Neurotransmitters & Neuropharmacology

Neurotramission in the CNS

• Hierarchical systems
• clear anatomic distribution
• large myelinated rapidly conducting fibres
• control major sensory & motor functions
• Major excitatory neurotransmitter
• aspartate
• glutamate
• inhibitory neurotransmitters
• GABA
• Glycine
• Diffuses systems
• broadly distributed
• divergent
• axons branched and synapses with many cells
• act diffusely far away from site of release
• produce slow and long lasting & diverse effects on NT synthesis, effect on receptors & ionic conductance
• Examples
• NA
• Adrenaline
• Dopamine
• serotonin
• peptides

Synaptic transmission

• Chemical mediators involved in synaptic transmission in CNS
• Neurotransmitter
• substance contained in a neuron, released by presynaptic terminals to produce excitatory/inhibitory responses in postsynaptic neurons
• eg
• acetylcholine
• serotonin
• noradrenaline
• adrenaline
• dopamine
• GABA
• glutamate
• Neuromodulator
• substance that is released by neurons & astrocytes – produces slower pre/postsynaptic responses
• eg
• CO2
• ammonia
• nitric oxide
• Neurotropic factor
• substance released by non-neuronal cells
• act on tyrosine-kinase-linked receptors
• regulate gene expression, control neuronal growth, & phenotypic characteristics
• eg
• growth factors
• cytokines
• chemokines

Neurotransmitter classification

• Classical, non-peptide NT
• Monoamines
• NA. A
• Dopamine
• 5-HT
• Histamine
• Acetylcholine
• Amino acids
• Inhibitory amino acids (IAA)
• GABA
• Glycine
• Excitatory amino acids (EAA)
• glutamate
• aspartate
• Peptide NT
• Substance P
• Opioid peptides
• Others
• Vasopressin
• Oxytocin
• Tachykinins
• CCK
• NPY
• VIP
• Others
• Nitric oxide
• Adenosine
• Cannabinoid
• Purines
• Arachidonic acid

Synthesis, storage, release & fate of neurotransmitters

*Revise from Dr Achike’s foundation 2 notes

_____________________________________________________________________

Neurotransmitter – Criteria for acceptance

1. Present in presynaptic terminal
2. Synthesised in the neuron

• Precursors
• Tryptophan (for 5-HT)
• Choline (for ACh)
• Presence of rate-limiting enzymatic step
• Enzymes usually in soma and nerve terminals

Stored in synaptic vesicles in nerve terminals

Released from nerve terminal

• following an action potential which causes calcium influx

Same substance applied exogenously in small concentrations produce same action

• same receptors

Specific mechanism exists terminating its action

• enzymatic breakdown
• ACh
• Specific uptake using transporter protein
• NA
• dopamine
• 5-HT
• Once in axoplasm, NT is subjected to enzymatic metabolism

Signalling mechanism for drug effects

1. Intracellular receptor
2. Transmembrane Enzyme Receptor

• Receptor & Effector on same molecule

Transmembrane Enzyme Receptor

• Effector on separate molecule from Receptor

Transmembrane ion channels

• Ionotropic

G-protein-coupled receptors

• Act on separate effector molecule
• Metabotropic

_____________________________________________________________________

NEUROTRANSMITTERS

Noradrenaline

• Clusters of cell bodies
• in the locus coeruleus (LC) in the brain stem
• Axons project to cortex, hippocampus, cerebellum
• via the medial forebrain bundle
• Other NA neurons lying close to the LC in the pons & medulla
• Nerve terminals release NA diffusely
• Actions
• reward system
• mood
• arousal, attention, learning, memory
• neuroendocrine regulation
• blood pressure regulation
• Actions in CNS
• Generally inhibitory
• Sometimes excitatory
• In LC
• Silent during sleep, increase in activity during arousal/unfamiliar wake-up stimuli
• depending on modd, depressed patients are unresponsive
• Effect of CNS drugs on NA
• CNS stimulants increase wakefulness and alertness
• amphetamine releases catecholamines in brain
• NA Involved in BP regulation
• Clonidine (in the nucleus tractus solitarus) reduce sympathetic outflow from the vasomotor center in the medulla oblongata leading to fall in BP
• Psychotropic drugs
• Excitation (related to biogenic amines)
• Tricyclic antidepressants, coccaine
• block reuptake
• amphetamines
• block uptake, increase release
• monoamine oxid
  ase inhibitors
• block metabolism
• Sedation/depression
• reserpine
• depletes stores
• clonidine, alpha-methyldopa
• reduce sympathetic outflow

Adrenaline

• Small group of adrenergic neurons with cells bodies
• lying more ventrally to the NA neurons in the brain stem
• their axons run in the pons, medulla and hypothalamus
• important in control of CVS
• Descending fibres which run to the lateral horn of the spinal cord
• increase sympathetic discharge in the periphery

Dopamine

• Cell bodies at all levels.
• Short, median and long axons
• Pathways
• Mesolimbic mesocortical pathway
• reward, motivation, hyperactivity
• increase – schizophrenia
• actions of antipsychotic drugs
• Nigrostriatal pathway
• motor control
• decrease – Parkinson’s
• actions of drugs for Parkinson’s disease
• Tuberoinfundibular/Tuberohypophyseal pathway
• endocrine control
• side effects of antipsychotic drugs
• Receptor families (G-protein coupled receptors)
• D1 family
• subtypes D1, D5
• D2 family
• subtypes D2, D3, D4
• Antipsychotic drugs block D2 receptors
• Clozapine act on D4 receptors
• Important in
• Schizophrenia
• Parkinson’s disease
• ADHD
• Drug dependence & certain endocrine disorders
• Inhibit
• release of prolactin – enchance release of growth hormone
• High concentration of dopamine found in
• basal ganglia
• limbic system
• hypothalamus
• Metabolised by
• MAO –> DOPAC
• COMT and MAO –> HVA
• Reuptake of Dopamine blocked by (block amine transporter)
• cocaine
• amphetamine
• block NA at presynaptic terminal of neuron
• Also stimulates
• chemoreceptor trigger zone (CTZ)
• -> nausea, vomiting

5-HT Systems/Serotonin

• Cell bodies in
• raphe/midline region of the pons & upper brain stem
• axons project diffusely via midbrain bundle to the cortex, limbic system, hypothalamus
• cells at the caudal part of the brain stem project to the cerebellum, medulla and spinal cord
• Functions
• feeding behaviour
• body weight regulation
• hallucinations
• sleep, wakefullness
• mood
• sensory impulse transmission (nociception)
• body temperature, blood pressure, sexual functions
• vomiting
• All receptor subtypes: metabotropic
• except 5HT3-R: ionotropic
• Receptors in CNS
• 5HT1A-R
• limit the firing of cells in raphe & limbic system
• anxiolytics
• antidepressants
• 5HT1B-R and 5HT1D-R
• presynaptic inhibitory receptors in basal ganglia
• 5HT1B-R and 5HT2C-R agonists
• decrease appetite
• 5HT-1D-R agonists (sumatriptan)
• treat migraine
• 5HT2-R
• excitatory postsynaptic effect
• abundant in cortex & limbic system
• target at various hallucinogenic drugs
• 5HT3-R (in area postrema)
• involved in vomiting
• in cortex and brain stem extending to the dorsal horn of the spinal cord
• excitatory in function
• 5HT3-R antagonist
• ondansetron
• used for nause, vomiting
• chemotherapy
• anxiolytic effect
• 5HT4-R (in striatum)
• has presynaptic effect to increase ACh release
• enhance cognition

Summary:

5HT 1	raphe & limbic system
5HT 2	cortex & limbic system
5HT 3	cortex & brain stem
5HT 4	striatum

Clinical uses:

5HT 1A-R	Antidepressants
5HT 1B & 2C-R agonists	Decrease appetite
5HT 1D-R agonists	Treat migraine (sumatriptan)
5HT 3-R antagonist	treat nausea & vomiting – chemotherapy (ondansetron)

Acetylcholine

• Cell bodies at all levels with short & long axons
• basal forebrain –> cortex, interneurons in basal ganglia
• brainstem –> thalamus
• septum –> hippocampus
• Action
• arousal, learning, motor control, memory
• Physostigmine (anti AChE)
• arousal (+ ACh)
• Atropine (muscarinic receptor antagonist)
• sedation (-ACh)
• Hyoscine (muscarinic receptor antagonist)
• amnesia
• Receptors
• Muscarinic-R (G-protein coupled)
• many subtypes
• Agonists
• inhibit ACh release
• Antagonists
• increase ACh release
• Nicotinic-R (ionotropic)
• widespread
• many subtypes
• located presynaptically
• facilitate release of other neurotransmitters (glotamate, dopamine)
• Abnormalities of cholinergic pathways (decrease cognition)
• dementia
• parkinson’s & huntington’s
• dysfunction of many local interneurons in corpus striatum
• associated with motor coordination loss
• alzheimer’s
• degene
  ration of neurons in the magnocellular forebrain nuclei
• associated with memory loss

Histamine

• Neurons originate in
• magnocellular nuclei in posterior hypothalamus (called tuberomamillary nucleus)
• Widespread distribution
• Action
• arousal
• neuroendocrine regulation
• strongly anti-emetic
• treat nausea, vomiting
• Receptors
• H1
• excitatory
• antagonist: strongly sedative
• H2
• inhibitory
• H3
• excitatory

Amino acid neurotramitters – Glutamic acid (eaa)

• Found in relay neurons at all levels
• 4 receptor subtypes
• NMDA receptor
• excitatory
• blocked by PCP and ketamine
• involved in synaptic plasticity related to learning & memory
• excessive activation following a neuronal injury may cause cell death
• AMPA receptor
• fast EPSP
• wide distribution
• Kainate-receptor
• fast EPSP
• limited distribution
• presynaptc inhibiton
• Metabotropic subtype
• G-protein coupled
• found in pre & post synaptic
• presynaptic: inhibitory
• postsynaptic: excitatory
• involved in synaptic plasticity and excitotoxicity

Amino acid neurotransmitters – GABA

• Main NT mediating IPSP in brain and spinal cord
• 2 receptor subtypes
• GABA-a
• open Cl- channels
• activated by:
• benzodiazepines
• sedative-hypnotic
• anxiolytic
• barbiturates
• gabapentin
• anticonvulsant
• GABA-b
• metabotropic
• coupled to G-protein that either open K+ channels / close Ca2+ channels
• activated by baclofen

Neuropeptides

• Most coexist with classical NT and act together with other NT
• Substance P & glutamate
• used in control of pain
• Examples of neuropeptides
• Opioid peptides
• distributed all over brain & spinal cord
• Presynaptic: inhibitory
• decrease Ca2+ conductance
• decrease cAMP
• Postsynaptic: inhibitory
• increase K+ conductance
• decrease cAMP
• Substance P
• found in type C neurons
• involved in pain/nociceptive sensory pathways in spinal cord
• Comparison between neuropeptides with classical neurotransmitter
• Difference
• synthesis of pro-peptides occur in rough endoplasmic reticulum of the soma
• the processed and secreted in vesicles which are transported via the axon to nerve endings
• during transport, active peptides are generated within the vesicles
• No reuptake /specific enzymes exist for terminating their action
• once empty, vesicles cannot be refilled, but must be replaced with preloaded vesicles
• Similarity
• at nerve terminals, peptides are released via exocytosis in response to increased intracellular Ca2+ / other signals
• effects can be
• excitatory
• inhibtory
• pre/post synaptic
• exerted over short/long distances
• peptides serve mainly as neuromodulators by activating G-protein coupled receptors
• Longer onset of action

Other neurotransmitters & neuromodulators

• Nitric Oxide (NO)
• Purines (ATP, Adenosine)
• Adenosine
• not stored in vesicles
• released by carrier
• Methylxanthines (caffeine, theophylline)
• antogonists of A2 receptors
• cause wakefullness
• Melatonin
• synthesised from 5HT in pineal gland
• Depends on light intensity
• low in the day
• high at night
• Causes sedation and resets biological clock
• medicine for jet lag

_____________________________________________________________________

Drugs acting on CNS

• General
• General anaesthetics
• Selective
• Analgesics, Antypyretics, antiemetics
• Stimulants
• Appetite suppressants
• Antidepressant, antipsychotic
• Drugs for
• epilepsy
• Parkinson’s
• Alzheimer’s
• Migraine

Site & Mechanism of drug actions

• Direct interactions with molecular components of ion channels on axons
• eg. carbamazepine, phenytoin, local anaesthetics, general anaesthetics
• Interaction at synapses (most drugs)
• Presynaptic
• alter synthesis, storage, release, reuptake or metabolism of the neurotransmitter
• Activate/inhibit both pre/post synaptic receptors for specific transmitters
• Interfere with actions of 2nd messengers

CNS drugs are selective, because different groups of neurons use different neurotransmitters. These are grouped into networks with different functions.