molecular neuropharma
Post on 08-May-2015
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NeuropharmacoNeuropharmacologylogy
(Central (Central Nervous Nervous System)System)
Nervous system:
Central nervous system (CNS): brain and spinalcord
Peripheral nervous system (PNS): cranialnerves and spinal nervessomatic- skeletomuscular sysemautonomic- internal organs
sympatheticparasympathetic
Two types of cells: neurons and supporting(glial) cells
Types of neurons:Interneuron- located entirely within CNS,
integrates functions in CNSSensory (from sensory receptor to CNS)
Motor (from CNS to effector organ)somatic- stimulates skeletal musclesautonomic- affects smooth and cardiacmuscle, also glandular secretion
Nerve- bundle of neurons (axons)Ganglion- bundle of nerve cell bodies outside
of CNSNucleus- within CNSTract- connects regions of CNS
Parts of a neuron
Cell body- contains the nucleus and other organelles
Dendrites- transmit electrical impulses TO thecell body
Axon- transmits impulse AWAY from the cell bodyaxons can be several feet long
“Axonal hillock” is located near the cell bodynerve impulses originate there
Structures of neurons
sensory
motor
retina
Supporting cells
Schwann cells, oligodendrocytes- producemyelin
Satellite cells- support neurons in PNSMicroglia-phagocytes in CNSAstrocytes- induces blood-brain barrierEpendymal cells- special epithelium that line
brain ventricles and central canal of spinal cord
also part of structure that makes CSF
Large axons are myelinated by Schwann cellsor oligodendrocytes
Gaps are left between the “wrappings” of eachcell (nodes of Ranvier)
Myelinated axons conduct nervous impulsesmore rapidly than unmyelinated
In CNS, myelinated axons form “white matter”(Cell bodies and dendrites are gray matter)
Schwann cells can help repair damaged nerves
Capacity for repair is much better in the periphery
In fetal brain, neurotropins promote neurongrowth
Some factors help maintain neural structuresin adult nervous systems
Some inhibitory factors also
Astrocytes
Most common glial cell in CNS
Form blood-brain barrier
Help with ion uptake
Help with neurotransmitter uptake
Many glucose transport carriers, which helpmove glucose from blood to brain
Blood-brain barrier (BBB)
Probably due to effects of astrocytes on braincapillaries
Everything must move into brain by diffusionand active transport
Many substances (including therapeutic drugs)cannot cross BBB
Electrical activity in axons
Resting membrane potential in neuronsis –70 mV
Large negatively charged molecules insidethe cell
Positively charged ions outside the cell(more Na out than K in)
Neurons are excitable: they can change theirmembrane potential in response tostimulation
Permeability to ion changes
Occurs in a very small area on the membrane
Depolarization- potential difference approacheszero
Repolarization- back to the resting potential
Hyperpolarization- potential difference increasespositive charges leave cellnegative charges enter cell
Gated ion channels for K and Na(lots of these at axon hillock)
Resting cell is more permeable to K than Na
Depolarization- membrane becomes permeable to Na, and Na can diffuse into cell
After Na gates close, K gates open and K diffusesout of the cell
Action potentials are very rapid
Inactivation occurs until membranes are repolarized (by sodium-potassium pumps)
Stronger stimuli stimulate more and more axons(more action potentials are stimulated, buttheir amplitude does not change)
Refractory period
When an action potential is being produced, asecond stimulus will not affect that partof the membrane
Stimulus when K gates are open and membranesare repolarizing
Relative refractory period- a very strong stimuluscan overcome repolarizing
Synapse- connection between a neuron anda second cell
From presynaptic to postsynaptic neuron
Release of neurotransmitters (chemicals)
A few electrical synapses in nervous system,In smooth muscle and heart
gap junctions
Chemical synapses
One-wayPresynaptic neuron has synaptic vesicles
Fusion of vesicles is mediated by calcium
Calmodulin is activatedProtein kinase activatedSynaptic vesicles fuse with membrane
Neurotransmitters diffuse across cleft andbind to receptors
Voltage-regulated channels in presynaptic axon
Chemically regulated channels in postsynaptic membrane
Ion channels are opened, depolarization occurs
Can be excitatory or inhibitory
Depends on which receptors are engaged
Integration of impulses in dendrites and cellbody of postsynaptic neuron
Criteria for establishing a Criteria for establishing a molecule as a neurotransmittermolecule as a neurotransmitter
synthesis synthesis the molecule is synthesized in the presynaptic the molecule is synthesized in the presynaptic
neurons neurons localization localization
the molecule is present in the presynaptic terminal the molecule is present in the presynaptic terminal release release
the molecule is released upon stimulation of the the molecule is released upon stimulation of the presynaptic neuron presynaptic neuron
mimicry mimicry when applied exogenously (e.g., from a when applied exogenously (e.g., from a
micropipette), in concentrations similar to those micropipette), in concentrations similar to those observed following stimulation of the presynaptic observed following stimulation of the presynaptic cellcell
the molecule mimics the action of the the molecule mimics the action of the endogenously released transmitter endogenously released transmitter
inactivation inactivation a specific mechanism or a set thereof exists to a specific mechanism or a set thereof exists to
remove the molecule from the synaptic cleft or to remove the molecule from the synaptic cleft or to degrade it degrade it
Acetylcholine
Excitatory to some neurons in CNS and motorneurons
Inhibitory to others
Different cells have different types of receptors
Nicotinic- stimulatory; nicotine also bindsskeletal muscle fibers, autonomic ganglia
Muscarinic- muscarine also bindssmooth and cardiac muscle; glands
Ion channel most direct type of activation
EPSP (excitatory postsynaptic potential)no thresholdcan be graded (number of stimulated receptors)no refractory period
summation: effect of several EPSPs added(i.e., graded)
Muscarinic receptors- operated by G proteins
Three subunits to G protein, different onescan be effectors
Tends to have in inhibitory effect (IPSP)
Why inhibitory?
K+ diffuses out, causing hyperpolarization
Both EPSPs and IPSPs can be producedvoluntarily- summate or cancel eachother out
Acetylcholinesterase (AChE)
Inactivates ACh. Otherwise ACh-receptorcomplexes would keep forming.
In PNS ACh stimulates muscles to contract
In ANS: sympathetic and parasympatheticnerves
Effect depends on whether nicotinic or muscarinic receptors are activated
If EPSPs are above threshold an actionpotential will be generated along the axon
Monoamines as neurotransmitters
Monoaminesdopaminenorepinephrineserotonin
Tend to be stimulatory; must be quickly inhibitedto maintain control
Control mechanisms:
Uptake of monoamines by presynaptic neuron
Degradation by monoamine oxidase inpresynaptic neuron
By post-synaptic neuron (COMT*, degradescatecholamines)
COMT= catechol-O-methyltransferase
Monoamines act through second messenger(cAMP)
Catecholaminesnorepinephrine- hormone and neuro-transmitter
controlled by:reuptakemonoamine oxidase (MAOIs inhibit this)COMT in postsynaptic neuron
Serotoninderived from tryptophanaffects specific cells in brain stem
regulates mood and behavior, appetite,cerebral circulation
SSRIs- serotonin-specific reuptake inhibitorsincrease effect of serotoninantidepressants
May have different effects depending onreceptor
Dopamine
dopaminergic cells located in midbraineffects on motor and emotional function
Nigrostriatal- motor; in substantia nigra
Parkinson’s disease- degeneration of theseneurons
L-DOPA and MAO inhibitors- increase dopaminetransmission
Drugs relieve symptoms for awhile, but do notstop killing of neurons
Growth factors?Transplants? (fetal cell, xenotransplants, auto-
transplants of carotid body cells, etc.)
Areas of research:what exactly is the probleminteraction with other neurotransmitterseffects on other parts of the brain (in
mood, behavior, physical activity, etc.)
Summary
1. The nervous system is comprised of the central nervous system (brain, spinal cord)and the periphery (cranial and spinal nerves)Periphery is divided into autonomic and motorneurons.
2. Cells of the nervous system are glial cells andneurons. Neurons conduct nervous impulses,glial cells “support” neurons.
3. Myelination affects the speed at which impulseis delivered.
4. Neurons conduct electrical and chemicalsignaling. Action potential starts at a verysmall area of the membrane and is conductedalong the length of the membrane.Action potential rises with Na influx and fallswith K efflux.
5. Speed of transmission is affected by a.) presenceof myelin, and b.) the diameter of the neuron.(faster in larger neurons)
6. Neurotransmitters deliver signals across synapses.
7. Sometimes signal is excitatory, sometimesinhibitory. Excitatory: receptors serve as ion channels,depolarizes, brings closer to threshold.Inhibitory: causes hyperpolarizationA given synapse is always one or the other.Some act as second messengers (morelong-term effects).
8. Neurotransmitters are typically small fast-acting molecules. Some are larger and slower-acting than otherslearning, motivation, response to stress, etc.
9. Long-term potentiation: if a neuron isstimulated once, synaptic transmissionis more efficient thereafterMay favor use of certain neural pathways:“learning”
10. Some transmitters are inhibitory.Postsynaptic: GABA and glycinePresynaptic: interference with axoninterferes with calcium influx
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