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