nicotine 2 Flashcards
1
Q
how many subunits in nicotininc receptor
A
5
2
Q
how many diff types of alpha and beta subunits in nicotinic receptors
A
9 alpha 3 beta
3
Q
what happens once the nicotinic receptor is triggered by nicotine
A
integral ion channel opens to let sodium and calcium into the cell (depolarization)
4
Q
does nicotinic activation cause depolarization or hyperpolarization
A
depol
5
Q
what kind of receptor is nic receptor
A
integral ion channel
6
Q
how many binding sites for nicotine in each receptor
A
2 nicotine
7
Q
where does nicotine bind compared to ACh
A
same place as ACh
8
Q
are nicotinic receptors pre or post synaptic
A
either
9
Q
where are nic receptors postsynaptic
A
neuromuscular junction
10
Q
what happens when postsynaptic nic receptor is activated
A
quickly depolarize and cause neuromuscular excitation
11
Q
what happens when presynaptic nic receptor is activated
A
induce release of NT glu, GABA, DA, NA, 5HT…
12
Q
what happens if the nic receptor is continually exposed to agonist
A
quickly desensitizes (Seconds, minutes)
13
Q
what happens with mutations in alpha 4 subunits in animals
A
they are hyper-sensitive to nicotine
14
Q
what happens with beta 2 subunit knockout in mice
A
nicotine no longer causes release of dopamine + no more self administration
15
Q
what happens with alpha4beta2 antagonists
A
rewarding effects of nicotine are gone
16
Q
what is the most important receptors involved in nicotine related DA release
A
alpha4beta2
17
Q
what other receptor may be implicated with glutamate release
A
alpha7
18
Q
what does the alpha7 subunit do
A
may be implicated with glutamate release
19
Q
where are 2 places where alpha4beta2 are found
A
dopaminergic neuronal cell bodies
nerve terminals that release other NTs
20
Q
are alpha4beta2 pre or post synaptic
A
both
21
Q
are alpha4beta2 in the reward pathway? what do they cause
A
yes, cause DA releasing effects
22
Q
do all nicotinic receptors desensitize the same way
A
no
23
Q
which nerve endings are alpha4beta2 found on a lot
A
GABA releasing neurons
24
Q
what happens with alpha4beta2 on GABA releasing neurons and their nicotine sensitivity (how sensitive are they to nicotine)
A
very sensitive to nicotine induced desensitization, desensitize very quick
-decrease GABA release
25
how long do alpha4beta2 on GABA releasing neurons take to cause desensitization
less than 1 min
26
how long do alpha4beta2 on GABA releasing neurons stay desensitised
at least 1 hour
27
how are GABA releasing neurons affected by nicotine
very affected if they have the alpha4beta2
28
how are glutamate releasing neurons affected by nicotine
nicotine activates them, but they still stay functional (alpha7)
29
which subunit is responsible for nicotines effect on GABA releasing neurons
alpha4beta2
30
which subunit is responsible for nicotines effect on glutamate releasing neurons
alpha7
31
what is the effect on DA due to nicotines effect on GABA releasing neurons
indirect stimulation of DA release
32
what is the effect on DA due to nicotines effect on glu releasing neurons
indirect stimulation of DA release
33
do the alpha4beta2 or alpha7 subunits become nonfunctional with nicotine
alpha4beta2
34
do the alpha4beta2 or alpha7 subunits stay functional with nicotine
alpha7
35
what NTs control dopaminergic neuron firing in the VTA
glutamate and GABA
36
is glutamate excitatory or inhibitory
excitatory
37
what causes the increase of DA release from nicotine (3)
more glu release (alpha7) less GABA release (alpha4beta2) onto DA releasing cells on VTA
receptors on cell bodies of DA releasing neurons can be activated by nicotine
38
when nicotine is applied directly to DA releasing neurons in the VTA, how long do levels remain above baseline
80mins
39
what does nicotine do to neuron firing of the neurons in the mesolimbic pathway
increases
40
what does nicotine do to DA release at the NAc
increase
41
what happens with monoamine oxidase with smoking and how
inhibited by cigarette smoke, likely via acetaldehyde
42
what does monoamine oxidase do
breaks down NTs
43
what may acetaldehyde be forming that is inhibiting monoamine oxidase
beta-carbolines
44
where do beta-carbolines come from
acetaldehyde
45
what do beta-carbolines do
inhibit monoamine oxidases
46
what happens when monoamine oxidases are inhibited
increased levels of dopamine, adrenaline and noradrenaline
47
how does acetaldehyde from cigarette smoke cause a reinforcing effect of nicotine
they form beta carbolines which inhibit monoamine oxidases,cause an increase in DA NA A levels
48
is there more monoamine oxidases in smokers or non smokers
more in non smokers (normal level)
49
is there less monoamine oxidases in smokers or non smokers
less in smokers (reduced level due to inhibition by beta-carbolines)
50
is nicotine involved in the MAO inhibition
no
51
what happens with nicotinic receptor level with chronic nicotine exposure
increase number of nicotinic receptors
52
what is the major type of upregulated nicotinic receptor
alpha4beta2
53
why are nicotinic receptors upregulated if nicotine is an agonist
because they get desensitized by nicotine (rapidly non functional so the brain makes more to compensate for it)
54
is nicotine an agonist or antagonist
agonist
55
what will happen to sensitization to effects of nicotine when they are upregulated
increased sensitization to the effects of nicotine (especially when receptors are resensitized)
56
where does tar adhere to in the airway
cells in the airways
57
what is an example of a carcinogen in tar
polycyclic aromatic hydrocarbons
58
why are polycyclic aromatic hydrocarbons dangerous
they are planar so can easily insert themsleves between base pairs in DNA
59
what does tar do to cilia in airways
inhibits their function
60
what happens to phagocytes in airways
function is inhibited
61
what causes polycyclic aromatic hydrocarbons to be produced
when proteins burn
62
what is benzo[a]pyrene
product of incomplete combustion and a procarcigogen
63
is benzo[a]pyrene a carcinogen
no its a procarcinogen
64
how does benzo[a]pyrene become a carcinogen
gets metabolized into an active form
65
how is the metabolized form of benzo[a]pyrene a carcinogen (what does it do that makes it a carcinogen)
inserts into DNA where it covalently binds to guanine and causes a bulge in the double helix (faulty replication)
66
what kind of modification on benzo[a]pyrene makes it a carcinogen
it becomes an epoxide (its probably okay if you dont know this)
67
does nicotine initiate cancer
no
68
where can nicotine support pro-cancer effects
in non-neuronal cells
69
what are 3 pro-cancer effects that nicotine causes
inhibits apoptosis, promotes cell proliferation and can cause mutation
70
how can nicotine cause prevention of apoptosis (which receptors and where)
activation of alpha7 receptors on mitochondria can prevent apoptosis
71
how can nicotine cause prevention of apoptosis
activation of alpha7 receptors on mitochondria can prevent apoptosis
72
what is dangerous with nicotine induced prevention of apoptosis
damaged DNA can keep proliferating
73
what does nicotine do to cancer cells in vitro
enhances growth
74
what does nicotine do to cancer cells that are injected into mice
promotes growth
75
what does nicotine do to tumor metastasis
increase in animal models
76
what does nicotine do to tumor recurrence
increase in animal models
77
how did they know that nicotine increase stumor recurrence (how did they do the experiment)
mice injected with cancer cells, then got either nicotine or control for 2 weeks, surgically removed tumors, continue with treatment, 2 weeks later there were more tumors and metastasis with nic treated group
78
did the nicotine treated mice have an increase tumor recurrence
yes
79
did the nicotine treated mice have an increase tumor metastasis
yes
80
which nicotine derivatives are formed during curing and burning
NNK and NNN
81
what are NNK and NNN and how are they formed
nitrosamines formed by nitrosation of nicotine (formed by curing/smoking)
82
do NNK and NNN directly cause cancer
yes
83
do NNK and NNN indirectly cause cancer
yes
84
how does NNN and NNK directly cause cancer
covalent modification of DNA after further metabolism
85
how does NNN and NNK indirectly cause cancer (2)
initiation of proliferation pathways, inhibition of repair pathways (via nAChR)
86
where do NNN and NNK bind and how strong
to certain nAChR and more tightly than nicotine
87
are NNN and NNK agonists or antagonist and at which receptor
agonists at the nAChR receptor
88
what pathway does NNK affect the most and how
increases the proliferation and survival of cells
89
what pathway does NNN affect the most and how
decreases motility and wound repair
90
what pathway does NNK and NNN affect together
adhesion, indirect modulation, causes metastasis
91
do e cigs smokers contain NNK and NNN
yes but 97% lower than cig smokers
92
if NNK and NNN were only formed by curing/smoking, how do e cig users have some in their body
nic may get directly metabolized into NNK and NNN in the body by P450 enzymes
93
how were mice's bodies converting nic into NNK and NNN
by P450 enzymes
94
what was evidence of NNK and NNN presence found in mice
DNA modifications
95
can exposure to e cig smoke induce lung cancer in mice studies
yes
96
what was the original use for bupropion (zyban)
antidepressant
97
what does bupropion (zyban) do to help with nicotine addiction (2 thing)
moderate increase in DA and NA levels (inhibites removal from synapse and increase release)
locks nicotinic into closed state
98
what does bupropion (zyban) do to NA levels
increase
99
what does bupropion (zyban) do to DA levels
increase
100
what does bupropion (zyban) do to NA and DA removal from synapse
inhibits their removal
101
what does bupropion (zyban) do to NA and DA release
increase
102
what does bupropion (zyban) do to nicotinic receptors (+ what is the effect of this)
locks them into a closed state
| prevents ions from entering its channel even with nic present
103
where does bupropion (zyban) bind to
the nicotine channel itself
104
can bupropion (zyban) help with cravings
yes
105
what is sucess rate ofbupropion (zyban) after a year
30%
106
what is varenicline (champix) mechanism of action
partial agonist at alpha4beta2 receptors
107
what activation % does varenicline (champix) do and to what receptors
30-60% activation of alpha4/beta2 receptors
108
what does varenicline (champix) do to the effects of nicotine added to the system
blocks the effects
109
what does varenicline (champix) do to craving and reinforcing effects of nic and how
reduces because it partially substitutes for nicotine
110
what is a downside of varenicline (champix)
increase suicide risk, aggression, hostility
111
what happens if you drink while on varenicline (champix)
it may make neuropsychiatric events worse
112
what is the 6 month success rate of varenicline (champix)
14% eek
