Nicotine II

Question 1

Which receptors mediate the central effects of nicotine?

Answer 1

neuronal nicotinic acetylcholine receptors

Question 2

How many subunits are there in the nicotinic AcH receptor? and what kinds of subunit types can there be?

Answer 2

there are 5 subunits, and at least 9 alpha subunits and 3 beta subunits

Question 3

What happens when nicotine binds to the nicotinic aCH receptor?

Answer 3

When triggered by nicotine, integral ion channel that allows sodium and calcium to flow into the cell and causes depolarization

Question 4

how many nicotine binding sites are in a aCH receptor?

Answer 4

there are two nicotine binding sites per receptor and they are the same sites as where aCH usually binds

Question 5

Where are the nicotinic AcH receptors located in the CNS? and where are they located in PNS?

Answer 5

they are located pre and post synaptically in the CNS and they are located post synaptically at neuromuscular junctions of the PNS

Question 6

what happens when neuronal nicotinic acH receptors are activated post-synaptically?

Answer 6

this is usually at neuromuscular junctions; causes quick depolarization of the cell and cellular excitation

Question 7

what happens when neuronal nicotinic aCH receptors are activated pre-synaptically?

Answer 7

They will induce release of NT dopamine, glutamate, GABA, noradrenaline, serotonin and others (neuronal)

Question 8

How long does it take for nicotinic ACH receptors to desensitize?

Answer 8

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

Question 9

What happens if theres a mutation in the alpha-4 subunit of ACH receptor?

Answer 9

makes animals hyper sensitive to effects of nicotine

Question 10

what happens if you remove via knock-out of the beta-2 subunit in mice?

Answer 10

nicotine no longer causes release of dopamine and self-administration of nicotine stops

Question 11

what do the antagonists specific for the alpha4 beta2 receptors do?

Answer 11

they block the rewarding effects of nicotine and this is the most important subtype in dopamine release

Question 12

what does a-7 subunit play a role in the aCH receptors?

Answer 12

they control glutamate release in the reward pathway and has been linked with spread of cancer when nicotine is present

Question 13

What is the mechanism behind nicotine binding directly to dopaminergic neurons to have an indirect effect on dopamine release?

Answer 13

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

Question 14

what controls the indirectly stimulation of dopamine release from dopaminergic neurons?

Answer 14

GABA and glutamate

Question 15

what happens when nicotine binds to nicotinic receptors that control release of GABA?

Answer 15

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

Question 16

what happens when nicotine binds to nicotinic receptors that control release of Glutamate?

Answer 16

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

Question 17

What effect does acute nicotine have on the dopamine release in the nucleus accumbens? (experiment)

Answer 17

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

Question 18

Describe the experiment done on people who smoke using more alcohol

Answer 18

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

Question 19

what is the mechanism behind nicotine influencing higher ethanol consumption?

Answer 19

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

Question 20

What is the effect of cigarette smoke (not nicotine) on monoamine oxidase receptors? and what does it result in?

Answer 20

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)

Question 21

How does tolerance arise with nicotine exposure?

Answer 21

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

Question 22

why up regulate if nicotine is an agonist?

Answer 22

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

Question 23

What is some of the harm associated with nicotine and smoking?

Answer 23

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

Question 24

what is Tar? what is it made out of and what is some of the dangerous associated with it?

Answer 24

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

Question 25

what is some of the links of cigarette smoke to cancer formation?

Answer 25

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

Question 26

How does nicotine increase spread of cancer?

Answer 26

• 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

Question 27

What did the experiment in animal modes tell us about how nicotine can promote tutor growth and metastasis?

Answer 27

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

Question 28

what are the 3 ways nicotine can promote cancer growth?

Answer 28

1. a-7 nicotinic receptors (apoptosis is blocked by this receptor being activated by nicotine)
2. 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
3. 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

Question 29

what is Bupropion (Zyban?)

Answer 29

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

Question 30

What is Varenicline (champix)

Answer 30

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%