Neuropharmacology 1 : Neurotransmitters Flashcards
What are the neurotransmitters in the PNS?
- Muscle nictonic cholinergic receptors = somatic efferent system
- Adrenergic receptors, Muscarinic cholinergic receptors
- Neuronal nicotinic cholinergic receptors
Neuronal nicotonic cholinergic receptors
Some drugs that target cholinergic or adrenergic systems in the CNS have significant peripheral side effects
Explain acteylcholine neurotransmitters
- Synthesis by choline acetyltransferase, acetyl CoA and choline - acteylcholine
- UPTAKE into vesicle via vesicular transporter
RELEASE : Action potential reaches terminal - activates Ca channels - ca influx - fusion of vesicles and release of ACh - Pre- synaptic receptors : Some may be activated by excess ACh. Others may respond to other neurotransmitters. In either case the result = inhibition of further ACh release (or occasionally increased ACh release)
- Breakdown/metabolism : ACh is broken down into acetate and choline by acetylcholinesterase. This mechanism prevents further receptor activation.
Action at receptor :
- Neurons and muscle : nicotinic AChR = ligand-gated ion channel passes Na + and K+ - depolarisation = excitatory response
- Muscarinic AChR = G protein - coupled receptor, activation of Gq- calcim signalling - excitatory
What are the key drugs of Acetylcholine?
RELEASE : inhibited by botulinum toxin near to injection site
BREAKDOWN/METABOLISM : Acetylcholinesterase inhibitors e.g. neostigmine ( used for myasthenia gravis) or poisons (e.g. novichok, Sarin gas, head lice treatments) increase ACh levels in synapse and so increase muscle tone (neostigmine) or paralyse (poisons). CNS selective AChE inhibitors = rivastigmine, galanthamine, donepezil
Action at receptor : mnicoyinic AChR antagonists at muscle nAChR e.g. tubocurarine, atracurium are used in surgery to achieve paralysis.
- Muscarinic AChR agonists e.g. pilocarpine used to mimic ACh in parasympathetic nervous system
- Muscarinic AChR anatgonists e.g atrophine used to antagonise parasympathetic responses, Ipratropium, tiotropium used as bronchodilators in COPD
Explain noradrenaline neurotransmitters
- Synthesis :
1. Tyrosine - via tyrosine hydroxylase - DOPA
2. DOPA - Via DOPA decarboxylase - dopamine
3. UPTAKE Into vesicles via vesicular transporter
4, THEN DOPAMINE via DOPAMINE B hydrolase - noradrenaline
Pre-synaptic receptors: some may be activated bt excess NA
Other may respond to other neurotransmitters. In either case the result is inhibition of further NA release ( or occasionally increased NA release)
- A2 adrenergic receptors are particularly important for autoregulation- feedback inhibition
BREAKDOWN / Metabolism : can occur inside presynaptic cell, or postsynaptic cell or extracellularly by :
MAO = Monoamine oxidase (Inhbition of MAO leads higher concentration of monoamines in the cytoplasm)
- COMT = catechol-o-methyltransferase
What is the non neuronal and neuronal uptake of noradrenaline?
NON-NEURONAL UPTAKE :
1/4 Taken up into non-neuronal cells
- EMT (Extraneuronal monoamine transport)
- Lower affinty and higher capacity
- Also transports dopamine, serotonin and histamine
NEURONAL UPTAKE :
- 3/4 of released noradrenaline taken up to presynaptic terminal
- Norepinephrine transporter
- High affinity and low capacity
- Inhibited by cocaine, amphetamine, tricyclic antidepressant drugs
ACTION AT RECEPTOR :
A1 adrenergic :
- Agonists : phenylephrine - nasal decongestant
- Antagonists:
Doxazosin, tamsulosin
- Prostatic hyperplasia and hypertension
A2 adrenergic :
Partial agonist = clonidine used for hypertension (tare), migraine prophylaxis
B1 adrenergic : agonists - doubtamine - cardiogenic shock. Antagonists : nebivolol, metoprololm hypertension, angia
B2 adrenergic : Agonists : salbutamol, salmeterol - asthma, premature labour
B3 adrenergic - Agonists : mirabegron- overactive bladder
How are CNS neurotransmitters classified?
- By role or by chemical structure
ROLE
Excitatory
* Glutamate, aspartate, acetylcholine, serotonin, dopamine, noradrenaline
Inhibitory
* GABA, glycine
Modulatory
* Serotonin, dopamine, noradrenaline, various peptides
CHEMICAL STRUCTURE
- Amino acids
- Glutamate, aspartate, GABA, glycine
- Monoamines
- Dopamine, serotonin, noradrenaline
- Peptides
- Somatostatin, CGRP, substance P, neurokinin
Explain the excitatory neurotransmission of glutamate
Synthesis : in neurons : Glutamine - via glutaminase - glutamate
Uptake : Glu is taken up by EAAT (Excitatory amino acid transporter) into neurons and astrocytes
Uptake :
- In astrocytesm Glu - via glutamine synthase - Gln which is transported out of the astrocyte and into the neuron by GlnT (glutamine transporter)
What are the iontropic ligand-gated ion channel receptors in Glutamate?
Agonists :
- NMDA - Glutamate aspartate NMDA
-AMPA - Glutamate AMPA
- Kainate - Glutanate Kainate domoate
Function :
- slow excitatory transmission , synaptic plasticity , exitotoxicity
- Fast exitatory transmission
- Fast excitatory transmission
Metabotropic mGluR :
- Group 1 - postsynaptic, linked to Gq and Ca 2+ signalling - excitatory
- Groups 2 and 3 - presynaptic linked to G1/o regulate glutamate release
What are the NMDA receptors in glutamate?
NMDA receptors
- Normally blocked by Mg2+
- Depolarisation removes block
- Activation requries glycine too
- Allosteric sites - potential new drugs
Role in synaptic plasticity :
- Mechanisms of Long-term potentiation (LTP)
A : Infrequent synaptic activity
- just AMPA receptors activated
B : after conditioning train of stimuli
- MGluR activated, NMDA channels unblocked
- Increased Ca signalling
- Ultimately results in changes in gene expression
What is the role of NMDA receptors in excitotoxicity?
- Excessive activation of NMDA, AMPA and mGluR receptors
- Large influx of Ca 2+
- increase glutamate release
- Activation of proteases and lipases
- Activation of NO synthase - ROS
- Arachidonic acid release - free radicals and inhibition of glutamate uptake
- Excitotoxic cell death in stroke and neurodegenrative diseases
What are GABA receptors?
GABA A receptors
= ligand-gated ion channel receptors
Cl- ion channel hyperpolarisation
GABA B receptors
= G protein coupled receptors
Generally inhibitory
What is the inhibitory neurotransmission of GABA ?
- GABA can activate both GABA A and GABA B receptors
Functional associations : - arousal and attention
- memory formation
- Anxiety
- Sleep
- Muscle tone
What are GABA agonists and antagonists?
- Muscimol = agonist from Amanita muscaria
- Bisculline = antagonist from Dicentra cullaria
What are benzodiazepines?
- allosteric modulators at GABA a receptors = only have effect if GABA is present
- Barbiturates (phenobarbital) - allosteric modulator and direct activation at higher doses
- Steroid anaesthetics (alphaxalone)
What are the clinical uses of benzodiazepines?
Benzodiazepines
Clinical uses of benzodiazepines
* Muscle relaxant
* Anxiolytic
* Anticonvulsant
* Amnesia (flunitrazepam = Rohypnol)
* Sedative
There are subtypes of GABAA receptor having distinct distributions.
These may account for the slightly different properties of different drugs in this class.
- Variation in half-life affects application
Tolerance and dependence occurs with prolonged treatment
