Nicotine II Flashcards
Which receptors mediate the central effects of nicotine?
neuronal nicotinic acetylcholine receptors
How many subunits are there in the nicotinic AcH receptor? and what kinds of subunit types can there be?
there are 5 subunits, and at least 9 alpha subunits and 3 beta subunits
What happens when nicotine binds to the nicotinic aCH receptor?
When triggered by nicotine, integral ion channel that allows sodium and calcium to flow into the cell and causes depolarization
how many nicotine binding sites are in a aCH receptor?
there are two nicotine binding sites per receptor and they are the same sites as where aCH usually binds
Where are the nicotinic AcH receptors located in the CNS? and where are they located in PNS?
they are located pre and post synaptically in the CNS and they are located post synaptically at neuromuscular junctions of the PNS
what happens when neuronal nicotinic acH receptors are activated post-synaptically?
this is usually at neuromuscular junctions; causes quick depolarization of the cell and cellular excitation
what happens when neuronal nicotinic aCH receptors are activated pre-synaptically?
They will induce release of NT dopamine, glutamate, GABA, noradrenaline, serotonin and others (neuronal)
How long does it take for nicotinic ACH receptors to desensitize?
takkes seconds to minutes if continually exposed to agonist
the receptors go from an open state to a closed state where they are no longer responsive to nicotine or ACH and the channel will close
What happens if theres a mutation in the alpha-4 subunit of ACH receptor?
makes animals hyper sensitive to effects of nicotine
what happens if you remove via knock-out of the beta-2 subunit in mice?
nicotine no longer causes release of dopamine and self-administration of nicotine stops
what do the antagonists specific for the alpha4 beta2 receptors do?
they block the rewarding effects of nicotine and this is the most important subtype in dopamine release
what does a-7 subunit play a role in the aCH receptors?
they control glutamate release in the reward pathway and has been linked with spread of cancer when nicotine is present
What is the mechanism behind nicotine binding directly to dopaminergic neurons to have an indirect effect on dopamine release?
Nicotine binds predominantly to the nicotinic acH receptors in the CNS; the primary is the alpha4-beta3 nicotinic receptor in the ventral tegmental area (VTA)
after nicotine binds to the alpha4-beta2 receptor in the VTA; it results in release of dopamine in the nucleus accumbens which is linked to reward
what controls the indirectly stimulation of dopamine release from dopaminergic neurons?
GABA and glutamate
what happens when nicotine binds to nicotinic receptors that control release of GABA?
the nicotinic receptors that control GABA release are very sensitive to nicotine-induced desensitization and desensitize very quickly (under 60 seconds) and that lasts for an hour so it causes decrease GABA release… these nicotinic receptors at the alpha4-beta2 subtype
what happens when nicotine binds to nicotinic receptors that control release of Glutamate?
the receptors that control glutamate release do not desensitize to nicotine quickly and are not as sensitive to nicotine as the GABA ones… these ones are the alpha-7 subtype of nicotinic receptors
this means that GABA will stop being release and glutamate will be predominant and excitatory signals to release dopamine in the pathway
What effect does acute nicotine have on the dopamine release in the nucleus accumbens? (experiment)
a single dose of nicotine applied directly to dopamine-releasing nerve terminals from VTA to the NA
dopamine levels remained above baseline for 80 minutes
nicotine generally increases firing of neurons In the mesolimbic pathway and enhances dopamine release at the NA … shows that the drug is reinforcing
Describe the experiment done on people who smoke using more alcohol
if you expose animal to smoking prior to receiving alcohol, they drink more alcohol when administered
- given at anima in operant self administration setting to administer Saccharin (Sugary water) for three hours, and then have 2 groups
- after the administration have a 3 hr period where you either give a saline pretreatment (control) or nicotine for 3 hours
- after, you add alcohol in the operant chamber with saccharin and see which group had higher alcohol consumption
results show that the group that took nicotine in the 3 hours before ethanol administration had the highest amount of ethanol intake
When adding RU486+ (a glucocorticoid receptor antagonist), it shows that there is more dopamine released because less stress hormones being released in the body
what is the mechanism behind nicotine influencing higher ethanol consumption?
Nicotine and ethanol when administered independently increase dopamine release in the NA
but when ethanol Is given to animals previously exposed to nicotine, there is LESS dopamine released
therefore, nicotine appears to be blunting the response to ethanol in the body by releasing less dopamine, therefore we need MORE ethanol to feel good
- nicotine activates stress responses, including release of glucose-corticoids (stress hormones)
- when both nicotine and ethanol are present, the glucocorticoids somehow increase GABA release in the VTA and inhibit dopamine release form dopaminergic neurons, so thats why we need more to feel drunk
What is the effect of cigarette smoke (not nicotine) on monoamine oxidase receptors? and what does it result in?
cigarette smoke inhibits monoamine oxidase (via acetaldehyde). MAO’s are enzymes that degrade neurotransmitters; acetaldehyde may be forming beta-carbolines (eg. harman) which is known to inhibit MAOs
this results in increase levels of dopamine, adrenaline, and noradrenaline and increases the reinforcing effects of nicotine in animals even without nicotine actually being involved in this process (just cig smoke)
How does tolerance arise with nicotine exposure?
with chronic exposure; nicotinic receptor numbers increase
alpha4-beta2 containing receptors are major type that is UPREGULATED
may cause increased sensitization to effects of nicotine especially when receptors are desensitized
why up regulate if nicotine is an agonist?
because nicotine rapidly desensitizes receptors and makes them non-functional, so you lose a lot of the receptors and the brain compensates by making more; when people smoke they are constantly desensitizing alpha-4-beta2 receptors (the ones on GABA) and the body makes more and when you stop smoking, all of those receptors WANT to become active by ACH or nicotine so that might be the cause of cravings
What is some of the harm associated with nicotine and smoking?
45,000 deaths in Canada per year because of it which is more than AIDS, car accidents, suicide, murder, fire and poison combined
linked to 85% of new cases of lung cancer
what is Tar? what is it made out of and what is some of the dangerous associated with it?
tar is sticky and adheres to cells in airways
it is full of carcinogens such as polycyclic aromatic hydrocarbons
inhibits function of chilli that line the airways
carcinogenic compounds that normally would be swept away sit on lung tissue
phagocyte (immune cell) function is also inhibited so the lungs are more prone to infection
what is some of the links of cigarette smoke to cancer formation?
smoke of cigs are shown to induce DNA strange breakage, DNA and protein modification
this results in faulty DNA replication
polycyclic aromatic hydrocarbons produced when proteins burn may be the culprits of this and a lot of the them end up on the tar
Benzo-[a]-pyrene is a product of incomplete combustion
it gets metabolized into active form and inserts into DNA
this causes a bulge in the double helix and results in faulty replication
How does nicotine increase spread of cancer?
- pro cancer effects in non neuronal cells caused by nicotine but does not initiate cancer
- nicotine can inhibit programmed cell death (apoptosis), promote cell proliferation and can perhaps cause mutations
- normally if theres faulty replication in a cell, it will self destruct (apoptosis) before it can ever be able to replicate, but in smokers, the alpha-7 receptors on the mitochondria respond to nicotine and promote growth of cells that are faulty (promote proliferation_)
this can allow cells with damaged DNA to eep proliferating which increases cancer risk
What did the experiment in animal modes tell us about how nicotine can promote tutor growth and metastasis?
in cancer cells grown in vitro, nicotine enhances their growth
in mice injected with cancer cells, nicotine promotes tutor growth
They had a group of mice who had been induced to have a tumour and then have it surgically removed, the group of cells that have been exposed to nicotine have surgical removal of their tumour had 20% recurrence of the tumour compared to the non-nicotine exposed ones
also cancer metastizied quicker to other parts of the body when animal was exposed to nicotine
what are the 3 ways nicotine can promote cancer growth?
- a-7 nicotinic receptors (apoptosis is blocked by this receptor being activated by nicotine)
- epidermal growth factor receptors (triggered by excess EGF production) –> trigger proliferation of cell growth and when alpha-7 receptor is activated you get increase secretion of epidermal growth factor and binds to the receptor to cause proliferation
- beta-adregernic receptors (beta-AR via nicotine-induced adrenaline release, and direct actions of nicotine and NNK) … NNK is a nicotine derivative molecule found in smoke, it binds with receptors and activates beta adregenic receptors and have proliferation effect of cells
what is Bupropion (Zyban?)
originally used as an antidepressant
produces moderate increase in dopamine and noradrenaline levels by inhibiting their removal from synapse or increasing their release
buprpion and at least one of its metabolites locks the nicotinic receptor into a close states and prevents ions from entering its channel even in the presence of nicotine by binding in the channel itself
seems to address craving issues and has up to 30% success rate after one year
What is Varenicline (champix)
it is a partial agonist at alpha4/beta2 nicotinic receptors (results in 30-60% of maximum possible activation of receptors)
seems to reduce craving and reinforcing effects of smoking by partially substituting for nicotine
now has warning because of increased suicide risk and warning that aggression and hostility may occur and that drinking Amy make neuropsychiatric events worse
some reports suggest 6 month success as low as 14%
