D’Hooge
Pharmacology
Les 1: Neural signaling and neuromodulation
Ondertitel
- Brain is part of central nervous system
▪ Motor, sensory and somatic part
- Afferent NS
▪ Info from PNS to CNS
▪ Sensory neurons
▪ Stimuli: intern/interoceptive or extern/exteroceptive
- Efferent NS
▪ Infor from CNS to PNS
▪ Motor neurons
▪ Autonomic & somatic NS
. Autonomic/vegetative/visceral NS
Things we can’t control
Parasympathisch en sympatische zenwustelsel
Ex: internal organs, blood, glands,…
. Somatic NS
Influenced by will
- Functions of the nervous system
▪ Receiving sensory input
▪ Integrating info, saves info
▪ Producing motoric output
- Neurons communicate with chemical and electrical signals
▪ Chemicals have influence on the brain (Ex: alcohol)
. Not always via blood
▪ Possibility to develop psychopharmacology
. Induce sleep, control pain, control some brain disorders
- Dark sides of pharmaco
▪ Not efficient
▪ Side effects (can lead to tolerance)
▪ Addiction
- Pyramidal cell: most typical cell in cerebral cortex
Structure of the brain
- Telencephalon
▪ Divided in 4 lobes
▪ Frontal cortex: problem solving, executive function, emotion/pain controlling
▪ Parietal cortex: sensory functions
▪ Occipital cortex: vision
▪ Temporal cortex: memory, sociative functions, emotion
. Also hearing, smell
. Responsible for laying down new information
. Information circuits here -> ability to form these networks require plasticity of the brain
Brain cells must communicate with each other
- See pics PPT
▪ Coronal section
. Cortex: outer/darker layer/grey matter
Cell bodies of pyramidal cell here
Also nuclei of gray matter in the middle
. White matter = myeline
Short associative connections
Fibers that connect brain strictions -> prevent that the brain starts functioning in 2
halves (separate functioning is not normal)
▪ Horizontal section
. Ventricles filled with cerebrospinal fluid
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Cells
- Purkinje cells
▪ Very much very tiny cells
▪ Typical for cerebellum
- Pyramidal cells
▪ Typical for cerebral cortex
▪ Biggest cells
- Glial cells
▪ More numerous than normal neurons
▪ Support cells: structural and chemical support (metabolic)
▪ Astrocytes
. Remove ntm
▪ Microglial cell
. Smaller
. Involved in defence systems of the brain
. Healing processing in the brain
Haemorrhage or stroke -> cells that are lost, will not return
Microglial cells are more local (not much neurogenesis)
Help with plasticity & attack pathogens
▪ Oligodendrocytes
. In the central system (in peripheral: Shwann cells)
. A lot of myeline
Synapses
- Contact axon and dendrite/other axon
- Dendritic spines: axon terminal can make contact here
- See pics PPT
Action potentials
- Zie zelfstudie deel -> is daar al uitgelegd
- Net result = Depolarisation: Na+ influx
- Propagation/movement of AP
▪ Adjacent parts will also get an AP
▪ Faster when axon has myeline
. Saltatory transmission
- Influx of calcium in synapse -> ntm free
- Ntm needs to be removed (pharmaco works here)
Receptors
- Ntm binds to receptor -> generate the signal
- Ligand-dated channel/ionotropic receptors
▪ Ntm binds -> receptor directly opens -> ion flow
▪ Ion specific
▪ Milliseconds
- G-proteine coupled receptors/metabotropic
▪ Not directly coupled to ntm
▪ Influence excitability of a cell
. G proteins can lead to inhibition of excitation
▪ Ntm binds to receptor -> activate G-protein
. 1. Can influence an ion channel
. 2. Can influence an enzyme (2nd messenger)
2nd messenger: product produced inside the cell
Can influence all kinds of stuff (Ex: genetics)
▪ Advantage: 2nd messenger stays very long in the cell (<-> ntm)
. Pharmaco can interact here
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- Kinase-linked receptors
▪ Kinase: enzyme that phosphorylates another enzyme
▪ Stay for hours
- Nuclear receptors
▪ Only relevant for ntm that can enter the cell
. Binds to receptor in nucleus
. Does something with the genetic material
▪ Ex: sex hormones/cortisol
▪ Ex: lipids -> can go through the membrane
▪ Vaak een steroïde
- First messenger – receptor – second messenger (example)
▪ Ex 1: G protein -> adenylate cyclase -> cAMP -> kinase -> phosphorylate canal
▪ Ex2: inhibitory and exciting ~ dopamine can do both
▪ G proteine has invloed op meerdere enzymen die dan ook weer invloed hebben op meerdere second
messengers
Neurotransmitters
- More than 100 substances identified as ntm
- Some are local, others work in large parts of the NS
- Different steps
▪ 1. Synthesis (can happen on different places)
▪ 2. Storage
▪ 3. Release
▪ 4. Receptor action
▪ 5. Inactivation
Small molecular ntm
- Acetylcholine
▪ First ntm described
▪ Location
. Motor neurons (neuromuscular junction), deep brain structures (striatum, nucleus basalis),
cortex, PS NS
▪ Disorders
. Myasthenia gravis: auto-immunie disorder that affect peripheral AChR
. Alzheimer (impact on memory -> intervention: ACh-acetate inhibitors)
▪ Cholinergic system
. 1. Magnocellular basal forebrain cholinergic system
Medial septal nucleus (MS)
Vertical and horizontal limbs of the diagonal band of Broca (DB)
Nucleus basalis magnocellularis (nBM)
(DB projects diffusely to neocortex, basolateral amygdala and olfactory bulb; MS and
vertical limb of the DB project to hippocampus and entorhinal cortices)
. 2. Brainstem cholinergic system: projects predominantly to thalamus/basal forebrain
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Pedunculopontine tegmental nucleus (PPT)
Laterodorsal pontine tegmentum (LDT)
. Zie PPT
▪ AChR (receptors)
. 2 major types with many subtypes
1. Muscarinic: metabotropic
Iets van een paddenstoel
2. Nicotinic: ionotropic
Ligand-gated ion chanel
Neuromuscular synapse: muscle contraction
BIOGENIC AMINES
- Biogenic amines (mono-aminergic ntm)
- Catecholamines: dopamine, adrenaline, noradrenaline
▪ (Fenylalanine → ) Tyrosine → L-DOPA → dopamine → noradrenaline → adrenaline
▪ Breakdown: catechol-O-methyltransferase (COMT), mono-amine-oxidase (MAO)
▪ Parkinson’s disease: administration of DOPA (dihydro-oxyphenylalanine), crosses BBB (dopamine
doesn’t)
. Dopamine cells are dying so give them extra DOPA
. At certain point, DOPA won’t have any affect anymore
. BBB: brain blood barrier
- Indolamines: serotonin
- Dopamine
▪ 5 receptor subtypes: D1, D2, D3, D4, D5
▪ D1R: stimulation of adenylate cyclase (AC)
▪ D2R: inhibition of AC
▪ Untrashort system
. Retina, bulbus olfactorius
▪ Intermediary system
. Hypophysis (pituitary), hypothalamus, medulla oblongata
▪ Long system
. Ventral tegmentum-substantia nigra -> striatum, limbic cortex (mesocortical projection) &
limbic structures (mesolimbic projections)
. Responsible for the rewarding elements of dopamine & addiction
▪ Dopaminergic neurotransmission
. NIET GEDAAN IN DE LES (*) -> zie foto PPT (staat geen tekst bij dit stuk)
▪ Dopaminergic drugs *
. Antipsychotics (major tranquilizers – Ex: phenothiazine): dopamine blockers
. Anxiolytics (minor tranquillizers): NA & DA antagonism
. Antidepressants: MAO inhibitors (fluoxetine), potentiate DA & NA transmission
. Stimulants (Ex: amphetamine): potentiate DA & NA transmission
. Drugs for Parkinson: DA precursors (L-dopa), MAO-I, D2 agonist (bromocriptine)
- Serotonin *
▪ Serotonin: 5-hydroxy-tryptamine
▪ Biosynthesis: Tryptophane (food) → 5-hydroxy-tryptophane → serotonin
. Tryptophane hydroxylase zorgt voor deze reactie
▪ Breakdown: 5-HT → 5-hydroxy-indolacetate (5-HIAA)
. MAO zorgt voor deze reactie
▪ Origin of 5HT projections
. 9 classes of serotonergic nuclei: central pons & top part of brainstem (Raphe nuclei)
. Brainstem: area postema & locus coeruleus
▪ Wide radiation to cortex (pacemaker activity)
. Homeostatic
. Modulation of cortical excitability
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