Neurotransmitters

Neurotransmitters

• Are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse.

• Are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse.

• Release of neurotransmitters usually follows arrival of an action potential at the synapse, but may also follow graded electrical potentials.

Neurotransmitter

Reuptake pump

Receptor

Synaptic vesicle

Voltage gated Ca channel

Postsynapticdensity

Axon terminal

Synaptic cleft

Dendrite

Structure of a typical synapse

Action of neurotransmitters

• 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 that the transmitter binds to.

Three major categories of neurotransmitters in the human brain

• Biogenic amine neurotransmitters– Serotonin– Norepinephrine– Epinephrine– Dopamine– Histamine– Acetylcholine

• Peptide neurotransmitters– Cholecystokinin– Vasopressin– Somatostatin– neurotensin

• Amino acid neurotransmitters– Gamma-aminobutyric acid (GABA)– Glutamate– Aspartic acid – Glycine

• Although there are many neurotransmitters in the CNS, the peripheral nervous system has only two: ACETYLCHOLINE and NOREPINEPHRINE.

Glycine

• The simplest of amino acids, consisting of an amino group and a carboxyl (acidic ) group attached to a carbon atom.

• Function: when release into a synapse, glycine binds to a receptor which makes the post-synaptic membrane more permeable to chloride ion. This hyperpolarizes the membrane making it less likely to depolarize. Thus, it is an INHIBITORY neurotransmitter

• A neurotransmitter only in vertebrate animals. • The glycine receptor is primarily found in the ventral

spinal cord.

Aspartic acid (Aspartate)

• Primarily localized to the ventral spinal cord.• An excitatory neurotransmitter, which

increases the likelihood of depolarization in the postsynaptic membrane.

• Aspartate and glycine form an excitatory/inhibitory pair in the ventral spinal cord comparable to the excitatory/inhibitory pair formed by glutamate and GABA in the brain

Glutamic acid (Glutamate)

• Most common neurotransmitter in the brain.• It is always excitatory.• The most abundant excitatory neurotransmitter.• At chemical synapses, glutamate is stored in

vesicles. Nerve impulses trigger release of glutamate from the pre-synaptic cell. In the opposing post-synaptic cell, glutamate receptors bind glutamate and are activated. It is involved in cognitive functions like learning and memory in the brain.

• Excitotoxicity due to glutamate occurs as part of the ischemic cascade and is associated with stroke and diseases like amyotrophic lateral sclerosis, autism, some forms of mental retardation, and Alzheimer’s disease.

• Excessive activation of glutamatergic synapses can lead to very large influxes of calcium into neurons, which can cause neuronal cell death.

• Because glutamate is an excitatory neurotransmitter, excessive glutamate release might lead to further excitation of neuronal circuits by positive feedback, resulting in a damaging avalanche of depolarization and calcium influx to neurons.

Gamma amino butyric acid (GABA)

• The major inhibitory neurotransmitter of the brain, occurring in 30-40% of all synapses (second only to glutamate as a major brain neurotransmitter).

• It is most highly concentrated in the substancia nigra and globus pallidus nuclei of the basal ganglia, followed by the hypothalamus, the periaqueductal grey matter and the hippocampus.

• Its concentration in the brain is 200-1000 times greater than that of the monoamines or acetylcholine.

Gamma aminobutyric acid

• Present relatively in large amounts in the gray matter of the brain and spinal cord.

• It is an inhibitory substance and probably the mediator responsible for presynaptic inhibition

Acetylcholine

• The first neurotransmitter discovered and is the major neurotransmitter in the peripheral nervous system.

• Usually (but not always) an excitatory neurotransmitter—in contrast to the monoamine neurotransmitters, which are nearly always (with a few exceptions) inhibitory.

• In the brain, it is produced from acetyl-CoA, resulting from glucose metabolism and from choline, which is actively transported across the blood-brain barrier.

Acetylcholine

• There are comparatively few acetylcholine receptors in the brain, but outside the brain acetylcholine is the major neurotransmitter controlling the muscles.

Dopamine

• The primary monoamine neurotransmitters are dopamine, norepinephrine and serotonin.

• Dopamine and norepinephrine are catecholamines.

• Serotonin is an indolamine.

• The amino acid tyrosine, synthesized in the liver is transported to the brain then converted to DihydrOxyPhenylAlanine (DOPA) by the tyrosine hydroxylase enzyme using oxygen, iron and tetrahydrobiopterin (THB) as cofactors. DOPA is converted to dopamine.

Functions of dopamine• Movement : Dopamine is a crucial part of the basal ganglia motor

loop. This means that it is absolutely critical to the way our brain controls our movements. Shortage of dopamine causes Parkinson’s disease, in which a person cannot execute smooth, controlled movements.

• Pleasure and motivation: Dopamine is connected with the pleasure system of the brain. It provides feelings of enjoyment and reinforcement which motivates us to do or continue doing certain activities

• Cognition and frontal cortex function: dopamine controls the flow of information to other parts of the brain. This occurs in frontal lobes. Disorders in this part of the brain can cause a decline in memory, problem solving and attention.

• Dopaminergic neurons form a neurotransmitter system which originates in substancia nigra, ventral tegmental area (VTA), and the hypothalamus. These projects axons to large areas of the brain through 4 major pathways:– Mesocortical pathway connects to the frontal lobe of the

prefrontal cortex– Mesolimbic pathway carries dopamine from the VTA to the

nucleus accumbens via the amygdala and hippocampus– Nigrostriatal pathway runs from the substancia nigra to the

neostriatum– Tuberoinfundibular pathway is from the hypothalamus to the

pituitary gland

Norepinephrine

• One of the two neurotransmitters in the peripheral nervous system.

• It is synthesized from dopamine by means of dopamine beta hydroxylase (DBH), with oxygen, copper and Vitamin C as co-factors. It is synthesized in the neurotransmitter storage vesicles.

• The most prominent noradrenergic nucleus is the LOCUS CERELEUS in the pons.

• Electrical stimulation of the locus cereleus produced a state of heightened arousal. The noradrenergic system is most active in the awake state, and it is important for focused attention, in contrast to the motor arousal of dopamine.

Serotonin

• Only 1-2 % of serotonin in the body is in the brain, insofar as serotonin is widely distributed in platelets, mast cells, etc.

• The serotonin in the brain is independently synthesized from tryptophan transported across blood brain barrier.

• The richest concentration of serotonin in the body can be found in the pineal body.

• Serotonin is methylated in the synthesis of melatonin.• Melatonin is of particular importance for regulating

diurnal (circadian) and seasonal behavior and physiology in mammals.

Serotonin

• An important regulatory amine in the CNS.• Serotonin-containing neurons are present in

the raphe nuclei in the pons and medulla.• Appear to play an important role in the

determining the level of arousal.