduction contd…

Types of NT-Large moleculesIntroduction contd…

• Peptides acts as both neurotransmitters and neuromodulators

• Release along with other small molecule neurotransmitters.

NT synthesis

• Neurotransmitters do not cross the BBB.

• All must be synthesized in neurons from precursors.

• Precursors come from synaptic cleft (products of NT catabolism) or from blood or From metabolic intermediates.

Dopamine

Norepinephrine

Epinephrine

Glutamate g-Aminobutyrate

Serotonin

Tyrosine

Tryptophan

PLP (vit B6)

deCO2ase

PLP (vit B6)

deCO2ase

PLP (vit B6)

deCO2ase

Introduction contd…

Neuronal proteinSynthesis and processing

PeptidesAmino acids

NT synthesis Introduction contd…

NT receptors

• Receptor clusters in postsynaptic structures.

• Also found in presynaptic membrane -feed back control.

• Each ligand (NT) has many sub types of receptor –different physiologic actions

• For a given ligand receptor types tends to group in large families.

• Many are G protein coupled (Metabotropic), Some are ion channel coupled (ionotropic).

• Prolonged exposure to ligand cause desensitization.

Introduction contd…

Termination of NT function

• Reuptake - They can be taken back up by the pre-synaptic nodule transporter.

• Degradation - Can be degraded by enzyme systems and eventually eliminated in urine.

Monoamine Oxidases (MAO ) Chatachole-O-methyl transferases (COMT) Acetylcholine esterase

• Simple diffusion

Introduction contd…

Acetylcholine

• Neurones that release acetylcholine are said to have cholinergic synapses.

• Found in neuromuscular junctions, parasympathetic branch of ANS and at some CNS synapses.

• Functions mainly as excitatory and some times inhibitory.

• Functions of AcetylcholineAll muscular movementFacilitates LearningFormation of some memoriesREM sleepParasympathetic branch of the ANS

• First neurotransmitter to be discovered in 1921 by Otto Loewi.

AcetylcholineSynthesis, secreation and removal

+ cholineAcetyl-CoAPyruvate

PDH complex(FAD, lipoamide, TPP)

Choline acetyltransferase(CAT)

(inhibited by mercurials)

Acetylcholine

Acetylcholinesterase (AChE)(membrane associated; inhibited by

nerve agents, sarin)

Acetate + choline

Reuptake or diet

(As soon as acetylcholine is synthesized,

It is stored within synaptic vesicles)

Acetylcholine

Ca 2+ dependant release

ReceptorsAcetylcholine

• The actions of acetylcholine are mediated by at least four nicotinic and five muscarnic Receptor sub types

• Nicotinic receptor Has many subunits crossing the cell membrane.

• Muscarnic receptors G protein coupled seven pass single polypeptide

Acetylcholine

Receptors

Serotonin• In 1935, Italian Vittorio Erspamer showed

that an extract from enterochromaffin cells made intestines contract and name them as enteramine.

• In 1948, Maurice and colleagues of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin

• In 1952 it was shown that enteramine was the same substance as serotonin

Origin• High conc. - Hypothalamus, midbrain, brainstem,

pineal organ • Moderate conc. – cerebral cortex, hippocampus,

striatum• Low conc. - cerebellum

Synthesis of Serotonin

Rate limiting step

Elementary Oxygen, pteridine cofactor

Release of Serotonin• Release from nerve

endings in clam hearts.

• It can be released from brain slices and synaptosomes in response to depolarizing stimuli.

• It can be released into the cerebrospinal fluid when raphe neurons are electrically excited.

Receptors• group of G protein-coupled

receptors (GPCRs) and ligand-gated ion channels (LGICs) found in the central and peripheral nervous systems

• 5- HT receptors – on nonserotonergic cells

• Autoreceptors – on serotonin containing neurons

Receptor typesFamily Type Mechanism Potential

5-HT1 Gi/Go-protein coupled.

Decreasing cellular levels of cAMP

Inhibitory

5-HT2 pGq/G11-rotein coupled.

Increasing cellular levels of IP3and DAG

Excitatory

5-HT3 Ligand-gated Na+ and K+cation channel

Depolarizing plasma membrane

Excitatory

5-HT4 Gs - protein coupled. Increasing cellular levels of cAMP

Excitatory

5-HT5 Gi/Go-protein coupled

Decreasing cellular levels of cAMP

Inhibitory

5-HT6 Gs - protein coupled. Increasing cellular levels of cAMP

Excitatory

5-HT7 Gs-protein coupled. Increasing cellular levels of cAMP

Excitatory

Actions in the body• 5-HT2A receptors : mediate platelet aggregation and

smooth muscle contraction. • 5-HT3 receptors - present in the gastrointestinal tract,

area postrema : related to vomiting. • 5-HT4 receptors - present in the gastrointestinal tract :

facilitate secretion and peristalsis. • 5-HT6 and 5-HT7 - are distributed throughout the limbic

system, and the 5-HT6 receptors have a high affinity for antidepressant drugs.

Metabolism and role of serotonin in pineal gland

Role of serotonin in the brain:• Regulate the anterior pituitary• Sleep• Appreciation of pain• Thermoregulation• Control of blood pressure• Appetitive behavior• Drinking• Respiration• Heart rate• memory

Histamine

Synthesized in 1907 by Windaus & Vogt and was found in body tissues.

Best, Dale, Dudley showed that histamine could be extracted from fresh samples of lung & liver.

In 1920 Dale concluded that it can mediate diverse phenomena- body reactions to injury and foreign agents

Origin• Most histamine in the body is generated in granules in

mast cells or basophiles

• Mast cells are especially numerous at sites of potential injury - the nose, mouth, and feet, internal body surfaces, and blood vessels.

• Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter.

• Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach.

• Highest conc. – hypothalamus, medial and ventral nuclei

• Moderate conc. – the midbrain, thalamus, basal ganglia.

Cerebral cortex has a modest amount of histamine.

Histamine synthesisL-aromatic aminoacid decarboxylase

or

Release of Histamine • Histamine release is immunologic.

• Sensitized by IgE antibodies , degranulate when exposed to the appropriate antigen.

• Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release.

• Antibiotics like polymyxin are also found to stimulate histamine release.

• The release follows potassium depolarization• Calcium dependent & Occur by means of exocytosis

Type Location Function

H1 histamine receptor smooth muscle, endothelium, central nervous system tissue

involved in allergic rhinitis symptoms ,vasodilation, bronchoconstriction, bronchial smooth muscle contraction, separation of endothelial cells ,pain and itching due to insect stings; the primary receptors and motion sickness; sleep regulation.

H2 histamine receptorparietal cells stimulate gastric acid

secretion

H3 histamine receptor

central nervous system peripheral nervous system tissue

Decreased neurotransmitter release: histamine, acetylcholine, norepinephrine, serotonin

H4 histamine receptor Found primarily in the basophils and in the bone marrow. It is also found on thymus, small intestine, spleen, and colon

Plays a role in chemotaxis

Actions in the body• Regulate - the water intake - Vasopressin release - thermoregulation - anterior pituitary function - cardiovascular function

• Sleep regulation• Suppressive effects• Schizophrenia

CatecholaminesEpinephrine :

- hormone and a neurotransmitter- Produced by the adrenal glandsDiscovery : - Polish physiologist Napoleon Cybulski in 1895 –

obtained adrenal extracts (nadnerczyna).- Japanese chemist J. Takamine discovered adrenaline

in 1900 and isolated and purified the hormone in 1901

Norepinephrine • The methyl group is replaced by a hydrogen atom

in norepinephrine.

• Released by the sympathetic postganglionic nerve endings

Dopamine

discovered in 1958 by Arvid Carlsson and Nils-Åke Hillarp

origins

Release of catecholamine• Epinephrine and

norepinephrine enter the storage vesicles.

• This is accomplished by VMAT

• In the granulated vesicles these are bound to ATP and associated with a protein – chromogranin A and some large granulated vesicles also contain neuropeptide Y

• Depend on depolarization & influx of Ca2+ ions

• stimulated by acetylcholine

• "stresses" stimulate such secretion

Following secretion into blood, the catecholamines bind loosely to and are carried in the circulation by albumin /serum proteins.

Adrenergic receptors -

Seven pass transmembrane protein coupled to G protein receptors.

2main families- α- β

Receptor Effect of Ligand Binding Effectively Binds

Alpha1 Epinephrine, Norepinphrine

Increased free Calcium

Alpha2 Epinephrine, Norepinphrine

Decreased cyclic AMP

Beta1 Epinephrine, Norepinphrine

Increased cyclic AMP

Beta2 Epinephrine Increased cyclic AMP

DA ReceptorsD1-Like:D1, D5

D2-Like:D2,D3,D4

Agonist(s):

Antagonist(s):

SKF 86393 Quinpirole

SCH 23390 Haloperidol

Locations: AccumbensCaudate/PutamenRetinaParathyroidHypothalamus

PituitaryStriatum (D2)Autoreceptors (all but D4)Accumbens (D2,D3)HippocampusFrontal cortex (D4)

cAMP cAMP

Post-synaptic Pre- and Post-synaptic

MetabotropicAction:

Synaptic Location:

Actions in the body

• Act on nearly all the body tissues• Action vary by tissue type and tissue

expression of adrenergic receptors• tissue type – • Causes smooth muscle relaxation in the

airways but causes contraction of smooth muscle in the arterioles.

NE

E

E

NE, E

Catabolism of catecholamine

oxidation

• Catalyzed by MAO• Present at the nerve endings

which secrete catecholamine• 3,4-didydroxy

phenylcycloaldehyde (DOPGAL)

methylation

• Catalyzed COMT• Methylate at the 3rd position• Widely distributed in liver,

kidney, smooth muscle cells.

metabolized to biologically inactive form

3,4-dihydroxyphenylethylene glycol(DOPEG)

3,4-dihydroxymandelic acid(DOMA)

Uptake or reuptake

• Facilitated by an amine uptake pump.• pump is driven indirectly by a sodium gradient,

which is generated by another plasma membrane protein, the Na+,K+-ATPase / sodium, potassium 'pump‘

• The amine uptake pump is selective for NE > E

Inactivation of Dopamine• In most areas of the brain, reuptake via the dopamine

transporter (DAT1) & then enzymatic breakdown by monoamine oxidase (MAOA and MAOB) into 3,4-dihydroxyphenylacetic acid

• In the prefrontal cortex dopamine is instead inactivated by reuptake via the norepinephrine transporter (NET), presumably on neighboring norepinephrine neurons, then enzymatic breakdown by catechol-O-methyl transferase (COMT) into 3-methoxytyramine

• Dopamine that is not broken down by enzymes is repackaged into vesicles for reuse by VMAT2.

Glutamate

• Glutamate was discovered by Kikunae Ikeda of Tokay Imperial Univ. in 1907, extract from seaweed – glutamate

• Peter Usherwood identified glutamate as a neurotransmitter (in locusts) in 1994

• Main excitatory neurotransmitter in the central nervous system.• Involved in most aspects of normal brain function including

cognition, memory and learning.

Synthesis

• Formed by reductive amination of the Krebs cycle intermediate α-ketoglutarate in the cytoplasm

• Glutamate should be in proper concentration in the right place for right time, both too much and too little glutamate is harmful.

• Almost exclusively located intracellularly (relatively inactive)

• Glutamate is concentrated in synaptic vesicles by the vesicle-bound transporter BPN1

• Three transporters that import glutamate from the interstitial fluid, and two additional transporters carry glutamate into astrocytes (glutamate–glutamine cycle)

The glutamate–glutamine cycle through glutaminergic neurons and astrocytes.

• Uptake into neurons and astrocytes -main mechanism for removal of glutamate from synapses.

Glutamate Receptors• Two types- metabotropic receptors and ionotropic

receptors.

• Metabotropic receptors are G protein-coupled receptors that increase intracellular IP3 and DAG levels or decrease intracellular cAMP levels. (Eleven subtypes)

– Both presynaptic and postsynaptic.– Widely distributed in the brain.– Involved in the production of synaptic plasticity,

particularly in the hippocampus and the cerebellum

• The ionotropic receptors are ligand-gated ion channels.

• Three types– Kainate receptors - 5 subunits, simple ion channel, permit

Na+ influx and K+ efflux. Located presynaptically on GABA-secreting nerve endings and postsynaptically at various localized sites in the brain.

– AMPA receptors – 4 subunits, two types, one is simple Na+

channel and one also passes Ca2+. Located in glia as well as in neurons

– NMDA receptor – Also a cation channel, but it permits passage of relatively large amounts of Ca2+ ,occur only in neuron

• NMDA receptor is unique in several ways– Binding of glycine– Normal membrane potentials, its channel is blocked by a Mg2+

ion– Phencyclidine and ketamine bind to another site inside the

channel

GABA (gamma aminobutyric acid)• In 1950, Eugene Roberts and J. Awapara discovered

GABA • Major inhibitory neurotransmitter of the CNS,

occurring in 30-40% of all synapses• Highly concentrated in the substantia nigra & globus

pallidus nuclei of the basal ganglia, followed by the hypothalamus, the periaqueductal grey matter ("central grey") and the hippocampus.

Synthesis & Catabolism

• Formed by decarboxylation of glutamate catalyzed by glutamate decarboxylase (GAD), present in nerve endings in many parts of the brain.

• Catabolized by transamination to succinic semialdehyde and then to succinate which is fed into citric acid cycle, catalyzed by GABA transaminase (GABA-T).

Synthesis & Catabolism • Both GAD and GABA-T require

Pyridoxal phosphate (PLP) as cofactor, a derivative of the vitamin B6 (B complex vitamin pyridoxine)

• Active reuptake of GABA in to secretory vesicles via vesicular GABA transporter (VGAT)

GABA Receptors• Three subtypes - GABAA, GABAB, and GABAC

• GABAA and GABAB widely distributed in the CNS, whereas in adult vertebrates the GABAC receptors are found almost exclusively in the retina.

– The GABAA and GABAC receptors - ion channels made up of five subunits surrounding a pore, upon activation, receptor selectively conducts Cl-through its pore causes hyperpolarization of the neuron and brings inhibitory effect on neurotransmission.

– The GABAB receptors – metabotropic, coupled to heterotrimeric G proteins that increase conductance in K+ channels, inhibit adenylyl cyclase, and inhibit Ca2+ influx.

GABA Receptors• Increases in Cl– influx and K+ efflux and decreases in Ca2+

influx all hyperpolarize neurons, producing an IPSP. The G protein is a heterodimer rather than a single protein

Actions in the body • Decrease neuron activity thus preventing them from

overfiring.• With niacinamide (Vitamin B3) and inositol, GABA

prevents anxiety and stress-related messages from reaching the motor centers of the brain, and is essential for brain metabolism.

• Too much, however, can lead to anxiety, shortness of breath, numbness around the mouth, and tingling in the extremeties.

• In addition, abnormal levels will interfere with the brain's message system, causing seizures.

Glycine• Glycine was discovered as an inhibitory

neurotransmitter in the spinal cord about 40 years ago (Aprison and Werman 1965).

• Glycine is the major inhibitory neurotransmitter in the brainstem and spinal cord.

• Glycine promotes the actions of glutamate, thus, glycine subserves both inhibitory and excitatory functions within the CNS

• The distribution of glycine in the CNS is more localized than that of GABA.

Synthesis & Catabolism • Synthesized from serine by

the mitochondrial isoform of serine hydroxymethyltransferase.

• Once released from the presynaptic cell, it is rapidly removed from the synaptic cleft by specific membrane transporters.

.

Mutations in the genes coding for some of these enzymes result in hyperglycinemia, a devastating neonatal disease characterized by lethargy, seizures, and mental retardation.

Glycine Receptors• GlyR is an ionotropic receptor that produces its

effects through chloride current. • Most widely distributed inhibitory receptors in

the CNS and has important roles in a variety of physiological processes, especially in mediating inhibitory neurotransmission in the spinal cord and brain stem.

• Activated by glycine, β-alanine and taurine, and can be selectively blocked by the high-affinity competitive antagonist strychnine. Caffeine also be a competitive antagonist.

Glycine Receptors• Members of a family of Ligand-gated ion channels and

are arranged as five subunits surrounding a central pore, with each subunit composed of four α helical transmembrane segments

Actions in the body • Binding to the receptor makes the post-synaptic

membrane more permeable to Cl- ion. This hyperpolarizes the membrane, making it less likely to depolarize. Thus, glycine is an inhibitory neurotransmitter.

• It is de-activated in the synapse by a simple process of reabsorption by active transport back into the pre-synaptic membrane.

• Strychnine can bind to the glycine receptor without opening the chloride ion-channel (it inhibits inhibition). The resultant spinal hyperexcitability is what makes strychnine a poison.

Large-Molecule Transmitters: Neuropeptides

• Substance P & Other Tachykinins

– Substance P is a polypeptide containing 11 amino acid residues, found in the intestine, various peripheral nerves, and many parts of the CNS.

– It is one of a family of six mammalian polypeptides called tachykinins that differ at the amino terminal end but have in common the carboxyl terminal sequence of Phe-X-Gly-Leu-Met-NH2, where X is Val, His, Lys, or Phe.

Substance P & Other Tachykinins

Gene Polypeptide Products Receptors

SP/NKA Substance P Substance P (NK-1)

Neurokinin A

Neuropeptide K Neuropeptide K (NK-2)

Neuropeptide

Neurokinin A (3–10)

NKB Neurokinin B Neurokinin B (NK-3)

• Three neurokinin receptors. Substance P and the neuropeptide K receptors, are G protein-coupled receptors.

• Activation of the substance P receptor causes activation of phospholipase C and increased formation of IP3 and DAG.

Actions in the body

• Substance P is found in high concentration in the endings of primary afferent neurons in the spinal cord, probably the mediator at the first synapse in pain transmission in the dorsal horn.

• Also found in the nigrostriatal system and in the hypothalamus, where it may play a role in neuroendocrine regulation.

• Upon injection into the skin, it causes redness and swelling, and it is probably the mediator released by nerve fibers that is responsible for the axon reflex.

• In the intestine, it is involved in peristalsis• The functions of the other tachykinins are not yet found.

Opioid Peptides• Peptides that bind to opioid receptors are called opioid

peptides.

• Synthesized as part of larger precursor molecules. More than 20 active opioid peptides have been identified.

• Three main precursors have been characterized.

Opioid Peptides and Receptors• The enkephalins are found in nerve endings in the

gastrointestinal tract and many different parts of the brain, and they appear to function as synaptic transmitters.

• Found in the substantia gelatinosa and have analgesic activity when injected into the brain stem and decrease intestinal motility.

• Opioid receptors have been studied in detail, and three are now established (µ,δ,κ), distribution in the brain and elsewhere.

• Different affinities for various opioid peptides. All three are G protein-coupled receptors, and all inhibit adenylyl cyclase.

Opioid receptors

Activation µ of receptors increases K+ conductance, hyperpolarizing central neurons and primary afferents. Activation of δreceptors and κ receptors closes Ca2+ channels.

References

• Neurotransmitters & Neuromodulators, Ganong’s Review of Medical Physiology - 23rd Edition.

• http://www.nature.com/nrn/journal/v2/n4/full/nrn0401_240a.html

• http://www.benbest.com/science/anatmind/anatmd10.html#intro

Neuromodulators

•Are chemicals released by neurons that have little or no direct effect on their own, but can modify the effect of neurotransmitters.

•Neurotransmitters – endogenous chemicals which rely, amplify and modify signals between a neuron & another cell.

•There are 2 major categories of neuromodulators & neurotransmittersSmall-molecule transmitters

Large molecule transmitters

Small molecule transmitters• Monoamines (acetylcholine, serotonin, histamine)• Catecholamine (dopamine, norepinephrine, epinephrine)• Amino acids (glutamate, GABA, glycine)

Large molecule transmitters• Neuropeptides enkephalin substance P vasopressin

• Generally, neuropeptides are colocalized with one of the small molecule transmitters.

• Other substances that act as neurotransmitters or neuromodulators of synaptic transmission.

Purine derivativesEx:adenosine,ATP

Gaseous molecule-nitric oxide (NO)

Neuromodulation

• A process in which several classes of neurotransmitters regulate diverse populations of central nervous system neurons.

• Neuromodulatory transmitters are secreted by a small group of neurons, diffuse through large areas of the nervous system , having an effect on multiple neurons.

ex: dopamine, serotonin, acetylcholine

• It’s a relatively new concept.

• It can be conceptualized as a neurotransmitter that is not reabsorbed by the pre-synaptic neuron or broken down to a metabolite.

• Ends up spending a significant amount of time in the CSF (cerebrospinal fluid); influencing the overall activity level of the brain.

• Therefore some neurotransmitters are also considered as neuromodulators.

• Many neuromodulators do also act as neurotransmitters.

• A group of neuromodulators are called ganglion. -32 pairs of ganglion throughout the body

Neuromodulation vs direct synaptic transmission

• Neuromodulation is contrast to direct synaptic transmission in which one pre-synaptic neuron directly influence a postsynaptic partner.

• In both cases, transmitters act on local post synaptic receptors, but in neuromodulation ,

o Receptors are 7-membrane spanning G-protein couple receptorso involve effect on voltage-gated ion channels

o Process is quite slow

• In direct synaptic transmission,o Involve effect on ligand gated ion channels.

o Process is much faster.

The role of Neurotransmitters in addictive substance pharmacology and clinical diseases

Structure of the presentation

1. Cannabis and neurotransmitters2. LSD, Ecstasy and “magic mushrooms”3. Nicotine4. Phenylketoneuria5. Bipolar mental disease6. Schizophrenia7. References

Cannabis

• Is a commonly used drug for medical and religious uses since ancient times

• Extracted from the plant Cannabis sativa

• The main psychoactive product is Δ9-tetrahydrocannabinol (THC)

• About 60 other cannabinoides are also identified from this plant

Cannabis and neural transmission

• Endogenous cannabinoids are produced by the human body as neurotransmitter substances, “anandamide” and “pamitoylethanolamide (PEA)” are examples.

• Anandamide is the natural ligand of CB1 receptor while PEA binds to CB2 receptor

• THC binds to CB1 receptor and produces euphoria, calmness, dream states, drowsiness and analgesia. Same effects are produced by Anandamide which is an Arachidonic acid derivative.

• CB1 receptor is a G-protein coupled receptor which decreases the cAMP levels in the neurons. It is found in cerebellum, hippocampus, cerebral cortex and also in peripheral tissues.

Structures of THC and Anandamide

THC

Anandamide

LSD• LSD or lysergic acid diethylamide was discovered accidently by a Swiss chemist named Albert Hoffmann who also discovered its psychedelic effects by accidently absorbing it through finger tips.• It activates 5-HT2 receptors in the brain and acts as a serotonin agonist.• Although LSD is a mind altering substance it is NON-ADDICTIVE.

Non-addictive nature of LSD

Fish, Jefferson M. (2006). Drugs and Society: U.S. Public Policy. Lanham, MD: Rowman & Littlefield. pp. 149–162. ISBN 0742542459.

Ecstasy• Ecstasy or 3,4-methylenedioxymethamphetamine (MDMA) is

an abused mind altering substance which causes euphoria.• It is followed by difficulty in concentrating and depression,

and in monkeys, insomnia. • Firstly It causes release of seretonin by phosphorylating its

transporters and later depletion of seretonin. • Euphoria could be due to release of seretonin and later

symptoms may be due to its depletion. • MDMA is a weak agonist of 5-HT1 and 5-HT2 receptors.• It is also a strong competitive antagonist of vesicular

monoamine transporter (VMAT).

“Magic mushrooms”• Magic mushrooms or

“psilocybin mushrooms” are fungi which naturally produce psychedelic substances psilocybin and psilocin.

• Most of them belong to the genus Psilocybe.

• They were used even among prehistoric Hominids in Africa some 1 million years ago.

Psilocybe cubensis

Pharmacology of psilocybin and psilocin

• Psilocybin is rapidly dephosphorylated in the body to psilocin which then acts as a partial agonist of the 5-HT2A receptor in the brain.

• Psilocin derivatives were used to determine the actions and structure of 5-HT2C G-protein coupled receptor.

Psilocybin

Psilocin

Nicotine

• Nicotine is an alkaloid obtained from Tobacco plant. The plant uses it as a defense against insects and herbivores.

• Nicotinic receptors are found in CNS and peripheral tissues.

• They are ligand gated Na+ ion channels that also mediate Ca2+ ion transport.

Phenylketoneuria (PKU)

• PKU is a disease where there is excess accumulation of the amino acid Phenylalanine and its metabolites in the blood steram.

• This may be due to either deficiency of enzyme Phenylalanine hydroxylase (PAH), which is an autosomal recessive genetic disorder or due to the deficiency of the cofactor Tetrahydrobiopterin (BH4) which is necessary for the action of PAH.

• PKU can be treated successfully with a low-Phenylalanine diet but if untreated it can cause mental retardation, brain damage and seizures.

• Phenylalanine when converted to Tyrosine produces Dihydroxyphenylalanine (DOPA), which is the precursor of Dopamine, Norephinephrin and Ephinephrin.

Bipolar mental disease (BPD)

• BPD or manic depressive disorder is a psychiatric disorder where the patient undergo changes of mood from manic to depressed.

• When the patient is in the manic phase a “high” is experienced and characteristics like insomnia, aggressive behavior, racing thoughts, increased sex drive and overconfidence are shown.

• In the depressed part of the cycle suicidal, sad and melancholic thoughts are prevalent and the patient also may lose appetite and sex drive.

• It has Genetic, Biochemical, Psychological, Social and Cultural roots but the exact cause remains elusive.

• It must be noted that there are repeated findings which correlate BPD with high creativity.

Hypotheses of causes of BPD in the context of neurotransmitters and their receptors

Hypotheses of causes of BPD in the context of neurotransmitters and their receptors

Biogenic amine

hypothesis

Mechanisms involving

AcetylcholineReceptor

hypothesis

Biogenic amine hypothesis

• Monoamines and Catecholamines are called biogenic amines.Relative deficiencies of Norephinephrin (NE),Dopamine (DA) and Serotonin (5-HT) in the synaptic cleft cause depression while their abundance causes mania.

• The use of Monoamine Oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs) as antidepressants suggest this view.

• Also it has been very consistently observed that patients with low CSF concentrations of 5-Hydroxyindolacetic acid (5-HIAA) are very prone to suicide.

• 5-HIAA is a metabolite of Serotonin. Therefore CSF levels of 5-HIAA is an indication of brain Serotonin level.

• There are inconsistencies in this hypothesis such as the anti-manic drug Lithium not chronically increasing synaptic Monoamine concentrations and Cocaine , which is a potent inhibitor of Monoamine reuptake not being effective for treating depression.

Mechanisms involving Acetylcholine

• It has been understood that hyper-cholinergic states in synaptic cleft cause depression while hypo-cholinergic states cause mania.

• Acetyl cholinesterase (ASE) inhibitors and cholinomimetics cause depressive symptoms while anticholinergic agents have some antidepressant and euphorigenic activity.

• In addition to this it has been observed that anticholinergic toxicity can result in a state of mania.

• It has been suggested that an abnormal imbalance between cholinergic and monoaminergic systems cause BPD and other mood disorders.

Receptor hypothesis• Several observations have pointed out the possibility of a strong

link between receptors and BPD.• For an example β-Adrenergic and 5-HT2 receptor density goes

down with antidepressant use.• Lithium and antidepressants reduce the expression of G-protein

subunits.• NE and isoproterenol mediated cAMP accumulation in brain

gets reduced with long term (>2weeks) exposure to antidepressants.

• Therefore secondary messenger signaling cascades lose their intensity.

• In addition to this BPD patients show an increase in expression of GS protein subunits. But in depressed patients GS protein expression is low.

Some notable people with BPD

• Kay Redfield Jamison• Ludwig Boltzmann• Frank Bruno• Kurt Cobain• Mel Gibson• Ernest Hemingway• Florence Nightingale• Jean-Claude Van Damme

Schizophrenia- “The broken mind”

• The psychotic disease schizophrenia is characterized by a cluster of symptoms.

• Delusions, hallucinations and disorganization of thought are common among schizophrenics.

• It is generally accepted that schizophrenia is a group of disorders with a common overlapping phenotype rather than a single disease entity.

• Approximately 1% of world population suffer from this disease.

• The suicide rate is very high among schizophrenics where 9 to 13% commit suicide.

Neurotransmitters, receptors and schizophrenia• Two neurotransmitters play a major role in schizophrenia,

Dopamine and Serotonin namely. • Genome scanning through linkage has shown that Dopamine

receptor genes D2 and D4 and Serotonin receptor gene 5-HT2A play important roles in disease.

• One established genetic alteration occurs in 5-HT2A receptor gene nucleotide 102 where the Thymine residue is replaced by a Cytosine residue.

• The suspicion that Dopamine and it’s receptors play a major role in schizophrenia is justified by the fact that all antipsychotic drugs that are prescribed for the disease inhibit Dopamine receptors.

• In addition to this GABA and other amino acids, Acetylcholine and even neuropeptides play a major role in schizophrenia.

References

1. Basic Neurochemistry; Molecular, Cellular and Medical aspects, 6th edition; G. Siegle, B. Agranoff, W. Albers, S. Fisher and M. Uhuler; Lippincott Williams and Wilkins, 1999.

2. Review of medical physiology, 23rd edition; W. Ganong, K. Barret, S. Barman, S. Boitano and H. Brooks; McGraw-Hill; 2010.

3. Textbook of medical physiology; 11th edition; A. Guyton and J. Hall; Elsevier; 2008.

4. Principles of Biochemistry, 5th edition; A. Lehninger, M. Cox and D. Nelson; Freeman; 2008.

5. Biology , 8th edition; P. Raven, G. Johnson, J. Losos, K. Mason, S. Singer; 2010.