Nicotine 2

Question 0

Explain some of the physiological effects of nicotine on GI

Answer 0

 suppresses GI ac&vity and hunger -
 weight increase in 70 - 80% of people who quit
 effects on hypothalamus and gut tissue
Effects seen on hypothalamus

Question 1

Explain some of the physiological effects of nicotine on skin

Answer 1

vasoconstric&on in skin (wrinkles) - Botox is an Ach antagonist - but most of its effects are at the muscle

Question 2

Explain some of the physiological effects of nicotine on respiration

Answer 2

 respiration rate increase - nicotine simulates receptors
 in carotid artery that indicate need for more oxygen
Some of the substances in nicotine also decrease hemoglobins binding to oxygen

Question 3

Describe some of the associated behaviours with smoking

Answer 3

Smokers are also more likely to:
 use other drugs like alcohol and caffeine
 frequently change their jobs
 get married and divorced more than average
 have more traffic accidents
 be more sexually active
 perform poorly in academic environments
 experience mental illness
 people with the gene that makes them take more risks also implicated in smoking

Question 4

Explain the mechanism of nicotine

Answer 4

 the central effects of nicotine are mediated mostly through neuronal nicotinic acetylcholine receptors
 ligand-gated pentameric ion channels
 nicotine is an agonist at these receptors

neuronal nicotinic acetylcholine receptors when activated:

 if postsynap&c, will quickly depolarize the cell and cause cellular excitation (neuromuscular)
 if presynaptic,will induce release of neurotransmiWers - dopamine, glutamate, GABA, , noradrenaline, serotonin and others (neuronal)

Question 5

Describe the structure of the nicotine receptor

Answer 5

 5 subunits
 there are at least 9 alpha subunits, 3 beta
subunits
 when triggered by nicotine, integral ion channel that allows sodium and calcium to flow into the cell (depolariza&on)
 different receptor subtypes have different subunit complements
 there are two nicotine binding sites per receptor – same site as where Ach usually binds
 mostly presynaptic in CNS
 postsynaptic at neuromuscular junctions

Question 6

How do we know which nicotine receptor subtype is important for addiction?

Answer 6

 mutations in alpha 4 subunit make animals hyper-sensitive to effects of nicotine
 remove (knock out) the beta 2 subunit in mice:
- nicotine no longer causes release of dopamine
- self-administra&on of nico&ne stops
Therefore, good evidence this subtype is probably most important in dopamine release
Others have been implicated as well – α6 and α7

antagonists specific for alpha4 beta 2 receptors block rewarding effects of nicotine

Question 7

What are the effects of dopamine at the VTA and NA

Answer 7

 a single dose of nicotine applied directly to dopamine-releasing nerve terminals from VTA at the nucleus accumbens
 note levels remain above baseline for at least 80 minutes (long lasting dopamine release in the brain)
 nicotine generally increases firing of neurons in the mesolimbic pathway and enhances dopamine release at the nucleus accumbens
 Facilitated by presynap&c receptors on dopaminergic neurons from the VTA

Question 8

Why does desensitization occur?

Answer 8

 continued exposure to nicotine causes receptor desensitization- the receptor enters a state in which it cannot be activated by agonist
 initial stimulatory effect no longer present and chronically may selectively decrease neurotransmitter release (mechanism of many antidepressants is to inhibit MAO)
- increasingly reinforcing effect seen in animals and nicotine not involved

Question 9

Explain the desensitization of GABA vs glutamate release

Answer 9

 not all nicotinic receptors desensitize the same way
 those that control release of GABA are very sensi&ve to nicotine-induced desensitization and desensitize very quickly (decreased GABA release) -α4β2 type
 those that release glutamate are not (still get release) – contain α7 subunit

this indirectly simulates release of dopamine from dopaminergic neurones that are under control of both GABA and glutamate (loss of inhibition and increased stimulation form glutamate)

Question 10

What are the peripheral effects of nicotine

Answer 10

 in periphery, nicotinic receptors are located postsynap&cally at neuromuscular junctions
 at low doses, nicotine simulates them and can give rise to tremours
 at high doses - paralysis, suffocation (decrease contraction f intercostal muscles) via desensitization
 also present in adrenal glands - nicotine can cause release of adrenaline - increases heart rate and blood pressure
 Peripheral receptors are structurally similar to central receptors but have unique subunits

Question 11

What are the effects of smoking on MAO

Answer 11

 cigarette smoke inhibits monoamine oxidase (likely via acetaldehyde)
 enzyme that degrades neurotransmitters
The increase in dopamine is said to be what leads to elevated mood

Question 12

What is the role of beta carbolines?

Answer 12

 Acetaldehyde may be forming beta- carbolines (eg harman) which is known to inhibit monoamine oxidases (MAOs)
results in increased levels of dopamine, adrenaline, noradrenaline

Question 13

Explain tolerance with nicotine

Answer 13

 with chronic exposure, nicotinic receptor numbers increase
 alpha 4 beta 2 containing receptors are major type that is
upregulated
 may cause increased sensitization to effects of nicotine especially when receptors are resensitized

Question 14

Why is there an unregulation of nicotine receptors if it is an agonist?

Answer 14

Because nicotine is so good at desensitizing the receptors that it begins to act as an antagonist so the body upregulate to get more Ach

Remover that smoking is especially reinforcing in the morning due to down regulation then upregulation

Question 15

What are the harms of smoking in Canada and in relation to lung cancer (percentage globally)

Answer 15

 in Canada, 45,000 deaths annually
 more than AIDS, car accidents, suicide, murder, fire and poison combined
 linked to 85% of new cases of lung cancer

Question 16

It has been shown that burning organic compounds produce carbon monoxide. Describe the effects of cabin monoxide

Answer 16

 extremely toxic gas
 200 X greater affinity for hemoglobin than oxygen -oxygen not able to bind
 causes subtle asphyxia&on of body
 primary culprit in producing cardiovascular disease

Question 17

What is tar and why is it so bad?

Answer 17

 tar is sticky - adheres to cells in airways
 full of carcinogens such as polycyclic aromatic hydrocarbons
 inhibits function of cilia that line the airways
 carcinogenic compounds that normally would be swept away sit on lung tissue
 phagocyte (immune cell) function also inhibited

Question 18

Why does smoking cause cancer?

Answer 18

• nicotine probably not involved
• smoke shown to induce DNA strand breakage, DNA and protein modification
• result in faulty DNA replication
• aromatic and heterocyclic amines produced when proteins burn may be culprits - a lot ends up in the tar

Question 19

What is benzo-a-pyrene and how does it cause cancer?

Answer 19

benzo[a]pyrene is a product of incomplete combustion
benzo[a]pyrene gets metabolized into an ac&ve form and inserts into DNA
This causes a “bulge” in the double helix and faulty replica&on

Question 20

How does smoking lead to heart disease

Answer 20

in addition to effects of carbon monoxide (CO), smoke components:
 inhibit tissue oxygen absorption
 induce hypercoagulation thus promoting blood clots
 increase platelet adhesiveness - increased blood clot risk - stroke, heart attack etc
 increase serum cholesterol and fatty deposits leading to atherosclerosis

Question 21

Explains nicotine replacement therapy and the results

Answer 21

 Idea is to give a pure, safe version of the addic&ve ingredient of tobacco
 Huge industry in NRT – $800 million per year in US
 But efficacy is questionable
 Many studies have shown no improvement in relapse rate compared to quitting with no NRT
 Latest study – 787 subjects – no difference between smokers using NRT and those who didn’t amer six months (Harvard University School of Public Health)

Question 22

Why does NRT act to poorly?

Answer 22

No rapid increase in the concentration of nicotine in the Brain (no spike seen)

Question 23

Drug Bupropion can be used to help curb smoking addiction, explains

Answer 23

 originally used as an an&depressant
 produces moderate increase in dopamine and noradrenaline levels by inhibiting their removal from the synapse
 thought to lead to increased levels of dopamine in the nucleus accumbens
 also blocks some nico&nic receptors
 seems to address some craving issues
 up to 30% success rate amer 1 yr

Question 24

Drug Vareincline (Champix) can be used to help curb smoking addiction, explain:

Answer 24

 A PARTIAL (not as string activation as nicotine) agonist at alpha4/beta2 nicotinic receptors (results in 30 – 60% of maximum possible activation of receptors)
 blocks the effects of any nicotine added to the system
 Seems to reduce craving and reinforcing effects of smoking by
partially substituting for nicotine
 Long-term abstinence better than buproprion in phase III trials
 But now has warning because of increased suicide risk
 Also warning that aggression and hostility may occur and that drinking may may neuropsychiatric events worse
 some reports suggest 6 mo success as low as 14%

Question 25

What are electronic cigarettes?

Answer 25

 They do not contain tobacco or require combustion but do provide a dose of nicotine via inhalation
 They contain a battery-powered atomizer that heats up and vaporizes a nicotine-containing liquid
 Idea is that they are a safe alternative to real cigarettes and provide behavioural cues that salsify some cravings

Question 26

What are some concerns with using electronic cigarettes and how have they been addressed?

Answer 26

Concerns?

 The FDA has published concerns about the inhalation of some of the liquid, propylene glycol, in which nicotine is dissolved in some E-cigs
 They also report finding some nitrosamines
 Also worry that children will break them and swallow the
nicotine

But..
 newer models use distilled water and glycol as a nico&ne carrier
 The levels of nitrosamines were lower than can be found in some tradi&onal cessation therapies
 CigareWes are legal and contain just as much nicotine as E-cigs

Question 27

What are the results with using E-cigs

Answer 27

 Several surveys and studies indicate they can be a successful component of cessation and may be as good or better than current therapies
 Although they do not provide the same plasma levels of nicotine, combined with the behavioural aspects of their use, including producing “throat catch” they appear to be a valid alternative
 Most users say they help to control cravings more than some other therapies
 However, many in the medical field and in medical agencies feel they should be tightly regulated and not available OTC until more evidence on their safety is collected