Fundamentals of Neurochemistry.chemical Signaling - Monoamines

7/31/2019 Fundamentals of Neurochemistry.chemical Signaling - Monoamines

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Spring 2012

Dr. Andre Ragnauth, Ph.D.

Course DirectorSDSBECCNY

HappyLosar


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the brain

Cortex


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Neurons

Santiago Ramn y Cajal (1852 1934)Spanish pathologist,histologist, neuroscientist,and Nobel laureate. His pioneering investigations ofthe microscopic structure of the brain were original;he is considered by many to be the father of

modern neuroscience. He was skilled at drawing,and hundreds of his illustrations of brain cells arestill used for educational purposes today.http://en.wikipedia.org/wiki/Santiago_Ram%C3%B3n_y_Cajal Cortex

Cerebellum

Purkinje cells Synaptic connectionsA Neuron


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Cartoon of interactions at a chemical synapse


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Structure of a typical chemical synapse


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Criteria for a Neurotransmitter

Localization A putative neurotransmitter must be localized to the presynaptic

elements of an identified synapse and must be present also within

the neuron from which the presynaptic terminal arises. Release

The substance must be shown to be released from the presynapticelement upon activation of that terminal and simultaneously withdepolarization of the parent neuron.

Identity Application of the putative neurotransmitter to the target cells must

be shown to produce the same effects as those produced bystimulation of the neurons in question.


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Steps in Synaptic Transmission That Are Affected by Drugs


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Steps in Synaptic Transmission That Are Affected by Drugs


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Cathecholamines

Dopamine (DA) Precursor of norepinephrine

Biological activity in the central nervous system and in theperiphery

Norepinephrine In the brain and in the sympathetic neurons

Epinephrine

Formed from norepinephrine Released by the adrenal gland

Stimulates receptors in several organs

D i i P h i h B i


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Dopaminergic Pathways in the Brain


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Dopaminergic Projection Systems

Mesolimbic tract

Nigrostriatal tract

Mesocortical

tract

http://www.beautifulfunnysadandtrue.com/how-do-you-say-dopamine-in-chinese/


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Dopamine (DA) Neurons

Nigro-striatal dopamineneurons

Cell bodies are in thesubstantia nigra

Project to striatum

Part of the extrapyramidalmotor system

Motor balance, gait andmuscle coordination and

control Die (degenerate) in

Parkinsons disease


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Dopamine Neurons

Mesocorticolimbicdopamine neurons Cells bodies as in the

ventral tegmental area(VTA)

Project to the nucleus

accumbens, the frontalcortex and theamygdala

Involved in reward and

reward seekingbehaviors Targets for many drugs

of abuse


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Dopamine Synthesis and Storage in nerve terminals

DA

Cell Body (VTA)

Projects to

Nerve terminal(nucleus accumbens)


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Dopaminestorageandrelease


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Dopaminereleaseand

recovery


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Dopamine and Cocaine

Cocainebinds to DAT Blocks DA

transport Increases

dopamineconcentration in thesynapticcleft

Results inincreased andprolongedactivation ofDA receptors


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Synapse: Dopamine

Dopamine

binding toreceptorsand uptakepumps inthe nucleusaccumbens

http://www.nida.nih.gov/pubs/teaching/largegifs/slide-12.gif

DA

DA receptor

DA reuptake pumps


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Cocainebinding touptakepumps:inhibition

ofdopamineuptake


DA

Synapse: Dopamine + Cocaine

DA receptor


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IncreasedcAMPproducedin post-synapticcell


cAMP

Synapse: Dopamine + Cocaine = postsynaptic effects


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Dopamine and Cocaine

Cocaine binds toDAT

Blocks DAtransport

Increases

dopamineconcentration inthe synapticcleft

Results in increasedand prolongedactivation of DAreceptors

http://schizophreniasymptoms.net/dopamine-receptors/


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Dopamine and Amphetamine

Competes with DA forthe DAT

Transported into the

DA containing vesiclesby VMAT

Inhibits MAO

Displaces DA from thevesicles


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MAO and antidepressants

Blocks thedegradationof DA

Used totreatclinicaldepression

and panicdisorders

MAO Mono-Amine Oxidase


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http://www.viewzone.com/dopamine.html


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Norepinephrine (NE)

neurons are a so part o t e


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neurons are a so part o t e

sympathetic nervous system

Fight or flightresponse

NE neurons are

contained in ganglia(small mass of nervetissue containing thecell bodies ofneurons) and these

neurons send longnerve fibers to thetarget tissues.


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Actions of NE

Supply many tissues to cause excitatoryresponses:

Increase excitability of cardiac muscle and heart rate

Constrict blood vessels causing an increase in blood

pressure Relax airways making it easier to breathe

Dilate pupils

Stimulates secretion epinephrine from the adrenal gland

Stimulate glucose production by liver Inhibits the gastrointestinal tract

Inhibits salivary secretion


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NE &d b


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NE &drug abuse Cocaine blocks NET

Contributes toincreased

attentiveness, loss ofappetite and lack ofsleep

Amphetaminetransported by theNET, taken up intothe vesicles Same effects

Someantidepressantsblock NET


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Cocaine & Amphetamine: Psychomotor Stimulants

Both increase sympathetic nervous system signaling totarget tissues

Increased heart rate

Increased blood pressure

Increased respiration

Increased pupil dilation Inhibition of gastrointestinal tract


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Indolamines

Serotonin (5HT) Derived from Tryptophan

Biological activity in the GI tract, blood platelets & thecentral nervous system.

Regulates mood, appetite & sleep

Melatonin

Found in animals, plants & microbial life

Regulates circadian rhythms

Potent antioxidant & protector of DNA


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Serotonin (5-HT) in the brain


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Synthesis of Serotonin (5-HT)


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Release and recovery of 5HT at the synapse


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5-HT and MDMA (ecstasy) MDMA

causes the release ofthe neurotransmitterserotonin.

blocks the reuptake of

serotonin by thesynaptic terminal thatreleases it.

depletes the amount

of serotonin in thebrain.


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5-HT and LSD (acid)

LSD mimics serotonin during the transmission process but does

not cause suppression

lead to hallucinations, visual after-images, distortions ofperception and eventually paranoia

LSD molecules are reabsorbed by the neuron for repeated"flashback" activity and persistent perceptual distortion Can get flashbacks up to a year after use

Cells of the associate visual cortex are particularly susceptible

LSD may be a last resort treatment for extreme depression


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5-HT - targets for a variety of therapeutic drugs


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Potential Changes Drugs can have on Neurotransmitters

Change inneurotransmission

Effect onneurotransmitter

release oravailability

Drug that acts this way

increase the number ofimpulses

increased neurotransmitterrelease

nicotinealcoholopiates

Release neurotransmitter

from vesicles with orwithout impulses

increased neurotransmitter

release

Amphetamines

methamphetamines

Release neurotransmitter inresponse to impulses

increased neurotransmitterrelease

Nicotine

Block reuptake more neurotransmitter

present in synaptic cleft

Cocaine

amphetamine

block receptor with anothermolecule

No change inneurotransmitter release orneurotransmitter cannotbind to its receptor on the

post synaptic neuron

LSDcaffeine


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Drugs and Reward

http://learn.genetics.utah.edu/content/addiction/drugs/mouse.html

http://learn.genetics.utah.edu/content/addiction/

http://www.youtube.com/watch?v=b17d_c9WANE&feature=related

http://www.youtube.com/watch?v=GiC-UuRwZFQ

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Fundamentals of Neurochemistry.chemical Signaling - Monoamines