1. Neurotransmitters: Catecholamines & Acetylcholine Chapters 5 & 6
Dopamine
Norepinephrine
Epinephrine
Acetylcholine
Serotonin
Glutamate
GABA
Let’s say you were in Iran during one of the wars
a bomb explodes and a mist surrounds you, you start panicking,
until you realize you can still breathe,
At which time you realize that you took the antidote earlier that day
Nerve gas – anyone know what it is?
It will cause sweating, salivating, vomiting, gasping for breathe, convulsing, and death
Why? works on acetylcholine, by over-activating it, and since ACh involved in motor movement, eventually you will not be able to breathe
(causes permanent AChE (acetylcholinesterase – which breaks ACh down) inhibition
Too much ACh released, so muscles of lungs are eventually paralyzed
Antidote works by protecting AChE somehow, so it is not destroyed)
We need to know how basic NTs work in order to understand how drugs will change their activity
Drugs work by either mimicking the effect of the original neurotransmitter (by binding to a receptor) or by changing something about the manufacture, release, or deactivation of an NT
These are some of the most important NTs in our brains (list), we’ll be taking a quick look at what each one does

2. Neurotransmitter Families
Neurotransmitters
Just to give you some idea of where these NTs fit with other NTs, here’s a list of the major ones
here are the catecholamines (dopamine, norepinephrine, epinephrine)
This list is divided up according to chemical composition of the NTs, as well as how big they are
small-molecules NTs because they are small molecules
There are other molecules that work as NTs called neuropeptides – which are very large molecules, often work outside of nervous system as well
Ex. endogenous opiates, substance P (when released, you feel pain), oxytocin (milk letdown, but also feelings of bonding)
Obviously a lot more out there, and more being discovered, but the ones we will cover have been studies the longest, and we know more about them
Some of the others are rather mysterious
like gases, like nitric oxide, that we only have discovered in the last 10 or so years
Nitric oxide – lack of it may cause penile dysfunction, what viagra does is boost NO activity in penis
We will be concentrating on the small-molecule NTs
Ach not chemically like any of the others
monoamines, NTs that have one amine group (see next slide)
When I say amine group I mean that they have an –NH2 subgroup attached to the main molecule
Monoamines have two groupings: Catecholamines (dopamine, norepinephrine) and indolamines (serotonin)
Given separate groups b/c of chemical similarities – all cate. made from each other
Those are the NTs that you have heard about most frequently – they were the first ones discovered
Also important are the amino acid NTs like glutamate and GABA (amino acids used to build more complicated protein molecules)

3. Structural features of catecholamines
Called catecholamines because made of a catechol nucleus attached to an amine group that has nitrogen in it

4. Synthesis of Catecholamines
“rate-limiting enzyme”
Notice catechol group for dopamine and norepinephrine, and amine group
Main precursor of cate. is tyrosine (an amino acid, from a dairy protein), which is acted on by an enzyme called tyrosine hydroxylase (TH), which turns tyrosine into DOPA
(hydroxlases add –OH group)
Next, AADC turns DOPA into dopamine (decarboxylase removes a carboxyl group –COOH)
Then, DBH turns dopamine into norepinephrine (adds in oxygen)
often NT production includes a long cascade to get to finished product, so drugs can work by interfering in any part of that process
It turns out that the slowest process in this whole cascade is the first step with TH, so it is the rate-limiting step, the step where interference will have the greatest effect
What determines which NT is made in a neuron?
Whether or not the right enzymes are present

5. Catecholemines Some adjectives
Dopamine (DA)
“dopaminergic”
Norepinephrine (NE)
“noradrenergic”
Epinephrine (EPI)
“adrenergic”
Dopamine (DA) - “dopaminergic”
Norepinephrine (NE) - “noradrenergic”
Epinephrine (EPI) - “adrenergic”
Last two have unusual spelling because they are sometimes called adrenaline or noradrenaline (released by adrenal gland during stress)
EPI not used very much in brain, so we won’t talk about it much

6. Storage of Catecholamines vesicular monoamine transporter protein (VMAT2)
Catecholamines are NTs that have to be encased in a vesicle or they will be destroyed by enzymes floating around in the neuron
There is a protein on vesicles called vesicular monoamine transporter protein (VMAT2) that recognizes catecholamines and transfers NT from cytoplasm to vesicle
Reserpine (comes from snake root plant) interrupts process by blocking transport molecule

7. Behavioral effects of reserpine
Snake root plant picture
Behavior effects of reserpine (and blocking transport of catecholamines into vesicles)
a. Reserpine present, sedation – no catecholamines - destroyed
b. Treatment with DOPA (precursor to dopamine and norepinephrine) restores animal to alert status
This played key role in development of catecholamine theory of depression, person who did experiments won Nobel Prize in 2000 (Carlsson)
Catecholamines usually released when AP travels down to axon terminal
Amphetamines disrupt system – cause NTs to be released independent of APs,
Behavioral effects - activation of behavior (increased locomotor activity or (high doses) stereotyped behaviors), increased alertness, and euphoria (probably from DA reward system)

8. Dopamine Systems in the Brain
Mesolimbic pathway
Reinforcement
Mesocortical pathway
Planning
Nigrostriatal pathway
Movement
Three pathways for dopamine in brain:
1. Mesolimbic pathway (another name for DA reward system)
Reinforcement – VTA to NA, hippocampus, amygdala (all parts of the limbic system) addiction
(“meso” means mesencephalon, or midbrain, where VTA and SN are)
2. Mesocortical pathway
Planning - VTA to frontal lobe
Schizophrenia – decrease in DA levels in prefrontal cortex – resulting in lack of judgment, loss of initiative
3. Nigrostriatal pathway
Cell bodies in midbrain
SN (in midbrain)  BG movement (striatum = putamen + globus palidus)

9. Parkinson’s Disease: Damage to the substantia nigra
Immediate cause = loss of dopamine neurons projecting from substantia nigra to striatum (part of globus pallidus)
People knew this for some time, but didn’t understand why disease was happening
Damage to substantia nigra (called nigra b/c looks black, as in right photo of brain)
Left side shows someone with Parkinson’s – notice lack of black – most of cells are dead
SN here in midbrain – show slice in brain – small blue area in right drawings
Sends axons up to basal ganglia, which release DA
This system very complex, but simple explanation – BG work to both initiate action and stop it, coordinates with motor cortex so that movements are smooth and not jerky, regulates exactly how tense muscles are
When BG on, no movement, when BG off, movement; DA from SN turns BG off so you can start a movement, then cortex sends signal down to SN telling it to shut off, so BG gets turned back on again and movement stops with disease, most of SN neurons dead or dying, so BG turned on most of the time, leading to difficulty starting and then stopping movement
As a result, the muscles are overly tense, causing tremor, joint rigidity, and slow movement.
Cognitive dysfunctions in memory, abstract thinking, language

10. Causes of Parkinson’s Disease
Degeneration of substantia nigra
Less dopaminergic activity in basal ganglia
Discovery of MPPP  MPTP and MPP+
Immediate cause = loss of dopamine neurons projecting from substantia nigra to striatum (part of globus pallidus)
People knew this for some time, but didn’t understand why disease was happening
late 70s and early 80s, heroin was in short supply due to conflict in and around Afghanistan and Turkey, so the underground supply chain turned to synthetic opioids as a substitute
MPPP (1-methyl 4-phenyl 4-propionoxypiperidine) is similar to morphine
illicitly synthesized by a graduate student called Barry Kidson (1976); he ended up having Parkinsonian symptoms, The National Institute of Health investigated, found residue of some of the poisonously mis-synthesized drug, and the NIH decided tested it in rats, which was really unlucky choice; the rats showed symptoms for a few hours and then were fine, unlike Barry. Two years later he committed suicide and the autopsy showed cell destruction in the substantia nigra, and the damage was, in fact, the same as that seen in PD patients.
In 1982, six young people in the Bay Area of California suddenly manifested a Parkinson-like syndrome. Doctors were baffled by these cases - the patients were too young, and the symptoms manifested too abruptly to be true Parkinson's disease. It was later determined that these patients were all addicts that had taken a synthetic heroin then going by the name of "China White", which a local drug dealer had been manufacturing in his garage.
However, synthesizing it was tricky (intermediate quaternary alcohol was liable to dehydration in hot, acidic conditions), and heating it too much in at an intermediate step turned MPPP into MPTP was formed.( 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine), which in turn metabolizes into the neurotoxin MPP+ (1-methyl-4-phenypyridinium), causes rapid onset of irreversible symptoms similar to Parkinson's Disease selectively kills brain tissue in the area of the brain called the substantia nigra and causes Parkinson’s symptoms. which would be impossible to find without a multi-thousand dollar gas spectrometer
From these two separate incidents, scientists were able to determine that MPTP was the responsible agent.
In addition, scientists determined that the action of MPTP's metabolite MPP+ is very similar in effect to that of paraquat, a pesticide, which has led to the investigation of pesticides and other environmental factors as influences in the development of Parkinson's disease.

11. A typical dopaminergic neuron
DA levels regulated by auto-receptors, which when activated decrease amount of Ca+ that enters neuron at axon terminal, so less catecholamines released
If a drug activates autoreceptor, it inhibits NT release
If drug deactivates autoreceptor, it encourages NT release
NE neuron works same way, but has different receptors specialized for NE
Inactivation of cate.
Two different processes:
Reuptake (left blue) at axon terminal
Tricyclic antidepressants (one of 1st antidepressants, replaced more recently by SSRIs) work by inhibiting reuptake of NE and (serotonin)
Cocaine inhibits reuptake of DA, NE and (serotonin)
2. Enzymes destroy cates. –break down into metabolites that are excreted in urine
COMT
MAO (monoamine oxidase) – (oxidation- addition of an oxygen atom, which causes loss of an electron – oxygen gets electron and forms a chemical bond with other substance, and the removal of the amine group)
MAO inhibitors – inhibit MAO enzymes and destruction of cates

12. D1 and D2 receptors
Five types of DA receptors, all metabotropic receptors (work thru G proteins)
Two most numerous types (below) have opposite effects
D1 – activate cAMP
More cAMP, more likely cell is to get excited and have an AP
Where cocaine, amphetamines work
D2 – inhibit cAMP, all current antischizophrenic drugs are D2 antagonists, like haloperidol (block receptors) – antipsychotics work in Nucleus Accumbens
Catalepsy – lack of spontaneous movement
can be produced by DA receptor antagonists for D2 receptors,
If D2 receptors are not working as well, what should happen? APs?
like haliperidol (which is why when people with schizo have high dose of hali they may show symptoms of Parkinsons)

13. Norepinephrine Now on to norepinephrine
Cell bodies in pons and medulla, esp. locus coeruleus in pons
Projections esp. to frontal cortex
Involved in hunger, sex, fear, pain, sleep and arousal
Also used in PNS in autonomic (fight/flight), increase blood pressure, heart rate,
Medication for asthma uses NE agonist, which constricts blood vessels so that less swelling in lungs (alpha receptor), OR causes lung muscles to relax (beta receptor)
NE antagonists can help treat anxiety by reducing physical symptoms of panic attacks
NE receptors also all metabotropic
Also have two receptor types, alpha and beta
Beta – like D1, activate cAMP
Alpha - like D2, inhibit cAMP

14. Role of the locus coeruleus in vigilance
Scientists measured activity in LC during various activities
Firing of LC low when sleeping or relaxed
High when novel stimulus or very alert (vigilance)
Example of how drugs interact with this system:
opioids normally inhibit firing of neurons in locus ceruleus (responsible for intense alertness),
When someone stops using opioids (morphine or heroin), NE system gets activated
Causes withdrawal symptoms - increased heart rate, elevated blood pressure, diarrhea
To treat withdrawal symptoms, you can stimulate these autoreceptors to decrease NE release (drug - clonidine)
NE also implicated in anxiety disorders, so if you increase activity of autoreceptors (leading to less NE release), you will theoretically decrease anxiety levels

15. Functions of Acetylcholine (ACh)
Neuromuscular junction (movement)
Central nervous system (learning and memory)
Functions of ACh
- NM junction – connection b/t neurons and muscle cells
– way black widow spider venom works is that it causes neuron to keep releasing ACh, muscles over-stimulated, causes spasms, eventually neuron runs out, then causes paralysis
- Or botulism, proteins taken up by ACh neuron, which interfere with ACh release  muscle weakness
This is where Botox came from – it paralyzes muscles in face so that wrinkles will not form, remains effective for a few months
Neurons (cell bodies) in pons and midbrain, project to amygdala, cortex, thalamus, involved in learning and memory
This is system that breaks down for Alzheimer's

16. Acetylcholine Receptors
Nicotinic receptors
Neuromuscular junctions
Ionotropic (ion channel)
Curare works on these receptors
Muscarinic receptors
Metatropic (second messengers)
Hippocampus, striatum
Morphine
Also located in heart and smooth muscles
Nightshade
Two main receptor types, named for substances that bind to them (in addition to ACh of course)
Nicotinic receptors – located at neuromuscular junctions
Tobacco - (nicotine improves alertness and concentration)
Ionotropic (ion channel)
Curare also works on these receptors
Muscarinic receptors – located in hippocampus, striatum
The fly agaric mushroom, Amanita muscaria
Metatropic (second messengers)
Morphine works here
Also located in smooth muscles, so side effects of some drugs used to treat depression and schizo like dry mouth (not producing enough salina)
Nightshade inhibits parasympathetic system (relaxing one – muscarinic receptors in PNS), too much will kill, a little bit in eyes causes dilation, beauty trick

17. Serotonin (5-HT) Mood Appetite Sleep 5-HT – 5-hydroxytryptamine
Been blamed for every possible human illness, depression, anxiety, obesity, aggression and violence, drug addiction
Media portray it as something that will destroy us or cure us of all ills (if it’s working right), and there are a lot of books out there that say changing your diet and affecting serotonin production can change things in our brain
Pathways go from raphe nuclei to rest of cortex

18. Features of a serotonergic neuron
Serotonin uses same transporter as catecholamines (VMAT2), so resperine has same effect here as it did there
SSRIs are selective serotonin reuptake inhibitors (like prozac) but cocaine and MDMA work on this system too (MDMA kills serotonin cells)
At least 15 receptor subtypes
LSD stimulates serotonin receptors (hallucinogen)
Schizo – blocking 5-HT receptors help relieve hallucinations?

19. Glutamate Is an amino acid Made from breakdown of glucose Used for:
Making other proteins
Metabolism (energy)
Excitatory neurotransmitter
Glutamate: Is an amino acid, Made from breakdown of glucose
Used for:
Making other proteins
Metabolism (energy)
Excitatory neurotransmitter

20. Glutamate Excitotoxicity Examples:
Excessive exposure to glutamate which leads to cell damage or cell death
Examples:
Domoic acid
Strokes
Excitotoxicity
Excessive exposure to glutamate which leads to cell damage or cell death
Does this happen in humans often?
Domoic acid – found in fish and shell fish, similar excitatory amino acid, makes people have headache, dizziness, confusion, muscle weakness
Hitchcocks Birds based on incident where birds ate tainted food
Strokes – interruption in blood flow to brain, causes excess release of glu

21. GABA
GABA is the major inhibitory neurotransmitter of the central nervous system.
The GABAA receptor interacts with a number of drugs.
Present nearly everywhere in brain, made from glutamate
GABA can decrease activation of a neuron
Drugs depress nervous system by increasing inhibition, (alcohol, benzo – valium, barb – anesthesia) (don’t activate receptor w/o GABA)
Combining any of these drugs could be life threatening, which is why physicians tell us not to combine medicines and/or drugs
muscimol (from same mushroom that produces cholinergic agonist) is a GABAa agonist, has some of same effects as LSD (hallucinations, loss of apetite, elevation of mood, problems concentrating)

22. Why is Inhibition Important?
Tetanospasmin (tetanus toxin) hitches a ride to the central nervous system from a wound site using the retrograde transport system within axons.
The toxin binds to receptor sites for gamma-aminobutyric acid (GABA), and can’t be dislodged.
Without normal inhibitory input from GABA, muscles begin to go into sudden, involuntary contractions, or spasms.
There is nothing telling the muscles to shut off, so they spasm