Neurotransmitters in CNS

Communication in CNS: Neurotransmitters

• Neurotransmitters are key to communication in the central nervous system.
• These include amino acid neurotransmitters, acetylcholine, catecholamine, 5-Hydroxytryptamine 5-HT, peptides, gasotransmitters, and endocannabinoids.
• Amino acid neurotransmitters include glutamic acid (glutamate), gamma-amino butyric acid (GABA), and glycine.
• Norepinephrine is associated with alertness, concentration, and energy.
• Serotonin is associated with obsessions and compulsions.
• Dopamine influence pleasure, reward, and motivation.

Glutamic Acid (Glutamate)

• Glutamate is the principal excitatory transmitter in the brain.
• It mediates most of the fast excitatory transmission and is present in most neuronal circuits.
• CNS glutamate is mainly derived from glucose via the Krebs cycle or from glutamine synthesized by glial cells and taken up by neurons.
• Glutamate has three main subtypes of ionotropic receptors, each named according to its specific agonists: NMDA, AMPA, and Kainate receptors.

N-methyl-D-aspartate (NMDA) Receptor

• NMDA receptors are multimeric ligand-gated ion channels.
• Drugs can act as agonists or antagonists at the neurotransmitter receptor site or at modulatory sites associated with the receptor.
• Activation requires both glycine and glutamate to be occupied for the channel to open.
• NMDA receptors are blocked by Mg2+, resulting in voltage dependence.
• NMDA receptor activity is linked to learning and memory.
• Overactivity is associated with excitotoxicity and various disorders.

Glycine

• Glycine functions as an inhibitory transmitter, particularly in the spinal cord.
• It acts on its own receptor, which is similar structurally and functionally to the GABAA receptor.
• Glycine does not cross the blood-brain barrier.

Gamma-Amino Butyric Acid (GABA)

• GABA is the main inhibitory transmitter in the brain.
• It is likely released at up to 40% of brain synapses, making it the most common neurotransmitter.
• Targets for GABA include GA, antiepileptics, and anxiolytics.
• GABA occurs mainly in brain tissue, with only trace amounts found in other mammalian tissues.
• It is synthesized from glutamate by glutamic acid decarboxylase (GAD), an enzyme found only in GABA-synthesizing neurons in the brain
• GABA acts on two receptor types: GABAA receptors are ligand-gated ion channels, while GABAB receptors are G-protein coupled.

Acetylcholine

• Acetylcholine functions as a neurotransmitter in the brain and peripheral nervous system.

• ACh neurons are only found in certain areas, indicating a localized distribution.

• Intrinsic interneurons are in the striatum and are active in motor control.

• Longer projection systems participate in attention and cognitive function

• Acetylcholine acts on both muscarinic (G-protein-coupled) and nicotinic (ionotropic) receptors in the CNS.

• Muscarinic receptors appear to be associated with arousal, learning, and short-term memory.

Catecholamine: Dopamine

• Dopamine serves as a neurotransmitter and a precursor for noradrenaline
• Dopamine receptors are D1 and D2 Family
• There are four main dopaminergic pathways:
  • Mesolimbic pathway: Affects emotion
  • Mesocortical pathway: Affects emotion.
  • Nigrostriatal pathway: affect motor control
  • Tuberohypophyseal: Neurons run from the hypothalamus to the pituitary gland, whose secretions they regulate
• The Nigrostriatal pathway is a significant pathway, contains 70% of all brain dopamine.
  • Nigrostriatal pathways affect motor control, and nigrostriatal dopaminergic neuron deficiency, with a deficiency associated to Parkinson's Disease

Catecholamine: Noradrenaline (NA)

• Noradrenaline is Found in the sympathetic nervous system, with receptors.
• Receptors are G-protein linked.
• The actions of noradrenaline are mediated through α1, α2, β1 and β2 receptors.
• Each noradrenaline containing neuron has many terminals and innervates many other cells.
• Locus coeruleus (LC) neurons are silent during sleep and their activity increases with behavioral arousal.
• Wake-up stimuli of an unfamiliar or threatening kind excite noradrenaline neurons.
• They may be involved in arousal and mood regulation and sensitive to noxious or stressful stimuli.
• Noradrenaline controls blood pressure via synapses in the medulla.

Serotonin (5-HT)

-Serotonin is expressed through subtypes of receptors, is linked to mood, sleep, feeding,behavior and sensory perception.

Peptides and Gasotransmitters

• This includes Opioid peptides
• Substance P : Neuropeptide, acting as a neurotransmitter and neuromodulator.
• Peptide transmitters differ from nonpeptide transmitters because :
  • Synthesized in -cell body transported to N ending via axonal transport
  • No reuptake or-specific enzyme mechanisms
• Gasotransmitter gaseous signaling molecules like Nitric Oxide are within CNS contains nitric oxide synthase (NOS)
• NO increases cGMP formation which affects neuronal function.
• Excitatory and Inhibitory effects on memory, cognition, and pain perception are affected by activation while these brain lipid derivatives bind to cannabinoids receptors.

CNS Drugs: Targets and Function.

• Targets of CNS drugs include:
  • Neurone protein molecules
  • Ion Channe
  • Receptors.
  • Enzymes.
  • Transport Proteins
• Include transmembrane ion channels.
• Are regulated by membrane potential through sodium, potassium, calcium channels and voltage gated ions.
• Ions controlled in chemically activation that uses receptors that regulated by interactions via neurotransmitters
• Chemically activated is called ligand-gated or ion channel including : - Ionotropic - Metabotropic - Proteins which either action on channels proteins or enzyme activation (protein second messengers)
• Drugs are based on the -type of neurotransmitters through -excitatory or inhibitory are stimulants and depressants such as:. - Stimulating E.g. Ach, Dopamine, epinephrine, Norepinephrine
  - Stimulating depressant’ E.g. GABA (brain) and Glycine spinal cord

The Blood-Brain Barrier (BBB)

• The Brain (25-30%) of cardiac output
• Not penetrated by small molecules
• The body uses capillaries with fenestra substances to pass through but brain cells tightly joined.
• Functions as a control system preserving homeostasis, facilitating necessary metabolites.
• Areas can be leaky areas medulla and the hypothalamus.
• The blood-brain barrier function to controls system and preserve nervous system homeostasis but block unnecessary Metabolites.
• Made from lipids and not large charged molecules