Lecture 1 CHEMICAL SIGNALLING IN THE NERVOUS SYSTEM

Chemical mediators: -Neurotransmission -Neuromodulator -Neurotrophic factor

-Chemical mediator within the brain can produce slow and long-lasting effect: -they can act diffusely, at a considerable distance from their site of release. -they can produce diverse effect, e.g.: -on transmitter synthesis -on the expression of neurotransmitter receptors -on neuronal morphology In addition to affecting the ionic conductance of the post synaptic cell membrane.

Neurotransmitter -A substance released by one neuron and acting rapidly, briefly and at short range on the membrane of adjacent (postsynaptic) neuron, causing excitation or inhibition.

Some types of neurotransmitter: -acetylcholine -monoamines (E, NE, dopamine, serotonin 5-HT, and melatonin) -amino acids, (glutamic acid, GABA, aspartic acid & glycine) -Purines, (Adenosine, ATP, GTP and their derivatives) -Over 50 neuroactive peptides (vasopressin, somatostatin, neurotensin, etc.) have been found, among them hormones such as LH or insulin -Single ions, such as synaptically-released zinc, are also considered neurotransmitters by some.[

The major "workhorse" neurotransmitters of the brain are -Glutamic acid (=glutamate) -GABA.

Glutamic acid is involved in cognitive :function -Nerve impulses trigger release of glutamate from the pre-synaptic cell. In the opposing post-synaptic cell, glutamate receptors, such as the NMDA receptor, bind glutamate and are activated. - (NMDA (N-methyl D-aspartate) Calcium flux through NMDARs is thought to play a critical role in synaptic plasticity, a cellular mechanism for learning and memory.

Synaptic Plasticity: - is the ability of the connection, or synapse, between two neurons to change in strength including changes in the quantity of neurotransmitter released into a synapse and changes in how effectively cells respond to those neurotransmitter -Since memories are postulated to be represented by vastly interconnected networks of synapses in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory

-In brain injury or disease, they can work in reverse and excess glutamate can accumulate outside cells. This process causes calcium ions to enter cells via NMDA receptor channels, leading to neuronal damage and eventual cell death, and is called excitotoxicity. -Excitotoxicity due to glutamate occurs as part of the ischemic cascade and is associated with stroke and diseases like amyotrophic lateral sclerosis(ALS) , lathyrism, autism, some forms of mental retardation and Alzheimer's disease

GABA: -GABA, or gamma-aminobutyric acid, is the most abundant inhibitory neurotransmitter in the brain. - While GABA is an a.a, it is a neurotransmitter and helps induce relaxation and sleep. - It balances the brain by inhibiting over-excitation. GABA contributes to motor control, vision, and many other cortical functions. -Anxiety is also regulated by GABA. Some drugs that increase the level of GABA in the brain are used to treat epilepsy.

Neuromodulator -the action of which do not confirm to original neurotransmitter concept. -it covers not only the diffusely acting neuropeptide mediators, but also mediators such as nitric oxide and arachidonic acid metabolites which are not stored and released like neurotransmitter, and may come from non neuronal cells (glai) as well as neuron.

Neuromodulator -Neuromodulation relates to synaptic plasticity, including short term physiological events such as the regulation of presynaptic transmitter release or post synaptic excitability .

Some types of neuromodulator -Opioid peptides : -Endorphins -Enkephalins -Dynorphins -Substance P

Endorphins -An endorphin produced by the pituitary gland that is a potent pain suppressant. - Beta-endorphin has the highest affinity for the μ1-opioid receptor μ-receptors are presynaptic, and inhibit neurotransmitter release; through this mechanism, they inhibit the release of the inhibitory neurotransmitter GABA, and disinhibit the dopamine pathways, causing more dopamine to be released.

Substance P -A short-chain polypeptide that functions as a neurotransmitter especially in the transmission of pain impulses from peripheral receptors to the CNS. - In the CNS, substance P has been associated in the regulation of mood disorders, anxiety, stress, reinforcement, neurogenesis, respiratory rhythm, neurotoxicity, nausea / emesis and pain.

Neurotrophic factor -Are released mainly by non-neuronl cells and act on tyrosine kinas-linked receptors that regulate gene expression and control neuronal growth and phenotypic characteristic.

-Neurotrophic factors are small proteins that exert survival-promoting and trophic actions on neuronal cells. -During development, play a critical role in mediating the ability of a target of a neuron to prevent the death of the nerve cell. -play a critical role in the "quality of life" of neurons. - regulate growth of neurons, associated metabolic functions such as protein synthesis, and the ability of the neuron to make the neurotransmitters that carry chemical signals .

Glial cells (astrocytes): -The main non-neuronal cells in the CNS and outnumber neuron by 10 to1. -Play an important signaling role. -express a range of receptors and transporters similar to those present in neuron , and also release mediators (glutamate, lipid mediator and growth factors) -they respond to chemical signals from neurons, from neighboring astrocyte and microglial cells. -controlling the chemical environment in which the neurons operate , surround neurons and hold them in place, to supply nutrients and oxygen to neurons, to insulate one neuron from another, and to destroy pathogens and remove dead neurons.

Mediator types: -Conventional small-molecule mediators -Neuropeptides -Lipid mediators -Nitric oxide -Neurotrophens, cytokines -steroids

Conventional small-molecule mediators: -Examples Glutamate, GABA, Ach, dopamine, 5-HT -Main function: fast synaptic neurotransmission neuromodulation. -Targets: ligand gated ion channels , G-protein-coupled receptors

Neuropeptides: -Ex. Substance P, neuropeptide Y, Corticotrophin releasing factor -Main function: neuromodulation. -Targets: G-protein-coupled receptors

Lipid mediatore -Ex. prostaglandins, endocannabinoid -Main function: Neuromodulation -Targets: G-protein-coupled receptors

Nitric oxide -Main function: Neuromodulation -Targets: Guanylate cyclase

Neurotrophens, cytokines -Ex. nerve growth factor, brain derived neurotrophic factor, interlukin-1 -Main function: Neuronal growth, survival and functional plasticity -Targets: Kinase-linked receptor

steroids -Ex. Androgens, estrogens -Main function: Functional plasticity -Targets; Nuclear , membrane receptors

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