Neurotransmitters

Purves et al., Chapter 6 and selections from Chapters 5, 17 and 21 (for autonomic nervous system)
Sylvius (there are many places where you might want to look up the structures discussed)
This outline will focus on transmitters. Although transmitter receptors will be mentioned, they will be covered in more detail on the next outline.

Alumna

Michelle Lugus (nee Li) took this course in 2006. I am showing you one of her papers, Li et al., Electroanalysis 17, 1171-1180, 2005. A microchip-based system for imobilizing PC 12 cells and amperometrically detecting catecholamines released after stimulation with calcium.
Topics to discuss:
PC 12 cells
microchip
why calcium

Background

Synaptosomes
After gentle homogenization, pre- and post-synaptic membranes stick together, and membranes seal back up; all the chemicals of the synapse can thus be found in one centrifuge tube layer.

Figure
Box 5A (Chapter 5) p. 84
criteria used to be real stringent
now (1) presence, (2) release and (3) receptors
They used to use the expression "putative neurotransmitter" a lot to cast doubt as to the universal acceptance that a substance was qualified.
Pharmacology was pivotal in criteria, and it still is in discussing chemical transmission.
agonist - a drug that mimics the neurotransmitter
antagonist - a drug that blocks the neurotransmitter

Types of molecules

Table 6.1 p 111
Fig 6.1 p. 110
Chemical synaptic transmitter substances:
Monamines (acetylcholine, catecholamines, serotonin, histamine, octopamine)
Amino Acids (GABA [gamma amino butyric acid], glutamate, glycine)

Figure 6.17 p. 134
Peptides (many)

gasses like Nitric Oxide (NO), see below

Purines - ATP (and AMP and adenosine) excitatory transmitters (not much to say)

endocanabinoids (see below)

General aspects about synthesis

(Fig. 5.5 was shown earlier, in the context of axon transport)

Fig. 5.5A p. 83
synthesis for small molecules in terminal
enzymes transported by slow axonal transport

Fig 5.5C p. 83
peptides are synthesized as pre-propeptides in rough endoplasmic reticulum
signal sequence (for secretion) is removed
Propeptide is processed in Golgi apparatus, put in vesicles, fast axonal transport using ATP and kinesin.

Fig. 6.16 AB p. 1\3
Further processing, especially cleavage (common for many peptide transmitters and hormones)

vesicles

Fig. 5.5 B p. 83
40 nm (small) electron lucent vesicles and just a few large dense core

Fig. 5.5 D p 83
somewhat larger dense core are catecholamines or peptides
100 nm diameter granules are secretory
Importantly, transporters concentrate transmitters into vesicles

General

Fig. (like Fig. 5.3, p. 80, only simpler)
Here, I show a typical synapse figure (again).
Receptors in this figure are channels

Fig. 5.16 A p. 97
This kind of transmission (channels) is called ionotropic.
For Acetylcholine (cholinergic transmission), the nicotinic receptor is an example.
Nicotine is an agonist (though it has some properties of an antagonist).

Fig. 5.16 B p. 97
There is another kind of receptor, the G-protein-coupled receptor.
For cholinergic transmission, the muscarinic receptor is an example

Monamines

Fig. 5.4 p. 81 (again)
Loewi 1936 Nobel Prize (already covered)
Reportedly, he thought of this experiment in a dream
vagus-stuff slows heart (10th cranial nerve, parasympathetic)

Acetylcholine

Fig. 6.2 p. 112
Aceylcholine metabolism
Dale 1936 Nobel "cholinergic" ("-ergic" used universally)
unique in that amino acid not involved
Dietary choline -reuptake or uptake (transporter is Na+ dependent) -> intraneural choline
-Choline-O-acetyltransferase-> H3-CO-O-CH2-N+-(CH3)3
Acetyl Co-A is acetate donor
Acetylcholinesterase blocked by malathion and neostigmine
organophosphates, nerve gas, etc

Catecholamines

Fig. 6.10 p. 125
Adrenergic

Landmark paper
(1970 Nobel Prize) Julius Axelrod, Noradrenalin: Fate and control of its biosynthesis, Science 173, 598-606, 1971. Science publishes Nobel Prize papers.

Reflection, I saw Axelrod (twice) and he gave great talks, in an easy-going manner, said everything that was known.

tyrosine hydroxylase - rate limiting and regulated by end-product inhibition
calcium activates
it is DOPA quinones which polymerase to make melanin
substantia nigra is pale in Parkinson's disease => synthesis overlap
DOPA decarboxylase - gets rid of l vs. d
in insects, dopamine quinones "tan the hide"
dopamine beta hydroxylase - adds optical asymetry back again
interestingly, within vesicle
ATP is released with NE, ATPase turns to adenosine
Important agonists and antagonists and other drugs
PNMT (phentolamine N-methyltraansferase)
interestingly, in cytosol, necessitating transport out then in vesicle

Table 6.1 p. 111 (again)
"Metabolism"
Most removal is by transporters, but there is breakdown
MAO - monamine oxidase intracellular, inhibitors (MAOI's) are antidepressants
on outer mitochondrial membrane
COMT - catechol O-methyltransferase extracellular, but there are no inhibitors)
but reuptake most important

Autonomic n.s.

Motor system for smooth muscle and glands, covered here because of acetylcholine and norepinephrine involvement

Part of Fig. 21.1 (left side) p. 455
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near target

Part of Fig. 21.1 (right side) p. 455
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal cord
Many targets are "push-pull" like heart
Some are unique like arterioles (sympathetic only) -- close in peripheral vascular beds (make hands cold), open in muscle (hyperemia).

Fig. 21.2 A p. 459
arrangement of sympathetic output from lateral horn neuron -> white ramus -> sympathetic ganglion -> gray ramus

Fig. 21.3 B p. 460
Simpler for parasympathetic, i.e. from brain stem nucleus...

or ...

Fig. 21.3 C p. 460
lateral horn in sacral cord to parasympathetic ganglion

Fig. 21.4 A p. 462
called "enteric" for gut. Contribution of neural network (plexus) to circular and longitudinal muscles to mediate peristalsis. Parasympathetic allows digestion, sympathetic puts it on hold. Atropine (I'll talk more about atropine in next outline) blocks muscarinic synapses and is in anti-diarrhea medications to slow motility.

Fig. 21.8 p. 470
heart as an example. Automaticity at SA and AV nodes (spread from myocardial cell to next myocardial cell). Sympathetic speeds heart, parasympathetic (via vagus, X) slows, and relaxed heart rate is slower than automatic rate.

Male sexual function as an example.

Fig. 21.9 p. 471
Important aspect of quality of life

Robert F. Furchgott, Louis J. Ignarro, Ferid Murad Nobel 1998 "for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system"

A few years ago, I wrote, "This is the only place where parasympathetic affects arterioles, dilating them in corpus cavernosum for erection. Sympathetic contributes to ejaculation."

Then I read a paper by Ignarro and then his Nobel "speech." Actually, for erection (relaxing arteriole smooth muscle), adrenergic (via alpha 1 receptors) contracts smooth muscle, cholinergic (via muscarinic receptors) inhibits adrenergic-induced-contraction (resulting in relaxation); more than cholinergic and adrenergic, a little mentioned autonomic component, the NANC (nonadrenergic noncholinergic) system, mediates relaxation.

In the 2003 movie Something's gotta give, Jack Nicholson has a heart attack while having sex, and the docs ask if he is on Viagra as they are about to give him nitroglycerine. (also listed in advertisements for ED (erectile dysfunction) medications because of interaction and resulting low blood pressure)

People take nitroglycerine for angina (chest pain), and it releases NO (nitric oxide) and relaxes the coronary arteries

Nitric Oxide (NO), made by endothelial nitric oxide synthase (eNOS), unusual in that it diffuses across "postsynaptic" membrane to affect guanylyl cyclase (GC) involved in making cGMP.
NO was endothelial derived relaxation factor (EDRF), mediator of parasympathetic nervous system's dilation of arterioles in corpus cavernosum. Viagra (sildenafil) inhibits the PDE that breaks down cGMP

Serotonin

Fig. 6.14 B p. 131
Serotonin = 5-HT (5-hydroxy tryptamine)
tryptophan hydroxylase
l-aromatic amino acid (5-HTP) decarboxylase
Serotonin from Raphe nucleus ispread widely and involved in sleep (discussed later in the semester). Tryptophan in turkey blamed for sleepyness after Thanksgiving dinner.

Alumnus interview relates to SSRIs
SSRIs (selective serotonin reuptake inhibitor)
Prozac (fluoxetine)
Paxil (paroxetine)
Zoloft (sertraline)
There is new controversy about whether these increase the incidence of suicide, now that they are given to teenagers, but there was also controversy overr a decade ago. The other side of the argument is that it is given to depressed people.

LSD (lysergic acid diethylamide) agonist of 5HT receptors in Raphe, cause decreased output to brain (as in sleep).

People used to take tryptophan, but bad batch caused eosinophilic-myalgia syndrome so FDA banned it in 1990.

The melatonin story

2 more steps after 5-HT to make melatonin (sleep promoting hormone, higher at night) in pineal
N-acetyltransferase (regulated) and hydroxy indole O-methyl transferase.
High at night, low during day, relates to biorhythms, see lecture later in the semester.
In animals where light can reach the pineal, it has photoreceptors.
For us, eye to suprachiasmatic nucleus of hypothalamus to pineal.
N-acetyltransferase is rate limiting step.
Melatonin sales went wild in mid-1990's after books stated that melatonin was a "wonder," "miracle" or keeps you young.
Thought to restore sleep cycle after jet lag.
Melatonin controls reproductive cycle in seasonally reproductive species.
Here is the diagram used in the Mizzou Physio lab on endocrinology.
Testes of short-day hamsters are smaller than long-day hamsters (Mizzou Physio Lab)
Melatonin was used at high doses for birth control by women in Holland

Amino acid transmitters

Fig. 6.5 p. 118
Glutamate
Central excitatory - like inputs to hippocampus - maybe half of CNS synapses
Synthesis is simple from glutamine (from nearby glia) by glutaminase.
Prof Bode in my department has a special interest in glutamine transport.
Affected by many toxins, for instance poison from mussels - domoic acid, and plants (Box 6B).
Involvement in ALS (Amyotrophic lateral sclerosis [Lou Gehrig's] ALS) and possibly Alzheimers.
Excitotoxicity - Box 6C - too much glutamate causes a cycle of Ca2+ influx.
May be involved in ischemia - induced injury.

Fig. 6.8 A p. 122
GABA (gamma amino butyric acid)
really important inhibitory neurotransmitter
synthesis GAD glutamic acid decarboxylase
made in a shunt in the TCA (Kreb's) cycle, present in brain
There is a lot of GABA in the brain, mostly local circuits, but also Purkinje output.
Incidentally, a natural breakdown product of GABA is gamma hydroxy butyrate (GHB), the date rape drug.

Fig. 6.8 B p. 122
Glycine is the other major inhibitory transmitter
transporter mutation causes hyperglycenemia - neonatal seizures, lethargy, retardation
synthesis by serine hydroxymethyltransferase
a lot in the spinal cord
strychnine blocks

Histamine

Fig. 6.14 A p. 131
Histamine is a transmitter (in addition to being a mediator of inflamation from mast cells)
antihistamines that cross BBB make you sleepy

Chemical neuroanatomy

Fig. 6.11 AB p. 127
Fig. 6.13 B p. p. 130
1960's technique of histochemical fluorescence allowed chemical anatomy -
Expose sections to vapor of paraformaldehyde
neurotransmitters have widespread effects but come from defined locations
Dopamine from substantia nigra
Norepinephrine from locus coeruleus
Serotonin from Raphe

Parkinson's
(mentioned here because of dopamine)
Miclelle Li, graduate student in 2006 class, gave a presentation on Parkinson's

Fig. 18.9A p. 408
degeneration of substantia nigra (left) relative to control (right)
Box 18.A p. 410 in Chapter 18
1817 Shaky palsey
Degenerate dopaminergic input to striatum from substantia nigra
Cells that survive have inclusions called Lewy bodies.
Aflicted have bradykinesia, akinesia, rigitystilted gait, tremors, walk in shuffle, stone (expressionless) face, loss of affect.
1% of people over 50 years old
Lateral hypothalamic lesions make thin rat and some motivational defects, dopamine in medial forebrain bundle toward basal ganglia.
Dopaminergic neurons degenerate, animal model - 6-OHDA uptake makes peroxide, cells die.
Cannot give dopamine because it coes not cross the blood brain barrier.
Give l-DOPA (in large doses because l-AAAdeCOOHase is everywhere); give decarboxylase inhibitor carbidopa. Jill Smith, Ph.D. 2005, in Dr. Fisher's lab (Bio, SLU) worked on this.
Extrapyramidal motor syndrome also comes from long term administration of antipsychotic phenothiozines such as chlorpromazine (brand name Thorazine).
(Chronic use of these drugs also cause a corioretinopathy.)
There was a bad batch of street drugs with an impurity called MPTP which gave its users a Parkinson's like disease.
The commonly used insecticide rotenone, and other insecticides, are like MPTP.
There had been some experimental cell transplant therapies - controversal.
Arvid Carlsson made contributions here and shared 2000 Nobel Prize in Physiology and Medicine.
Several famous people have Parkinson's - the late Pope, Mohammad Ali, Michael J Fox.
Mostly it is "sporatic" (not genetic), but familial cases have been interesting.
Alpha-synuclein, Parkin and DJ-1.

Psychiatry

Personal reflection.
I took abnormal psychology when I was an undergraduate at Columbia College in New York in the 1960's. We were sent up the the Psychiatric Institute at Columbia Physicians and Surgeons to see a psychiatrist interview patients for two classes. That part of New York is hilly, and the ground floor of PI was the 9th floor. An odd coincidence was that we had all read Dante's Inferno recently in literature humanities. The first patient was an 18 yr old kid who played chess instead of basketball who was being fed a shovel full of chlorpromazine every day. After he left the room, the doctor asked the class what was wrong with the kid and we all looked in the pony for the abnormal psych text and said things like "paranoid neurotic" etc., and the doctor said "you guys are far too cerebral, this kid's a schmuck, he has the schmuck syndrome." The next week we saw a person more normal than any of us who seemed to think an appeal to the class was his only means of escape. We were all happy to get out of the PI without being sent down to one of the lower floors (Dante's inner circles) and chained to the wall.

Alumnus interview relates to Psychiatry
Box E biogenic amines and psychiatric disorders.
Psychosis - severe.
Neuroses not so severe.
Schizophrenia (dementia praecox= early loss of intelligence) (paranoid, catatonic, etc.), real thought disorders, progressive and degenerative, used to be the cause of more "hospitalization" than everything else put together.
They were called "insane asylums" (These were the days before political correctness.)
Borris Karloff old movie "Bedlam" is about insane asylum.
It is popular to mistrust psychiatry, for instance the movie "One flew over the cuckoo's nest" with Jack Nicholson (1975), but people with schizophrenia are really crazy without a doubt.
Reserpine storage blocker, used for hypertension (for NE [andDA, 5HT]) for psychosis; 1950s - revolutionized psychiatry (nowadays, the disparaging phrase is "went off his or her meds").
There was a 1960s radio advertizing slogan "mental illness [again before political correctness] is no longer hopeless" (that kids used to say to each other).
There was a book, D.W.Woolley, The biochemical bases of psychoses (subtitle - the serotonin hypothesis about mental diseases (New York, Jhhn Wiley and Sons, Inc., 1962), and the understanding that LSD affected serotoninergic transmission fit in.
It seems every time a neurotransmitter was characterized, there was a band wagon of attributing everything to it, a catecholamine (norepinephrine) theory of affective disorders (partly attributed to Stein (J. J. Schildkraut and S. S. Kety, Biogenic amines and emotions, Science, 156, 21-30, 1967), and this fit in with the idea that amphetamine caused psychosis (Amphetamine stimulates NE release); this is before dopamine was appreciated as a transmitter.
Methedrine (speed, drug of abuse, MO (Jefferson Co famous for manufacture, explosions, fires), dexedrine (once used as a diet pill, recently, oddly, used for ADHD [attention deficit hyperactivity disorder]) [works on explorer, not netscape], and benzedrine (mild uppers, abused by students cramming for exams); now ritalin used for ADHD; I repeat that is it odd that stimulants would help hyperactivity; it is also controversial and troublesome how many kids are given such drugs. (Later in the semester, we will talk about "amphetamine and cocaine regulated transcription factor."
Now thought to be over-activation in dopamine pathway.
Dopamine receptor blockers (antagonist) - haloperidol, chlorpromazine are antipsychotics.
Chronic chlorpromazine treatment causes chorioretinopathy and Parkinson's tremors.
Incidentally, a controversal 1971 book (D. Rosenthal, Genetics of psychopathology, New York, McGraw-Hill Book Co) suggested an underlying genetic predisposition for schizophrenia, now widely believed.

Depression, unipolar, bipolar ("manic depression is a frustrating mess" - Jimi Hendrix)), involutional melancholy (in elderly) - great suffering.
Bipolar seems to run in families, treated with lithium salt, my theory is that, since Li+ can replace Na+ for the action potential but not in the Na+ pump, action potentials would be smaller.
Unipolar Tricyclic antidepressants (desipramine) blocks NE (and other) reuptake.
SSRI's covered above.
Antidepressants MAOI's (phenylzine)
After electroconvulsive shock (ECS), patients seem much happier; sounds barbaric, but still used and, with correct control medications, it is not cruel; Interestingly, there is a memory loss for the time before the shock, and ECS fits in with the idea that correctly reverberating neural circuits are important for memory consolidation.

Anxiety - Tranquillizers - benzodiazepines (chlordiazepoxide = Librium, diazepam = Valium) enhance GABA-A receptors

Treat panic with MAOI's, also serotonin receptor blockers, also benzodiazepine alprazolam (Xanax).

Peptides

substance P - 11 amino acids known for 60 years, named after "powder"
involved in pain

Landmark paper CBPert and SHSnyder, Opiate receptor: Demonstration in nervous tissue, Science 179, 1011, 1973, see also J NIH Res 2, 73-79, 1990
Tritiated naloxone, opiate antagonist, binds to places in the brain and is displaced by opiates in parallel with their strength.

Table 6.2 p. 135
Solomon Snyder discovery of opiate receptors - binding studies
(While you have receptors but do not know what the ligand is [yet], these are called "orphan receptors."
then discovery of endogenous opiates (enkephalins, endorphins dynorphins)
met-enkephalin and leu-enkephalin, 5 amino acids
beta-endorphin 31 amino acids
cleaved from pro-opiomelanocortin or proenkephalin precursor

Marijuana

Fig. 6.18 p. 136
Box G p. 137
Cannabis sativa

Recent paper R. A. Nicoll and B. E. Alger, The brain's own marijuana, Scientific American, pp 68-75, Dec 2004.

BoxG p. 137
THC used to treat anxiety, pain, nausea, obesity, glaucoma.

BoxG p 137
Affects hypothalamus, basal ganglia, amygdala, brain stem, cortex, hippocampus, cerebellum.

A. C. Howlett, 1988, SLU, receptor CB1, later CB2 was found.
G protein coupled receptors.
Presynaptic CB1 prevents GABA release to block glutamate excitation

Fig 6.18A p. 136
Anandamide

Fig. 6.18B p. 136
2-arachidonoyl glycerol (2-AG)
2-AG released from postsynaptic cell

Test questions from 2005 - 2012 relating to this outline

How is Met-enkephalin produced from pre-proenkephalin A?

it is cleaved from the larger protein

Blocking the muscarinic cholinergic receptor on the heart with atropine would save your life if you were poisoned with what class of molecules?

acetylcholinesterase inhibitors

How is a norepinephrine breakdown enzyme an important target in the pharmacology of treatment for depression?

norepinephrine is obviously an "upper", so potentiating its action by inhibiting its breakdown would certainly be uplifting

"The nicotinic receptor is ionotropic." Translate: What is the transmitter? What is the molecular structure of the receptor? (Answer both.)

acetylcholine gates a channel

While administering Prozac to a patient with depression, the doctor needs to closely monitor (what?).

any suicidal thoughts or actions

In order to produce hamsters with large vs small testes, what did the lab prep technician need to do ahead of time?

put some on cycles of 8 hrs lights on vs 16 off and vice versa for the others

While light stimulates tells small-headed animals whether it is day or night, how is the pineal informed about the light-dark cycle in people?

input from the suprachiasmatic nucleus

Give one of the two possible reasons a diet high in tryptophan might make you sleepy.

precursor to serotonin and to melatonin

"Reuptake into the nerve terminus terminates the synaptic action of glutamate." How else is glutamate's action terminated?

it is also taken up into glia

What is sent throughout the brain from the Raphe nucleus?

serotonin

A symptom of Parkinson's disease is bradykinesia. What is bradykinesia?

not moving much

Explain either (1) why schizophrenia was once attributed to a serotonin defect, or (2) why this hypothesis was later excluded.

an LSD trip seemed like psychosis and LSD affected serotonergic transmission, bur amphetamine induced psychosis was more similar to schizophrenia

How did your professor rationalize that action potentials would be smaller in manic-depression patients who are on lithium therapy?

the gradient of lithium plus sodium, seen by the channel, would not be as steep because the pump cannot pump lithium

Phosphatidylinositol and phosphatidylethanolamine, precursors for endogenous cannabinoids, are supplied from what compartment in the cell?

membranes

"Tetrahydrocannabinol (THC) binds to CB receptors to mediate the effects of marijuana." Regarding the endogenous transmitters, answer either (1) Characterize the chemical PRECURSOR of one of these transmitters. Or (2) Where (in the cell) would this PRECURSOR be found?

membrane phospholipid, membrane

What is the general term for a pharmacological agent that mimics the action of an endogenous neurotransmitter?

agonist

For peptide transmitters, it is thought that vesicles are transported out the axon. In contrast, what goes out by anterograde axonal transport for small molecule transport like amines?

enzymes

Opium is not a neurotransmitter. Name an endogenous molecule functionally related to opium that is a transmitter.

endorphin or enkephalin

You were introduced to the function of the small G protein ras.in vesicle release. In contrast, how is the larger, heterotrimeric G protein involved in neurotransmission?

metabotropic receptors like the muscarinic acetylcholine receptor are 7 transmembrane spanning G protein linked receptors that signal to this G protein.

Reuptake is the standard mechanism for the termination of neurotransmitter action. In contrast, how is the action of acetylcholine terminated?

breakdown by acetylcholinesterase

To study what type of neurotransmitter did a neuroscience course alumna use pheochromocytoma (PC) cells?

Why is the color of the substantia nigra related to the neurotransmitter it produces?

DOPA is the common precursor of melanin and dopamine

Potentiating the action of (what?) is the rationale for the use of inhibitors of MAO (monamine oxidase) as antidepressants.

since norepinephrine is not metabolized, there is more of it

Acetylcholine and nicotinic receptors are used in parasympathetic ganglia. What transmitter and transmitter receptor would you find at sympathetic ganglia?

same

One portion is called thoraco-lumbar. What is the equivalent name for the other portion (of the autonomic nervous system)?

cranio-sacral

Where does the nitric oxide (NO) responsible for smooth muscle relaxation come from? (cell type or enzyme)

endothelium, eNOS (endothelial nitric oxide synthase)

Cyclic GMP's breakdown is inhibited by what drug (or class of drugs)?

Viagra (Levitra Cialis) ED meds

"Now that there are antidepressants, there is no reason to be depressed." Then why is there so much controversy about drugs like Prozac (and Paxil and Zoloft)?

some critics implicate them in increased risk of suicide or homicide

Melatonin... (answer either) (1) ...is synthesized from what transmitter? Or (2) ...is synthesized in what part of the brain?

(1) tryptophan (2) pineal

"Testes of short day hamsters are smaller than testes of long day hamsters" because of what hormone?

melatonin

For glutamate and GABA, what mechanism supplements reuptake into the nerve terminal to terminate the action of the transmitter?

reuptake into glia

GHB (gamma hydroxy butyrate, the infamous date rape drug) is related to transmission by what neurotransmitter?

GABA

Why does it take a lot of DOPA to treat Parkinson's disease?

very little is available to cross the blood brain barrier because the decarboxylase is everywhere

Receptor antagonists for what transmitter are considered to be the most effective treatment of schizophrenia?

dopamine

"People on lithium treatment might have smaller action potentials." Answer either (1) Why would some people be given lithium? Or (2) Why would their action potentials be expected to be smaller?

(1) to treat the manic phase of manic depression (2) b/c, since lithium does not get pumped out, the gradient of cations seen by the sodium channel is not normally steep

What is the common precursor for dopamine and melanin?

l-DOPA

In presenting the synthesis of glutamate, what cell is the source of the precursor, glutamine?

glia

SSRIs (selective serotonin reuptake inhibitors) are used to treat what disorder?

depression

What is the source (location) of serotonin that is spread widely through the brain?

Raphe nucleus

l-aromatic acid decarboxylase, used to convert 5-HTP to 5-HT, also makes what other neurotransmitter?

dopamine

In which part of the nervous system is glycine widely used?

spinal cord

Where are the enzymes for norepinephrine synthesis?

in the terminal

The benzodiazepine tranquillizers (chlordiazepoxide = Librium, diazepam = Valium) affect transmission with what transmitter?

GABA

At the autonomic ganglia, what is the transmitter?

acetylcholine

From what transmitter is melatonin synthesized in the pineal?

serotonin

What transmitter is most closely related to the date rape drug?

GABA

How is POMT (proopiomenanocortin) processed to yield b-endorphin?

cleved

What transmitter from the sympathetic nervous system would speed the heart beat?

NE

What class of molecules serves as the precursor for endocannabinoids?

membrane phospholipids

What does NO=nitric oxide do to arteriole smooth muscle?

relax

On the news this week is the case of a defendent blaming the murder on Zoloft (the Zoloft defense). Why would he have Zoloft in his system?

for depression

"Thoraco-lumbar" is another term for what component of the nervous system?

sympathetic

Name two monamines synthesized from amino acids.

dopamine, norepinephrine, epinephrine, serotonin, histamine

Tell me about the vesicles for endocannabinoid transmission.

there are none

How is GABA different from the 20 amino acids coded in the genetic code and used as the building blocks of proteins?

NH2 and COOH are on different carbons

What is the difference in how acetylcholine and norepinephrine are cleared from the synaptic cleft?

ACh broken down, NE reuptaken

Dopamine beta-hydroxylase converts dopamine to norepinephrine. Discuss optical isomerization (l- vs. d-) for precursor and product.

dopamine lacks a carbon with 4 separate groups while there could be l- and d-NE (it is l- that we use)

The garden tomatoes were not cooked enough before being "canned" in mason jars. What would happen to your muscle contractions if you eat them?

botulism would block muscle activation by nerve vesicles

In addition to cranial nerves, what other nerves make up the parasympathetic nervous system?

sacral

"The parasympathetic nervous system dilates arterioles in the corpus cavernosum, mediating erection." Give either of the reasons that this statement is not the whole truth according to more modern research.

the parasympathetic ns actually works by inhibiting the sympathetic. Also, the NANC (non adrenergic non cholinergic)ns is predominant.

What would sympathetic activation do to the blood flow in muscle?

increase it, hyperemia, "pumpitude"

How would you get beta-endorphin from proopiomelanocortin?

proteins are chopped down to make peptide transmitters

"Muscarine is an agonist for the cholinergic receptor." Translate.

muscarine is a drug that would activate one type of synapse for acetylcholine

Refering to schizophrenia, in interview, Bob said "receptor subtypes are very important. Block them all ... and you can get a Parkinson like movement disorder. Block only certain subtypes ... and you get relief of symptoms without the movement disorders." Receptors for what transmitter?

dopamine

How do sodium channel and sodium pump respond when lithium ions are substituted for sodium ions?

lithium goes in through sodium channels but is not pumped out by sodium pump

What pineal hormone is implicated in the differing testes of long- vs. short-day hamsters?

melatonin

Talk about the regulation of release (vesicles?) for nitric oxide (NO).

made on demand by eNOS (endothelial nitric oxide synthase) and diffuses directly across 2 membranes into the "postsynaptic cell" to stimulate GC (guanylyl cyclase)

Excitotoxicity, and too great an influx of calcium ions, is caused by overstimulation of synapses for what transmitter?

glutamate

What is the standard treatment to increase dopamine in the striatum in Parkinson's syndrome patients with low dopamine from degeneration of dopaminergic neurons?

feed them l-DOPA

Histochemical fluorescence demonstrated a place in the brain that spreads norepinephrine throughout the brain. What is the name of this place?

locus coeruleus

Ritalin is given for ADHD which stands for what?

attention deficit hyperactivity disorder

What type of molecule is arachidonic acid and how is it related to endocannabinoids?

fatty acid, it is the major portion of the molecule

How does epinephrine differ from norepinephrine?

NE is sympathetic neurotransmitter, PNMT converts NE to E which is hormone from adrenal medulla

Before it was shown to be nitric oxide (NO), it was called "endothelial derived relaxation factor (EDRF)." What did it relax?

arteriole smooth muscle

Title of a published paper: "Localization of cholecystokinin to cells of the retina." What is a gut hormone doing in that part of the nervous system?

originally identified as a gut hormone, it has different functions in different places

Met-enkephalin and Leu-enkephalin are chopped out of what kind of molecule?

larger protein precursor

A neurotransmitter activates a G-protein-coupled receptor, and that signals to (what is next in the cascade)?

duh! G protein (the heterotrimeric kind)

Say something about l- vs d- in the synthesis of catecholamines.

start w/ l-aa. lose when DOPA to Dopamine. Back to l- when dopamine goes to epinephrine

"End-product inhibition regulates synthesis by controlling the rate-limiting enzyme." If norepinephrine is the end product, what is the rate-limiting enzyme?

tyrosine hydroxylase

By what mechanism would monamineoxidase (MAO) inhibitors relieve depression?

increase presence of norepinephrine

A hormone that is formed from serotonin by two additional enzymatic steps is produced in what brain structure?

pineal

While glycine is an inhibitory transmitter of the spinal cord, what is the main inhibitory transmitter in the brain?

GABA

Transporters in what two cell areas terminate the action of glutamate?

nerve terminal and glial cell

What would Prozac, Paxil or Zoloft do the the concentration of what transmitter in the synaptic cleft?

increase serotonin

When more acetylcholine is needed, vesicles are released. How is the "transmitter" NO (nitric oxide) increased when it is needed?

turn on endothelial nitric oxide synthase (eNOS)

What does output from a famous cranial nerve do to heart rate?

vagus slows heart

Where is the chain of sympathetic ganglia?

near spinal cord, on each side, in thoracolumbar area

Chronic chlorpromazine administration causes "extrapyramidal motor syndrome" which is like what named disease?

Parkinson's disease

Theories that defects in serotonin and norepinephrine metabolism cause schizophrenia were replaced with the current explanation involving what transmitter?

dopamine

What ion has long been used to treat manic-depression?

lithium

"Naloxone, an antagonist, displaced certain narcotic analgesics in brain binding." This finding led to the isolation of what kind of receptor?

the opiate receptor

In the synthesis of anandamide and 2-arachidonylglycerol (2-AG), answer one: either What class of molecules are the original precursors? OR What kinds of enzymes are used?

membrane phospholipids (phosphatidylethanolamine or phosphadidyl inositol), phospholipases

More important than monamine oxidase (MAO) and catechol-O-methyltransferase (COMT), how is the action of norepinephrine terminated?

reuptake

Considering the localization in the perikaryon of translation (protein synthesis) talk about the location of function of enzymes responsible for synthesis of norepinephrine and acetylcholine.

steps in terminal so anterograde transport from cell body

Tell me 2 of 3 products, fragments "chopped" from pre-proenkephalin A. Be very specific.

signal sequence, met enkephalin, leu enkephalin

Contrast the presence or lack of l- vs d- isomers for DOPA, dopamine, and norepinephrine.

dopa cold be l or d, also NE but dopamine's carbons do not have 4 separate groups

The white communicating ramus is on the way to (what?) and the gray communicating ramus is on the way from (what? - same answer).

sympathetic ganglion

Atropine affects the enteric nervous system to achieve (what?)?

decrease in gastrointestinal motility

Out of the four CNS locations from which autonomic nerves eminate, where is the origin of the nerves that mediate erection?

sacraol spinal cord

With respect to the corpus cavernosum, "norepinephrine contracts smooth muscle via alpha-1 receptors." What is the functional effect?

inhibit erection by decreasing blood flow through arterioles

NO activates guanylyl cyclase (GC) an enzyme whose product is (what?).

cGMP

I heard on a TV talk show "an enzyme in turkey makes you sleepy." Correct that incorrect statement, at least with respect to the conventional wisdom.

an amino acid, tryptophan, not an enzyme

In terms of regulation of neurotransmitter action, how does Prozac affect mood?

seretonin reuptake is inhibited

Melatonin is made (answer one of the following) (1) from what neurotransmitter? Or (2) predominantly in what part of the brain?

5HT (serotonin) pineal

How did they show that the Raphe nuclei send serotonin all over the brain?

histochemical fluorescence tract tracing, formaldehyde turned serotonin into a fluorescent product

The discovery that MPTP was a contaminant in a bad batch of heroin helped to develop an animal model to study (what?).

Parkinson's disease

What is bradykinesia?

decreased movement seen in Parkinson's

Although it sounds barbaric, electroconvulsive shock is still sometimes used for the treatment of (what?).

depression

Opiates displaced tritiated naloxone to help Pert and Snyder identify what molecule?

opiate receptor

Lysophosphatidylinositol is converted to 2-arachiconylglyceol, an endogenous transmitter related to what drug?

cannibis (marijuana)

"Acetylcholine is used in the sympathetic nervous system." Where?

at ganglia

In what way is the expression "putative neurotransmitter" distinguished from the meaning of the word neurotransmitter?
 
Putative implies that they are not yet convinced it qualifies as a neurotransmitter
 
Say something about how vesicles or enzymes for transmitter synthesis get from the cell body to the synaptic terminal.
 
Axon transport along microtubules
 
Beta-endorphin is cleaved from what protein precursor?
 
POMC
 
"Nicotinic acetylcholine receptor." Answer either (1) On precisely what membrane is it located at the neuromuscular junction? Or (2) What is the nature of its molecular configuration that leads its activation to generate a potential?
 
End plate (on muscle cell), it is a channel
 
Does Viagra function "upstream" or "downstream" of NO (nitric oxide) action? Explain your reasoning.
 
Since NO activates GC and Viagra inhibits cGMP PDE, downstream
 
Potentiating or inhibiting (which?) the action of a neurotransmitter (which one?) explains the action of Prozac.
 
An uptake inhibitor would potentiate seretonin
 
"Day length" (what fraction of a 24 hr period is illuminated) affects the size of the testes in a hamster by Answer either (1) What hormone? Or (2) From what brain structure?
 
Melatonin, pineal
 
Why does the neighboring glial cell have special significance for glutaminergic transmission?
 
Reuptake and delivery back to the neuron
 
Atropine affects the enteric nervous system to achieve (what?)?
 
decrease GI motility
 
Out of the four CNS locations from which autonomic nerves originate, where is the origin of the nerves that mediate erection?
 
sacral
 
In the cases of both norepinephrine and serotonin, a decarboxylase turns an amino acid into (what chemical class of molecules?).
 
amine (monamine)
 
When more acetylcholine is needed, vesicles are released. How is the "transmitter" NO (nitric oxide) increased when it is needed?
 
Activation of enzyme (NO synthase)
 
"Acetylcholine is used in the sympathetic nervous system." Where?
 
At the ganglion
 
The discovery that MPTP was a contaminant in a bad batch of heroin helped to develop an animal model to study (what?).
 
Parkinson's disease
 
l-DOPA Answer either (1) Why do you need to give a lot of it? Or (2) Why do you give that instead of dopamine? (for Parkinson's)
 
because it gets decarboxylated everywhere, dopamine does not cross the blood brain barrier
 
"Lesions of the lateral hypothalamus result in a thinner rat." In what way does this story relate to Parkinson's disease?
 
Loss of affect (motivation) results from disrupting dopaminergic tract
 
Explain why action potentials might be smaller if lithium were given?
 
Since lithium is not pumped but does go through channels, the gradient of sodium plus lithium is less steep
 
What is the general class of molecules that serve as the precursor of "endogenous tetrahydrocannabinol?"
 
membrane phospholipids

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This page was last updated 10/25/12