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1
Q

what is the main excitatory NT in the brain ?

A

Glutamate

2
Q

what is the main inhibitory NT in the brain ?

A

GABA (gamma aminobutyric acid)

3
Q

how many different neurotransmitters are there ?

A

more than 100

4
Q

what are the two types of NT ?

A

neuropeptides (large, from 3-36 aa) and small molecule NTs.

5
Q

what are biogenic amines ?

A

small molecule NT that share similar chemical properties and postsynaptic actions
- dopamine, serotonin, histamine, E, NE

6
Q

what kind of NT are GABA and glutamate ?

A

small molecule NTs

7
Q

which NT would be responsible for moving a racket ?

A

glutamate, Ach

8
Q

which NT would be responsible for paying the right amount of attention to a stimulus ?

A

serotonin, Ach, dopamine, histamine

9
Q

what is glycine as compared to GABA ?

A

the GABA (inhibitory NT) of the spinal cord

10
Q

what type of vesicle do Ach, glutamate, glycine, GABA have ?

A

they’re small molecule NT so small, clear vesicles.

11
Q

what types of vesicle do catecholamines (dopamine, NE, E) have ?

A

they’re also small-molecule so mostly small dense-core but may be large irregular dense-core vesicles.

12
Q

what types of vesicle do neuropeptides have ?

A

large dense-core vesicles

13
Q

are neuropeptides excitatory or inhibitory ?

A

both

14
Q

what are the 4 NTs that are the most likely to be hit by a prove ?

A

Ach, glutamate, GABA, dopamine

over 80% prevalence

15
Q

what are the 4 places where Ach serves as a NT ?

A

1- skeletal neuromuscular junction
2- neuromuscular synapse between vagus nerve and cardiac fibers
3- synapses in ganglia of visceral motor system
4- variety of places in CNS

16
Q

where is Ach synthesized, and from what ?

A

Ach is synthesized in nerve terminals from the
precursors acetyl coenzyme A (acetyl CoA, which is synthesized from glucose) and choline, in a reaction catalyzed by choline acetyltransferase

Ach is loaded into vesicles via VACht

Choline is taken up by cholinergic neurons by a Na+ co-transport (ChT, requires energy), and Ach is therefore created.

17
Q

what kind of pH is required for Ach synthesis within the vesicle lumen ?

A

acidic (co-transporter of choline exchanges N+ for Ach)

18
Q

how is the postsynaptic action of Ach different from other small-molecule NT ?

A

instead of being terminated by reuptake, it is terminated by a hydrolytic enzyme called acetylcholinesterase in the synaptic cleft, rapidly catalyzes Ach into acetate and choline. Choline is recycled by being transported back to nerve terminals to produce more Ach.

19
Q

how do organophosphates (used in chemical warfare) affect Ach ?

A

they inhibit acetylcholinesterase, allowing Ach to accumulate at synapses. This depolarizes the postsynaptic cell & renders it refractory to subsequent Ach release, causing neuromuscular paralysis.

20
Q

two types of Ach

A

nicotinic and muscarinic

21
Q

describe the properties of nicotinic Ach receptors

A

nicotine (CNS stimulant) also binds to these receptors.

ligand-gated cation channels generating postsynaptic excitatory responses
2 binding sites with 5 subunits. Both binding sites need to have Ach in it for the receptor to be activated (can also bind to toxins and to nicotine)
in NMJ and brain
direct response

22
Q

describe properties of muscarinic Ach receptors

A

metabotropic (G protein coupled)
mediated most effect in brain
indirect response

23
Q

describe the structure of the nicotinic Ach receptor

A

5 sub-units to create a pore (2 alpha, beta, gamma, etc). The alphas contain the 2 binding sites.
Binding of ACh to its alpha binding sites on the two a subunits causes a conformational change in part of the extracellular domain, wnich causes the pore-forming
helices to move and open tne pore gate.

24
Q

what areas of nAch do drugs usually target ?

A

the different subunits of the receptor binding sites.

25
Q

describe the structure of the muscarinic Ach receptor

A

mAChRs have seven helical membrane-spanning domains (Figure 6.4A). ACh binds to a single binding site on the extracellular surface of the mAChR; (formed from loops that connect several of the transmembrane helices)

Binding of Ach causes conformational change that permits G-proteins to bind to the cytoplasmic domain
of the mAChR.

26
Q

where are muscarinic receptors located ? how do their response vary depending on their location ?

A

mostly in the brain, however they have different functions depending on where they are located.

INHIBITORY
- in striatum (basal ganglia) and forebrain, inward rectifying K+ channels or Ca2+ activated K+ channels —- inhibitory influence on dopamine-mediated motor activity.
- mediate cholinergic response of autonomic effector
organs such as heart, smooth muscle, and exocrine glands and are responsible for the inhibition of heart rate by the vagus nerve.

EXCITATORY

  • in hippocampus, mAChRs are excitatory and act by closing KCNQ-type K+channels
  • in ganglia of PNS
27
Q

what do mAChR blockers do ?

A

[block Ach muscarinic receptors]

atropine (used to dilate the pupil), scopolamine
(effective in preventing motion sickness), and ipratropium
(useful in the treatment of asthma).

28
Q

how many mAChR subtypes are there ?

A

5

29
Q

how many nAChR subunit types are there ?

A

5

30
Q

metabotropic, gap junction, peptide, ionotropic synapse- which one would be fastest ?

A

gap junction
ionotropic
metabotropic
peptide

31
Q

on what NT does normal brain function depend most on ?

A

glutamate
Nearly all excitatory neurons in the central nervous
system are glutamatergic, and it is estimated that over half of all brain synapses release this neurotransmitter

32
Q

what happens to glutamate in brain trauma ?

A

there may be an excess in release of glutamate, which leads to “excitotoxic” brain damage

33
Q

where and what are the ways glutamate can be synthesized ?

A

it doesn’t cross the BBB, therefore it must be synthesized in neurons from local precursors

Glutamine is taken up by system A transporter 2 (SAT2) from glial cells & metabolized into glutamate by glutaminase.
OR glucose metabolized by neurons can make glutamate by transamination of 2-oxoglutarate

34
Q

describe glutamate release and transport into glial cells (glutamate- glutamine cycle)

A

packaged into synaptic vesicles
by vesicular glutamate transporters (VGLUT).

removed from the synaptic cleft by the excitatory, Na+ dependent amino acid transporters (EAATs)

EAATs transport glutamate into glial cells.
Converted into glutamine by the glutamine synthetase.
Released by glial cells through the SN1 transporter and transported to nerve terminals via SAT2.

There, glutamine is made into glutamate.

This cycle allows glial cells and presynaptic terminals
to cooperate both to maintain an adequate supply of glutamate.

35
Q

what are the different sort of glutamate receptors ?

A
IONOTROPIC: glutamate-gated cation
charmels that allow the passage of Na+ and K+,
- NMDA
- AMPA
- Kainate

METABOTROPIC

36
Q

which excitatory postsynaptic potential lasts longer - from an AMPA or an NMDA receptor ? why ?

A

NMDA- slower (due to blockage), but last longer

AMPA- faster and more powerful, making them the primary mediators of excitatory transmission in the brain.

37
Q

what is the role of kainate receptors ?

A

(ionotropic glutamate receptors)

sometimes on presynaptic terminals, act as a feedback mechanism to regulate glutamate release.

on postsynaptic cells: EPSC that rise quickly but decay more slowly than those mediated by AMPA receptors.

38
Q

what 3 properties differentiate the NMDA receptor from the other glutamate ionotropic receptors ?

A

1) allow entry of Ca2+ as well as Na+ and K+

Therefore, EPSPs by NMDAs increase the concentration of Ca2+ within the postsynaptic neuron, which means Ca2+ can activate a second messenger system cascade.

2) voltage dependence on current flow, since Mg2+ blocks the pore of this channel at hyperpolarized membrane potentials, while depolarization pushes Mg2+
out of the pore

therefore, NMDA receptors can only pass cations when the membrane is depolarized (eg during strong excitatory outputs and/or AP firing)

3) gating of NMDA receptors requires a co-agonist -the amino acid glycine,

39
Q

how are NMDA receptors and Mg+ related ?

A

Mg+ works as a magnetic pole blocking the opening of the NMDA receptor at hyperpolarized membrane potentials - it’s positive while potential is negative.

40
Q

describe the structure of AMPA receptors.

A

AMPA receptor is Y shaped
3 domains: the aminoterminal domain (AID), the ligand-binding domain (LBD), a transmembrane domain CTMD)
4 subunits

41
Q

describe the structure of NMDA receptors

A

NMDA receptor tetramers typically are composed of two glutamate- binding subunits (GluN2) and two glycine-binding subunits (GluNl)

42
Q

metabotropic glutamate receptors - what sort of reaction do they have ?

A

slower postsynaptic responses that can either excite
or inhibit postsynaptic cells (unlike ionotropic who are excitatory)

a lot of them inhibit postsynaptic Ca2+ and Na+ channels.

43
Q

GABA/glycine- what is its general effect ?

A

inhibitory

44
Q

GABA/glycine- what are the different receptors ? what are their properties ?

A

GABAa & GABAc- ionotropic, use Cl- (this is what glycine uses)

GABAb- metabotropic, uses K+ or blocks Ca2+ channels

45
Q

what are predominant precursors for GABA ?

A

glucose

also pyruvate and glutamine

46
Q

how is GABA synthesized ?

A

glutamic acid decarboxylase catalyzes conversion of glutamate to GABA in presynaptic terminal.

glutamic acid decarboxylase needs cofactor pyridoxal phosphate, derived from Vit B- therefore a Vit B deficiency can lead to decreased GABA synthesis, leading to lethal seizures

transported into synaptic vesicles via a vesicular inhibitory amino acid transporter (VIATT)

47
Q

what is the NT problem in epilepsy ? how is this treated ?

A

lack of inhibition (decreased GABA) therefore over-firing occurs.

to compensate for this, patients are given B6 in order to create more pyridoxal phosphate to enable more GABA synthesis.

48
Q

what is glycine synthesized from ?

A

usually from serine in the brain.

also transported into synaptic vesicles by vesicular inhibitory amino acid transporter (VIATT)

49
Q

how is GABA removed and brought back to neurons and glia

A

co-transport with Na+ dependent GATs

50
Q

what eventually happens to most of GABA ? what enzymes help this process ?

A

converted to succinate that goes into Krebs cycle.

enabled by two enzymes : GABA transaminase and succinic semialdehyde dehydrogenase.

OR degradates to gamma- hydroxybutyrate (date rape drug), creates euphoria, unconsciousness.

51
Q

ionotropic GABA receptors- what is their structure ?

A

pentameric

GABA-gated anion channels

52
Q

GABAa and GABAc- how do they function ?

A

ionotropic anion channels

activation of these GABA receptors causes an influx of negatively charged Cl- that inhibits postsynaptic cells

53
Q

what drugs act as agonists or modulators of GABA receptors ?

A

benzodiazepines & barbiturates

used to treat epilepsy, effective sedatives and anesthetics

54
Q

GABA receptors contain binding sites for which substances ?

A

barbiturates, steroids, and picrotoxin (in the pore)

benzodiazepines (outside the pore, modulate channel activity)

55
Q

where do benzodiazepines bind ?

A

outside of the pore, on alpha and delta subunits of GABA receptor.
enhance GABAenergic transmission

56
Q

where do barbiturates bind ?

A

in the pore, on alpha and beta subunits of GABA receptor

used for anesthesia and control epilepsy (not so much now)

57
Q

how are alcohol and GABA connected ?

A

aspects of drunken behavior are caused by alcohol mediated alterations in ionotropic GABA receptors.

58
Q

how do metabotropic GABAb channels work ?

A

they’re also inhibitory

however GABAb-mediated inhibition is due to the activation of K+ channels, or the blocking of Ca2+ channels

59
Q

what NTs do inhibitory synapses in the spinal cord use ?

A

glycine, or GABA

60
Q

what are the receptors for glycine

A

ligand-gated Cl- channels, mirroring the structure of GABAa receptors

61
Q

is GABA only inhibitory ?

A

NOPE it is also excitatory in the developing brain.

62
Q

explain the excitatory role of GABA in the developing brain (foetus)- compare a mature and immature neuron

A

an immature neuron excited by GABA causes a lot of involuntary movement since there is less inhibition.

in an immature neuron, there is a high [Cl-] inside and a low [Cl-] outside. Ionic transport is ensured by a Na+/K+/Cl- co-transport which pumps a lot of Cl- into the cell.

then, in a mature neuron, there is a shift in homeostasis as ionic transport becomes ensured by a K+/ Cl- co-transporter which mostly pumps Cl- out of cell.
therefore we observe a progressive reduction of Cl- in the cell.

63
Q

why, in our development, does GABA switch from being excitatory to being inhibitory?

A

GABA can produce electrical activity that controls neuronal proliferation, migration, growth, and maturation, as well as determining synaptic connectivity. Once these developmental processes are completed,
the resulting neural circuitry requires
inhibitory transmission that can then
also be provided by GABA.

64
Q

how does membrane potential caused by GABA change as we mature ?

A

immature: depolarizing action
mature: hyperpolarizing (inhibitory) action

65
Q

what do all catecholamines have in common ?

A

their precursor, tyrosine.

66
Q

what is dopamine’s role ?

A

a neuromodulator
has an influence in motivation/reward/reinforcement
also has a role in symphathetic ganglia

67
Q

how many types of dopamine are there ?

A

5, each with particularities (D1 to D4 with subtypes)

68
Q

where can dopamine be found principially ?

A

in the striatum (basal ganglia)- receives major input
from the substantia nigra and plays an essential role in
the coordination of body movements.

69
Q

what NT receptors do drugs of abuse often target ?

A

dopamine

70
Q

how is dopamine produced ? how does it make it to the presynaptic vesicles ?

A

action of DOPA decarboxylase on DOPA in cytoplasm of presynaptic terminals.

loaded into synaptic vesicles via a vesicular monoamine
transporter (VMA1).

71
Q

how is dopamine action in the synaptic cleft terminated ?

A

reuptake of dopamine into nerve terminals
or surrounding glial cells by a Na+-dependent dopamine
co-transporter, termed DAT

72
Q

how does cocaine work ?

A

inhibits DAT (the Na+ dependent dopamine co-transporter that is responsible for the reuptake of dopamine into the nerve terminals)

73
Q

how does amphetamine work ?

A

inhibits DAT (the Na+ dependent dopamine co-transporter that is responsible for the reuptake of dopamine into the nerve terminals) as well as the reuptake transporter of norepinephrine (NET).

74
Q

when it comes to dopaminergic synapses, what would we inhibit to treat depression ?

A

we inhibit enzymes used in the catabolism of dopamine monoamine oxidase (MAO) and catechol 0-
methyltransferase (COMT)

75
Q

where in the brain does norepinephrine originate from ?

A
locus coeruleus (upper brainstem)
radiates towards cortex, cerebellum, spinal cord
76
Q

how does dopamine act on receptors ?

A

exclusively second messenger G-protein system.
either activate or inhibit adenylyl cyclase

activation: hyperactivity & repetitive activity, or inhibits vomiting in the medulla

77
Q

what are dopamine antagonists used for ?

A
  • inducing vomiting

- catalepsy, difficult to initiate voluntary mvmt

78
Q

what is norepinephrine responsible for ?

A

sleep, wakefulness, attention, feeding

79
Q

how does reuptake of NE from synaptic cleft happen ?

A

Norepinephrine is cleared from the synaptic cleft by the norepinephrine transporter (NET), a Na+-dependent co-transporter that also is capable of taking up dopamine.

80
Q

what can happen if the NET gene mutates ?

A

NET- NE transporter responsible for NE reuptake.

In case of mutation, orthostatic intolerance (lightheadedness while standing up)

81
Q

how do the 2 subclasses of alpha-adrenergic receptors differ ?

A

Activation of A1 receptors usually results in a
slow depolarization linked to the inhibition of K+ channels

Activation of A2 receptors produces a slow hyperpolarization due to the activation of a different type of K+ channel.

82
Q

where are epinephrine-containing neurons usually found ?

A

in the lateral tegmental system and medulla, project to hypothalamus & thalamus.

83
Q

where are histamine-containing neurons found ?

A

hypothalamus, sends projections to everywhere in brain and spinal cord.

84
Q

what do central histamine projections mediate ?

A

arousal and attention
reactivity of vestibular system
allergic reaction causes release of histamine from mast cells (may also influence brain blood flow)

85
Q

what kind of receptors are histamine receptors ?

A

metabotropic

86
Q

how are different histamine receptors controlled by medication ?

A

in general, antihistamines cross BBB to interfere with histamine role in CNS arousal.

H1 antagonists prevent motion sickness (since histamine is involved in vestibular function)

H2 receptors control gastric action secretions (therefore H2 antagonists help treat ulcers)

87
Q

where is serotonin found ?

A

in the raphe nuclei (brainstem), spreading to everywhere in brain, also in the spinal cord.

88
Q

what is serotonin involved in ?

A

sleep and wakefulness
emotions, circadian rhythms, motor behaviors, and state
of mental arousal
satiety and decreased food consumption

89
Q

what is a popular form of drug to treat depression ? how does it work ?

A

Selective Serotonin Reuptake Inhibitors (SSRI)

inhibit transport of 5-HT serotonin by SERT

90
Q

are most serotonin receptors metabotropic or ionotropic ?

A

metabotropic

91
Q

what do all synaptic vesicles contain, along with NTs?

A

ATP (is it a co-transmitter?)

92
Q

how does ATP act as an NT

A

as an excitatory neurotransmitter in motor neurons of the spinal cord, as well as in sensory and autonomic ganglia.

93
Q

why can’t adenosine be considered an NT?

A

it is not stored in synaptic vesicles or released in a Ca2+ -dependent manner. it is created when extracellular enzymes degrade ATP to adenosine.