Neurotransmitters

and

Neuromodulators

Neurotransmitters

Chemical that diffuses across a synapse, and thus transmits impulses between nerve cells or between nerve cells and effector organs (for example, muscles). Common neurotransmitters are the amino acids glutamate and GABA (gamma-amino butyric acid), as well as noradrenaline (which also acts as a hormone) and acetylcholine, the latter being most frequent at junctions between nerve and muscle.

Schematic representation of the main neurotransmission steps at a synapse. The neurotransmitter is synthesized in the presynaptic neuron, stored in synaptic vesicles (by the VNT), and released by exocytosis. The neurotransmitter then acts at metabotropic and/or ionotropic receptors (RNT, E: effector), and is removed from the synaptic cleft by uptake in presynaptic or postsynaptic neurons and/or glial cells. The uptake process is carried out by plasma membrane-bound neurotransmitter transporters (PNT).

Neurotransmitters and Neuromodulators

In chemical synapses, there is a gap between the

presynaptic cell membrane and the postsynaptic

cell membrane, known as the synaptic cleft. Information is transmitted across the synaptic cleft

via a neurotransmitter (synaptic transmitter),

Which is a substance that is released from the presynaptic terminal and binds to specific receptors on the postsynaptic terminal.

Neurotransmitters
The following criteria are used to formally designate a substance as a neurotransmitter: The substance must be synthesized in the presynaptic cell. The substance must be released by the presynaptic cell upon stimulation. If the substance is applied exogenously to the postsynaptic membrane at physiologic concentration, the response of the postsynaptic cell must mimic the in vivo response.

Classes of neurotransmitters
Transmitter molecule Acetylcholine Derived from Choline Site of synthesis CNS,Parasympathetic Nerve

Serotonin
GABA

5-Hydroxytryptamine (5-HT)

Tryptophan
Glutamate

CNS, chromaffin cells of the gut, enteric cells

CNS CNS CNS spinal cord

Glutamate Aspartate Glycine Histamine Epinephrine synthesis pathway Norpinephrine synthesis pathway Histidine Tyrosine Tyrosine

hypothalamus Adrenal Medulla ,some CNS cells CNS, sympathetic nerves

Transmitter molecule

Derived from

Site of synthesis

Dopamine synthesis pathway

Tyrosine

CNS

Adenosine

ATP

CNS, peripheral nerves

ATP

sympathetic, sensory and enteric nerves

Nitric oxide, NO

Arginine

CNS, gastrointestinal tract

Classes of neurotransmitters
Small-Molecule, Rapidly Acting Transmitters

Classes of neurotransmitters (cont.)

Neuropeptide, Slowly Acting Transmitters or Growth Factors

Small Molecule Transmitter Transport and Synthesis

synthesis of transmitter within the axon terminal required enzymes transported from the cell body (slow ax. trans.) precursors taken up at terminal

Large Molecule Peptide Transmitter Synthesis and Transport

precursors synthesized in cell body transported to nerve terminal via fast axonal transport precursors packaged into synaptic vesicles further post-translational modification of precursor to form final peptidergic transmitter (s)

Neurotransmitter receptors
1. Ionotropic (Direct) 2. Metabotropic (Indirect)

Ionotropic receptors

Directly--Activated Ion Channels (Ionotropic)

The receptor that binds neurotransmitter is the ion channel FAST--acting channel Terminology: Ligand-gated or ligand activated or ionotropic Channel can flux anions or cations

Metabotropic receptors (Indirect)

Metabotropic receptors (Indirect)

Metabotropic Receptors (Indirect)

Indirectly- Activated Ion Channels (Metabotropic)

SEPARATE ion pore (from the receptor that binds neurotransmitter) Ion pore activated by a G--protein or second messenger (released as NT binds receptor) Slower-- acting, more long lasting effect Channel can flux anions or cations

Second messenger system by which a transmitter substance from an initial neuron can activate a second neuron

Acetylcholine
It exists enclosed in small, clear synaptic vesicles in the terminal buttons of neurons that release acetylcholine (cholinergic

neurons).

Acetylcholine Synthesis and hydrolysis

Acetylcholine (cont)
Acetylcholine receptors
They are divided into two types on the basis of their pharmacologic properties

1- Muscarinic cholinergic receptors 2- Nicotinic cholinergic receptors

Acetylcholine (cont)
Acetylcholine receptors (cont.)
Muscarinic receptors
The nomenclature of these receptors has not been standardized, but the receptor designated M1 in is abundant in the brain. The M2 receptor is found in the heart.

The M4 receptor is found in pancreatic acinar and islet tissue, where it mediates increased secretion of pancreatic enzymes and insulin. The M3 and M4 receptors are both found in smooth muscle. The exact status of M5 is uncertain

Acetylcholine (cont)
Acetylcholine receptors (cont.)
Nicotinic receptors are subdivided into those found in muscle at neuromuscular junctions and those found in autonomic ganglia and the central nervous system. Both muscarinic and nicotinic acetylcholine receptors are found in large numbers in the brain.

Muscarinic ACh receptors in the pacemaker cells of the heart

Nicotinic Ach receptors

It also function as ligand-gated ion channels. It contains a channel that is closed (a) until the receptor binds to ACh. (b) Na+ and K+ diffuse simultaneously, and in opposite directions, through the open ion channel. The electrochemical gradient for Na+ is greater than for K+, so that the effect of the inward diffusion of Na+ predominates, resulting in a depolarization known as an excitatory postsynaptic potential (EPSP).

Acetylcholine (cont)
Acetylcholine is secreted by neurons in many areas of the nervous system but specifically by (1) the terminals of the large pyramidal cells from the motor cortex, (2) several different types of neurons in the basal ganglia, (3) the motor neurons that innervate the skeletal muscles, (4) the preganglionic neurons of the autonomic nervous system, (5) the postganglionic neurons of the parasympathetic nervous system, and (6) some of the postganglionic neurons of the sympathetic nervous system. In most instances, acetylcholine has an excitatory effect; however, it is known to have inhibitory effects at some peripheral parasympathetic nerve endings, such as inhibition of the heart by the vagus nerves.

Classification of CHOLINERGIC DRUGS

Acetylcholine receptor agonists Alvameline Muscarine (muscarinic receptors) Nicotine (nicotinic receptors) Pilocarpine (M3 receptors) Suxamethonium (muscle type receptors) Acetylcholine receptor antagonists Scopolamine Dicycloverine Tolterodine Oxybutynin Ipratropium

Acetylcholinesterase inhibitors (abbreviated AChEIs)

Donepezil Galantamine Huperzine A Neostigmine Physostigmine Rivastigmine

STIMULATION OF ACETYLCOLINE
Direct acting agents (agonists) activate the receptor site by mimicking the effects of acetylcholine. Cholinesterase inhibitors act indirectly by preventing the enzyme from hydrolyzing (inactivating) acetylcholine at the receptor site. This inhibition permits the buildup of acetylcholine and results in more intensive and prolonged activation of the receptor site

The effects of cholinergic stimulation include: vasodilation of blood vessels; slower heart rate; constriction of bronchioles and increased secretion of mucus in the respiratory tract; intestinal cramps; secretion of salvia; sweat and tears; and constriction of eye pupils. Direct Acting Cholinergic Agents Agonists: Direct stimulation of acetylcholine receptors is achieved by: Arecholine, Pilocarpine, Urecholine(Betanechol), Carbachol, Choline, Metacholine

Indirect Acting Cholinergic Stimulating Agents:

Acetylcholine Inhibitors Toxic Poisons

Catecholamines

The catecholamines are so named because they contain a catechol ring (a six carbon ring with two adjacent hydroxyl groups) and an amine group.

The catecholamines are 1- Dopamine 2- Norepinephrine 3- Epinephrine

Catecholamines (cont.)

The chemical transmitter present at most sympathetic postganglionic endings is norepinephrine. It is stored in the synaptic knobs of the neurons that secrete it in small vesicles which have a dense core (granulated vesicles)

Norepinephrine and epinephrine are secreted by the adrenal medulla

There are also norepinephrine-secreting, dopaminesecreting, and epinephrine-secreting neurons in the brain

The synthesis of Catecholamines

The production, release, and reuptake of catecholamine neurotransmitters. The transmitters combine with receptor proteins in the postsynaptic membrane. (COMT = catecholO-methyltransferase; MAO = monoamine oxidase.)

Catabolism of Catecholamines

Norepinephrine

Norepinephrine is secreted by the terminals of many neurons whose cell bodies are located in the brain stem and hypothalamus.

Specifically, norepinephrine secreting neurons located in the locus ceruleus in the pons send nerve fibers to widespread areas of the brain to help control overall activity and mood of the mind, such as increasing the level of wakefulness.

In most of these areas, norepinephrine probably activates excitatory receptors, but in a few areas, it activates inhibitory receptors instead.

Alpha & Beta adrenergic receptors

Epinephrine and norepinephrine both act on and receptors, with norepinephrine having a greater affinity for -adrenergic receptors and epinephrine for -adrenergic receptors

Adrenergic Receptor Sites:

Alpha Receptor Site: Important features of the site include in order of importance: An anionic site - which binds the positive ammonium group. 2) One hydrogen bonding area 3) A flat area non-polar area for the aromatic ring.

Beta Receptor Site: Important features of the site include in order of importance 1) An anionic site - shown as Asp anionic negative acid group which binds the positive ammonium group. 2) Two hydrogen bonding areas - shown as two Serine with alcohol (OH) groups hydrogen bonding to the phenol OH groups of the NE. 3) A flat area non-polar area for the aromatic ring.

Tissue

Receptor Subtype

Agonists

Antagonists

Heart

beta1

NE, EP, dobutamine, xamoterol

atenolol, metoprolol.

Adipose tissue

beta1, beta 3

Vascular Smooth Muscle Airway Smooth Muscle

beta 2

EP, salbutamol, terbutaline, salmeterol terbutaline, salbutamol, salmeterol and zinterol, NE, EP, phenylephrine, oxymetazoline

butoxamine

beta 2

butoxamine

Smooth muscle contraction Inhibition of transmitter release

alpha 1

prazosin, doxazocin

clenbuterol, alphayohimbine, methylnoradrenaline idazoxan,

Receptor Sites
alpha-receptor Vasoconstriction iris dilation intestinal relaxation intestinal sphincter contraction beta-receptor vasodilation (b2) cardioacceleration (b1) intestinal relaxation (b2) uterus relaxation(b2)

bladder sphincter contraction

bronchodilation (b2)

Adrenergic Stimulants:
Adrenergic drugs stimulate the adrenergic nerves directly by mimicking the action of nor epinephrine. Adrenergic stimulants may have three modes of action: direct interaction with specific receptors (examples are epinephrine and phenylephrine) indirect action by stimulating release of neurotransmitters; or a mixed action involving both of the above (examples are phenylpropanolamine and ephedrine).

Bronchodilators:
Epinephrine and ephedrine are mainly used in the treatment of bronchial asthma This respiratory disease results from a spasmodic contraction of the smooth muscles of the bronchi In an acute asthmatic attack, manifested by great difficulties in breathing, epinephrine or isoproternol is administered by injection or inhalation. These drugs act directly on beta receptors to relax the smooth muscles (bronchodilation).

The swelling of blood vessels of the mucous membranes of the nasal passage causes nasal discharge and obstruction. Vasoconstrictor agents or nasal decongestants act on local sympathetic nerves and shrink swollen nasal membranes. Decongestants are either topically administered as drops and inhalants or are orally ingested. Although topically administered nasal decongestants do shrink membranes, the relief is only temporary and is followed by "rebound congestion"

Nasal Decongestants and Vasopressors

nasal decongestant alpha or beta

vasopressor, bronchodilator, nasal decongestant alpha or beta vasopressor, bronchodilator, nasal decongestant alpha or beta

nasal decongestant

vasopressor nasal decongestant

alpha

Vassopressor, bronchodilator, nasal decongestant alpha or beta

alpha

Cardiac Activation:

Ephinephrine can be injected directly into the heart to stimulate it after it as stopped beating due to drowning, suffocation, shock, electrocution, and anesthesia.

Adrenergic Blocking Agents or Antagonists:

Adrenergic blocking agents are drugs that selectively inhibit specific receptor sites from sympathetic stimulation. There are several modes of action which over all result in a depression of adrenergic nerves. Blocking agents may interact with specific alpha and beta receptors. The release of nor epinephrine from storage sites may be blocked. The storage of nor epinephrine may be inhibited.

Antagonists which block alpha receptors sites include: Prazosin and analogs - terazosin, doxazosin, trimazosin These are used to treat hypertension by relaxing arterial and venous smooth muscle, decreasing vascular resistance and venous return, and decreasing blood pressure without a significant increase in heart rate

Antagonists which block beta receptors sites include: Hypertension. Inderol or Propranolol and Nadolol is effective in treating mild to moderate hypertension. In severe hypertension, it is useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. Xylocholine bromide is an example of an agent which blocks the release of norepinephrine from storage.

Serotonin
Serotonin (5-hydroxytryptamine; 5-HT) is present in highest concentration in blood platelets and in the gastrointestinal tract, where it is found in the enterochromaffin cells and the myenteric plexus. Lesser amounts are found in the brain and in the retina.

Serotonin receptors

Currently, there are 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5HT5, 5-HT6, and 5-HT7 receptors. Within the 5-HT1 group, there are 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F subtypes. Within the 5-HT2 group, there are 5-HT2A, 5-HT2B, and 5-HT2C (formerly called 5-HT1C) subtypes. There are two 5-HT5 subtypes, 5-HT5A and 5-HT5B.

Most of these receptors are coupled to G proteins and affect adenylyl cyclase or phospholipase C. However, the 5-HT3 receptors, like nicotinic cholinergic receptors, are ion channels. Some of the serotonin receptors are presynaptic, and others are postsynaptic.

Biosynthesis and catabolism of serotonin

Serotonin (cont.)

Serotonin is secreted by nuclei that originate in the median raphe of the brain stem and project to many brain and spinal cord areas, especially to the dorsal horns of the spinal cord and to the hypothalamus.

Serotonin acts as an inhibitor of pain pathways in the cord, and an inhibitor action in the higher regions of the nervous system is believed to help control the mood of the person, perhaps even to cause sleep.

SER0TONIN SYSTEM