nicotine 2 Flashcards
how many subunits in nicotininc receptor
5
how many diff types of alpha and beta subunits in nicotinic receptors
9 alpha 3 beta
what happens once the nicotinic receptor is triggered by nicotine
integral ion channel opens to let sodium and calcium into the cell (depolarization)
does nicotinic activation cause depolarization or hyperpolarization
depol
what kind of receptor is nic receptor
integral ion channel
how many binding sites for nicotine in each receptor
2 nicotine
where does nicotine bind compared to ACh
same place as ACh
are nicotinic receptors pre or post synaptic
either
where are nic receptors postsynaptic
neuromuscular junction
what happens when postsynaptic nic receptor is activated
quickly depolarize and cause neuromuscular excitation
what happens when presynaptic nic receptor is activated
induce release of NT glu, GABA, DA, NA, 5HT…
what happens if the nic receptor is continually exposed to agonist
quickly desensitizes (Seconds, minutes)
what happens with mutations in alpha 4 subunits in animals
they are hyper-sensitive to nicotine
what happens with beta 2 subunit knockout in mice
nicotine no longer causes release of dopamine + no more self administration
what happens with alpha4beta2 antagonists
rewarding effects of nicotine are gone
what is the most important receptors involved in nicotine related DA release
alpha4beta2
what other receptor may be implicated with glutamate release
alpha7
what does the alpha7 subunit do
may be implicated with glutamate release
where are 2 places where alpha4beta2 are found
dopaminergic neuronal cell bodies
nerve terminals that release other NTs
are alpha4beta2 pre or post synaptic
both
are alpha4beta2 in the reward pathway? what do they cause
yes, cause DA releasing effects
do all nicotinic receptors desensitize the same way
no
which nerve endings are alpha4beta2 found on a lot
GABA releasing neurons
what happens with alpha4beta2 on GABA releasing neurons and their nicotine sensitivity (how sensitive are they to nicotine)
very sensitive to nicotine induced desensitization, desensitize very quick
-decrease GABA release
how long do alpha4beta2 on GABA releasing neurons take to cause desensitization
less than 1 min
how long do alpha4beta2 on GABA releasing neurons stay desensitised
at least 1 hour
how are GABA releasing neurons affected by nicotine
very affected if they have the alpha4beta2
how are glutamate releasing neurons affected by nicotine
nicotine activates them, but they still stay functional (alpha7)
which subunit is responsible for nicotines effect on GABA releasing neurons
alpha4beta2
which subunit is responsible for nicotines effect on glutamate releasing neurons
alpha7
what is the effect on DA due to nicotines effect on GABA releasing neurons
indirect stimulation of DA release
what is the effect on DA due to nicotines effect on glu releasing neurons
indirect stimulation of DA release
do the alpha4beta2 or alpha7 subunits become nonfunctional with nicotine
alpha4beta2
do the alpha4beta2 or alpha7 subunits stay functional with nicotine
alpha7
what NTs control dopaminergic neuron firing in the VTA
glutamate and GABA
is glutamate excitatory or inhibitory
excitatory
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
when nicotine is applied directly to DA releasing neurons in the VTA, how long do levels remain above baseline
80mins
what does nicotine do to neuron firing of the neurons in the mesolimbic pathway
increases
what does nicotine do to DA release at the NAc
increase
what happens with monoamine oxidase with smoking and how
inhibited by cigarette smoke, likely via acetaldehyde
what does monoamine oxidase do
breaks down NTs
what may acetaldehyde be forming that is inhibiting monoamine oxidase
beta-carbolines
where do beta-carbolines come from
acetaldehyde
what do beta-carbolines do
inhibit monoamine oxidases
what happens when monoamine oxidases are inhibited
increased levels of dopamine, adrenaline and noradrenaline
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
is there more monoamine oxidases in smokers or non smokers
more in non smokers (normal level)
is there less monoamine oxidases in smokers or non smokers
less in smokers (reduced level due to inhibition by beta-carbolines)
is nicotine involved in the MAO inhibition
no
what happens with nicotinic receptor level with chronic nicotine exposure
increase number of nicotinic receptors
what is the major type of upregulated nicotinic receptor
alpha4beta2
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)
is nicotine an agonist or antagonist
agonist
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)
where does tar adhere to in the airway
cells in the airways
what is an example of a carcinogen in tar
polycyclic aromatic hydrocarbons
why are polycyclic aromatic hydrocarbons dangerous
they are planar so can easily insert themsleves between base pairs in DNA
what does tar do to cilia in airways
inhibits their function
what happens to phagocytes in airways
function is inhibited
what causes polycyclic aromatic hydrocarbons to be produced
when proteins burn
what is benzo[a]pyrene
product of incomplete combustion and a procarcigogen
is benzo[a]pyrene a carcinogen
no its a procarcinogen
how does benzo[a]pyrene become a carcinogen
gets metabolized into an active form
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)
what kind of modification on benzo[a]pyrene makes it a carcinogen
it becomes an epoxide (its probably okay if you dont know this)
does nicotine initiate cancer
no
where can nicotine support pro-cancer effects
in non-neuronal cells
what are 3 pro-cancer effects that nicotine causes
inhibits apoptosis, promotes cell proliferation and can cause mutation
how can nicotine cause prevention of apoptosis (which receptors and where)
activation of alpha7 receptors on mitochondria can prevent apoptosis
how can nicotine cause prevention of apoptosis
activation of alpha7 receptors on mitochondria can prevent apoptosis
what is dangerous with nicotine induced prevention of apoptosis
damaged DNA can keep proliferating
what does nicotine do to cancer cells in vitro
enhances growth
what does nicotine do to cancer cells that are injected into mice
promotes growth
what does nicotine do to tumor metastasis
increase in animal models
what does nicotine do to tumor recurrence
increase in animal models
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
did the nicotine treated mice have an increase tumor recurrence
yes
did the nicotine treated mice have an increase tumor metastasis
yes
which nicotine derivatives are formed during curing and burning
NNK and NNN
what are NNK and NNN and how are they formed
nitrosamines formed by nitrosation of nicotine (formed by curing/smoking)
do NNK and NNN directly cause cancer
yes
do NNK and NNN indirectly cause cancer
yes
how does NNN and NNK directly cause cancer
covalent modification of DNA after further metabolism
how does NNN and NNK indirectly cause cancer (2)
initiation of proliferation pathways, inhibition of repair pathways (via nAChR)
where do NNN and NNK bind and how strong
to certain nAChR and more tightly than nicotine
are NNN and NNK agonists or antagonist and at which receptor
agonists at the nAChR receptor
what pathway does NNK affect the most and how
increases the proliferation and survival of cells
what pathway does NNN affect the most and how
decreases motility and wound repair
what pathway does NNK and NNN affect together
adhesion, indirect modulation, causes metastasis
do e cigs smokers contain NNK and NNN
yes but 97% lower than cig smokers
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
how were mice’s bodies converting nic into NNK and NNN
by P450 enzymes
what was evidence of NNK and NNN presence found in mice
DNA modifications
can exposure to e cig smoke induce lung cancer in mice studies
yes
what was the original use for bupropion (zyban)
antidepressant
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
what does bupropion (zyban) do to NA levels
increase
what does bupropion (zyban) do to DA levels
increase
what does bupropion (zyban) do to NA and DA removal from synapse
inhibits their removal
what does bupropion (zyban) do to NA and DA release
increase
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
where does bupropion (zyban) bind to
the nicotine channel itself
can bupropion (zyban) help with cravings
yes
what is sucess rate ofbupropion (zyban) after a year
30%
what is varenicline (champix) mechanism of action
partial agonist at alpha4beta2 receptors
what activation % does varenicline (champix) do and to what receptors
30-60% activation of alpha4/beta2 receptors
what does varenicline (champix) do to the effects of nicotine added to the system
blocks the effects
what does varenicline (champix) do to craving and reinforcing effects of nic and how
reduces because it partially substitutes for nicotine
what is a downside of varenicline (champix)
increase suicide risk, aggression, hostility
what happens if you drink while on varenicline (champix)
it may make neuropsychiatric events worse
what is the 6 month success rate of varenicline (champix)
14% eek
