Neurotransmitters

A chemical released by one neuron that affects another neuron or an effector organ (e.g., muscle, gland, blood vessel)

• Excitatory neurotransmitters – cause depolarization• Inhibitory neurotransmitters

– cause hyperpolarization

Neurotransmitters

Attributes of “classical” neurotransmitters

Synthesized in the presynaptic cell Stored in membrane-bound vesicles

(synaptic vesicles) Released from the presynaptic vesicle in

response to membrane depolarization Induction of a physiological response in the

post synaptic cell (by depolarizing or hyperpolarizing its membrane)

inactivated (rapidly) in the synaptic cleft

Classification of neurotransmitters

GROUP EXAMPLES amines acetylcholine (Ach),

norepinephrine, epinephrine, dopamine, 5-HT

amino acids glutamate, GABApurines ATP, adenosinegases nitric oxidepeptides endorphins, tachykinins, many

others

EXCITATORYAcetylcholine GlutamateNorepinephrine AspartateEpinephrine Histamine

INHIBITORYGABA Glycine

MIXEDDopamine Serotonin

Excitatory/inhibitory neurotransmitters

Release of neurotransmitters

Neurotransmitters bind to receptors

Ionotrophic receptors: these act as ion channel themselves to produce their effects.

Metabotrophic receptors: these activate second messenger system (cAMP, PIP3) to produce their effects.

biogenic amines

Neurotransmitters – biogenic amines

Catecholamines• Dopamine• Norepinephrine• Epinephrine

Indoleamines• Serotonin (5-HT)• Melatonin

Catecholamines – functionsDopamine: control of voluntary movement (nigrostriatal tract), emotional responses and memory (limbic system)Norepinephrine: “fight or flight response” such as stimulation of heart rate, sweating, skin vasoconstriction and bronchodilation (sympathetic nervous system), state of alertness (brain stem)Epinephrine: response to stress, redirection of blood from skin to heart, glycogen metabolism, blood pressure (adrenal medulla under influence of Ach-containing nerves)

Tyrosine

L-Dihyroxyphenylalanine (DOPA)

Tyrosine hydroxylaseBH4

BH2

Dopamine

Dopa decarboxylase PLPCO2

Norepinephrine

Dopamine β hydroxylase Cu++, Vit CO2

NEU

RON

SADREN

AL MEDU

LLA

Epinephrine

Phenylethanolamine N-methyltransferase

SAM

SAHVit B12 Folate

Catecholamines - Synthesis

Parkinson’s disease• Degeneration of nigrostriatal dopamine neurons in the

brain resulting in a deficiency of Dopamine• Symptoms include trembling of hands, arms, legs, jaw

and face; stiffness of the arms, legs and trunk; slowness of movement; poor balance and coordination

• Treatment with L-DOPA which enters the brain and is decarboxylated to dopamine.

• L-DOPA is given together with carbidopa, DOPA carboxylase inhibitor that cannot enter the brain, preventing unwanted formation of dopamine outside the brain

Serotonin: involved with mood, anxiety, appetite, sleep induction, memory and learning

Melatonin: involved in response to light-dark cycle organizing seasonal and circadian rhythms, regulating reproductive functions

Indoleamines – functions

Tryptophan

5’hyroxytryptophan

Tryptophan hydroxylaseBH4

BH2

Serotonin

Dopa decarboxylase PLPCO2

Vit B12 Folate

Synthesis – indoleamines

Acetyl CoA

Melatonin

SAM

SAH

CoASH

Degradation–Norepinephrine

Degradation–monoamines Norepinephrine

epinephrine

Vanillylmandelic acid

Dopamine

Homovanillic acid

Serotonin

Hydroxyindoleaceticacid

MAO-A,-BCOMT

MAO-BCOMT

MAO-A

Endocrine tumors (pheochromocytoma, Carcinoid syndrome) diagnosed by the measurements of these breakdown products in urine.

monoamines- release and uptake

Monoamines and depression

• “amine theory of depression” states that depression is caused by a relative deficiency of amine neuro-transmitters at central synapses

• Prevention of catabolism of catecholamines and serotonin reduce depression by elevating the levels of these compounds. MAOA inhibitors act as antidepressants

• Inhibitors of norepinephrine and serotonin transport into neurons also act as antidepressants (e.g. prozac; serotonin reuptake inhibitor)

Histamine

Histamine – Functions

• Dilates blood vessels, increases capillary permeability, contracts bronchial and intestinal smooth muscle, stimulates gastric acid secretion and nasal fluid discharge

Histamine - synthesis and degradation

Acetylcholine

Acetylcholine - functions

• Major neurotransmitter at the neuromuscular junctions to induce muscle contraction

• Play an important role in attention, learning, reward pathways and memory by reinforcing the ability to detect and respond to meaningful stimuli

Neurons associated with Ach degenerate in Alzheimer's disease resulting in declining language and perception, confusion and memory loss.

Acetylcholine – synthesis and degeneration

Acetylcholine- release and inactivation

Disorders of acetylcholine metabolism

Myasthenia gravis: a disease characterized by muscle weakness. Autoimmune disorder due to formation of antibodies against the nicotinic Ach recptors, preventing trnsmission of nerve impulses to muscles. Treated by inhibitors of Ach esterase (pyridostigmine, neostimine) and corticosteroids

Lambert-Eaton myasthenic syndrome: autoimmune disorder also characterized by muscle weakness. Due to auto-antibodies against the presynaptic voltage-gated calcium channels

Acetylcholinesterase inhibitors

• Organophosphate insecticides and nerve gases (sarin) inhibit acetylcholinesterase resulting in an excess of Ach, initially causing uncontrolled muscle contraction and eventually paralysis. Treatment by atropine.

Amino acids as neurotransmitters

Amino acids as neurotransmittersRecruited as neurotransmitters by packaging into

synaptic vesicles Their action is terminated by sodium dependent

high affinity uptake with need for any specific degradative enzymes

EXICTATORY INHIBITORYGlutamate GlycineAspartate GABA

Glutamate/GABA - synthesis

Inhibitors of Amino Acid NT

Benzodiazapines (valium, Xanax) bind GABA receptors reducing anxiety, inducing sleep and guarding against seizures (anticonvulsants)

Barbiturates produce a wide spectrum of effects, from mild sedation to total anesthesia by potentiating inhibitory GABA receptors and inhibiting excitatory AMPA glutamate receptors

Strychnine binds to glycine rectorss leading to convulsions, spastic contraction of skeletal muscles and death due to impairment ot muscles of respiration.

NITRIC OXIDE

NITRIC OXIDENO is not stored in vesicles but released directly into the extracellular space

Functions• Relaxation of vascular and intestinal smooth

muscle• Neural transmission• Regulation of mitochondrial energy production• Cytotoxic action on parasites and tumor cells

NITRIC OXIDE - synthesis

Peptides

Peptides

Over 80 peptides shown to influence neural functionsSynthesized as precursor proteins, packaged into vesicles and cleaved to the active form by peptidases

e.g.Opioids peptides (endorphins, enkephalins)Regulate pain and pleasure pathways Substance P transmits signals in response to pain

Opioid receptors are sites of action for morphine and codeine which are powerful analgesics

Opiates affect pleasure pathways in the brain resulting in the associated euphoric effects. Endorphins released after strenuous exercise give the so-called “jogger's high”

Peptides inhibitors

the end!!