Nicotine Flashcards
What is the number one cause of preventable premature death in North America?
Smoking.
Read slides 1-15 for history and prevalence data.
:)
How many chemicals can be found in a cigarette?
> 7,000 in tobacco and tobacco smoke.
List some dangerous chemicals found in cigarettes.
- acetone
- acetic acid
- ammonia
- arsenic
- benzene
- butane
- cadmium
- CO
- formaldehyde
- hexamine
-lead - naphthalene
- methanol
- nicotine
- tar
- toluene
List the short-term effects of tobacco use.
- euphoria
- enhanced cognition (attention)
- decreased appetite
- stimulation of nausea and vomiting reflex
- increased heart rate, breathing rate and blood pressure
- CO blocks O2 from getting into the bloodstream
- bad breath
- stimulation of the reward system and other neurochemical systems
List the neurochemicals. involved in the short-term effects of tobacco use and their effects.
1) DA
→ pleasure, reward
2) Serotonin
→ mood modulation, appetite suppression
3) NE
→ arousal, appetite suppression
4) Acetylcholine
→ arousal, cognitive enhancement
5) Glutamate
→ learning, memory enhancement
6) Beta-endorphin
→ reduction of anxiety and tension
7) GABA
→ reduction of anxiety and tension
List the long-term effects of tobacco use.
- tobacco addiction
- bronchitis, emphysema, COPD
- heart and artery disease
- cancer
- diabetes
- osteoporosis
- vision changes/loss
- fertility problems
On average, people who smoke die _____ years earlier than non-smokers
13 to 14 years.
List the long-term effects of adolescent tobacco use.
1) altered trajectory of normal brain development
2) diminished cognitive function that persists into adulthood
3) greater mental health problems
How does adolescent tobacco use alter the trajectory of normal brain development?
1) dendritic remodeling
2) lower gray matter volume in the thalamus and amygdala
3) aberrant functional connectivity
4) changes in the reward system
5) changes in 5-HT synaptic function
How does adolescent tobacco use diminish cognitive function that persists into adulthood?
1) reduced attention
2) poorer memory
3) enhanced impulsivity and lower inhibitory control
T or F: Damages to cognitive function resulting from adolescent tobacco use are reversible.
False.
There is no recovery of the cognitive deficits resulting from adolescent tobacco use.
How does adolescent tobacco use cause greater mental health problems?
1) increased anxiety and depression-like behaviours in adults
2) more severe tobacco addiction later in life
T or F: Adults show comparable effects to those who used tobacco during adolescence.
False.
Tobacco exposure in adolescence has effects that last into adulthood; adults do not show comparable effects.
T or F: Most smokers begin smoking during adulthood, around age 30.
False.
83% of all smokers began smoking during adolescence, between the ages of 14-25.
List some risk factors for tobacco use disorder (TUD).
1) genetic predisposition
2) parental exposure
3) lower SES
4) peer pressure
5) poor academic performance
6) impulsivity
7) low self-esteem
8) mood disorders
9) mental illness
10) substance use
11) onset of tobacco smoking during childhood or adolescence
What is the greatest risk factor for TUD?
Onset of tobacco smoking during childhood or adolescence
T or F: Americans can get about 9mg of nicotine per cigarette.
False.
American cigarettes contain about 9 mg of nicotine, but because much of the nicotine is burned off, a smoker gets about 1 mg of nicotine in every cigarette.
T or F: Nicotine is a stimulant.
True.
Define: Nicotine.
Primary psychoactive component of tobacco which underlies the addictive properties of tobacco.
What is the most common mode of delivery for nicotine?
Cigarettes.
How is nicotine delivered to the brain via cigarettes?
1) When smoked, nicotine is distilled from the tobacco and is carried in smoke particles into the lungs.
2) It moves quickly to the brain (10-15s).
3) It binds to nicotinic acetylcholine receptors (nAChR)
4) The onset of CNS actions occur within seconds.
T or F: For nicotine to reach the brain, IV is faster than smoking.
False.
Define: Nicotinic Acetylchlorine Receptors (nAChR)
nAChR are ligand-gated ion channels that play a key role in modulating neuronal excitability.
Which ions do nAChR regulate?
nAChR regulate the flow of cations Na+, K+, Ca2+ across the cell membrane.
Describe the structure of nAChR.
5 distinct membrane-spanning units (alpha/beta) combine to form a functional receptor.
How many alpha nAChR subunit isoforms exist?
9 (alpha2-alpha10)
How many beta nAChR subunit isoforms exist?
3 (beta2-beta4)
T or F: There are a limited number of nAChR heteromeric subtypes.
False.
There are many nAChR subtypes, and each is composed of various combinations of alpha/beta units.
What are the most abundant nAChR subtypes in the brain?
1) alpha4-beta2
2) alpha7
T or F: Nicotine has high affinity for he alpha4-beta2 and alpha7 subtypes.
False.
Nicotine has the highest affinity for alpha4-beta2 and low affinity for alpha7.
List the regions of the brain in which nAChR can be found.
1) cortex
2) hippocampus
3) amygdala
4) NAcc
5) caudate, putamen
6) VTA
7) cerebellum
8) thalamus
9) insula
In the brain, in which part of the neuron are nAChR mostly expressed?
Pre-synapse
Which compounds act as nAChR agonists?
1) Acetylcholine
2) Nicotine
Describe nAChR activation and desensitization.
1) Activation of nAChR occurs when acetylcholine or nicotine binds.
2) Binding induces a conformational change that allows cations to flow through an intrinsic channel, causing depolarization of the neuron.
3) Following activation, nAChR enter into a desensitized state, where channels close and the receptor cannot be reactivated
Slide 29
The nAChR desensitization state limits the duration of _____
Acute effects
T or F: The receptor spends more time in the activation phase compared to the desensitized phase.
False.
The receptor spends more time in the desensitized phase compared to the activation phase.
T or F: Desensitized nAChR have low affinity for ligands.
False.
Desensitized nAChR still have high affinity for ACh and other ligands, but the receptor is inactive.
In which phase is GABA tone strongest?
Active > Inactive > Desensitized
In which phase is DA neuron tone strongest?
Desensitized > Active > Inactive
What are the consequences of nAChR desensitization linked to nicotine?
1) Decreased receptor responsiveness for a subsequent stimulus
2) Reduced satisfaction of nicotine
3) Acute tolerance of nicotine
T or F: with acute nicotine use, nAChR do not regain sensitivity once desensitized.
False.
nAChR regain sensitivity and can become reactivated.
However, with chronic nicotine use, nAChR spend more time in the desensitized state.
T or F: Chronic nicotine use leads to the downregulation of nAChR.
False.
Chronic nicotine use leads to the upregulation of nAChR.
It sesults from the frequent desensitization of nAChR.
Where has nAChR upregulation been documented? (ie. studies)
1) Animal studies with chronic nicotine exposure
2) Postmortem tobacco smokers compared to non-smokers
3) Beta2 nAChR densities are increased in the striatum, cerebellum and cerebral cortex of living human smokers compared to non-smokers
What’s the reason behind nAChR upregulation?
Compensation mechanism to augment nAChR response.
T or F: nAChR upregulation is reversible.
True.
However, it still persists for up to 1 month of abstinence.
How might nAChR upregulation negatively contribute to TUD?
May contribute to difficulties with tobacco cessation.
How long might it take for nAChR levels to return back to normal after chronic nicotine exposure?
After 6-12 weeks of abstinence.
Read slide 33.
you got this!
T or F: DA surge following nicotine administration is quite low.
False.
DA surge occurs very quickly and at a high level, reinforcing its rewarding effects and explaining its addictive potential.
T or F: Tobacco has one of the highest capture rates.
True.
Actually, the highest!
In which brain region are nAChR expressed in high densities?
VTA (reward centre!)
On which neurons are nAChR found?
1) DA neurons
2) GABA neurons
3) Glu neurons
Explain how nicotine exerts its rewarding effects.
Nicotine directly activates VTA DA-ergic neurons, which release DA in the NAcc through stimulatory (DA, Glu) and inhibitory (GABA) effects and differential desensitization of nAChR.
What are the three different ways (direct/indirect) nicotine can increase DA in the NAcc?
1) DIRECT: Nicotine directly activates VTA dopamine
neurons, which releases dopamine in the NAcc.
2) INDIRECT: Simultaneously, nicotine activates α7 nAChRs glutamatergic neurons, which indirectly increases NAcc dopamine release
3) INDIRECT: Nicotine activates GABA neurons which express β2-containing nAChRs which inhibits dopamine release. This occurs at the same time that dopamine neurons themselves are directly activated and Glu is indirectly activated
How might activation of a7 nAChR glutamatergic neurons sustain nicotine’s rewarding effects?
Remember that a7 nAChR have low affinity for nicotine such that they are less prone to desensitization.
How might activation of b2 nAChR GABAergic neurons sustain nicotine’s rewarding effects?
Remember that a4b2 nAChR desensitize rapidly, such that GABAergic drive to the dopamine neurons is reduced over a longer time frame when low levels of nicotine are continually present, helping to sustain dopamine levels
Map out the acute and sustained effects of nicotine on DA release.
Slide 38
1) ACUTE
Nicotine directly stimulates (+) neurons in the VTA to release DA in the NAcc.
Nicotine stimulates the release of Glu onto DA neurons, triggering additional DA release (+).
Nicotine stimulates the release of GABA onto DA neurons to moderate DA’s effect.
2) SUSTAINED (minutes later)
Nicotine continues to directly stimulate (+) neurons in the VTA to release DA in the NAcc.
Glu cells continue to sitmulate DA release since they have a7 nAChR.
GABA release becomes inhibited since they have a4b2 nAChR.
Where are a4b2 nAChR highly expressed?
Midbrain DA pathways
What do a4b2 nAChR regulate?
a4b2 nAChR regulate many of the addiction-relevant behavioural responses to nicotine.
What is b2 nAChR linked to?
DA release
T or F: In an experiment, a b2-KO mouse would increase nicotine self-administration.
False.
b2 nAChR subunit KO mice do not self-administer nicotine.
What is a4 nAChR linked to?
Nicotine sensitivity
T or F: Mice with genetic mutations that increase nicotine sensitivity of α4 nAChR subunit show enhanced addiction-relevant behavior to nicotine.
True.
T or F: nAChR containing a3 and a4 subunits are low-affinity nicotine binding sites.
True.
In which brain regions are a3 and a4 nAChR subunits enriched?
In brain sites involved in aversion.
T or F: Tobacco addiction is only due to nicotine.
False.
Non-nicotinic components in tobacco smoke also contribute to the reinforcing properties of nicotine.
What is another element (aside from nicotine) that contributes to tobacco’s addictive nature?
Monoamine oxidase inhibitors (MAOi)
→ eg. Beta-carbolines harman
How do MOA inhibitors contribute to tobacco’s addictive effect?
MAOi increase DA in the reward regions by decreasing DA breakdown.
T or F: In an experiment MAO inhibition would enhance nicotine self-administration in animals.
True.
T or F: MAO inhibition occurs acutely.
False.
MAO inhibition by smoke requires long-term exposure.
T or F: MAO inhibition is rapidly reversible.
False.
MAO inhibition is not rapidly reversible.
What is tranylcypromine?
Non-selective MAOi
Where is nicotine mainly metabolized?
Majority of nicotine is metabolized in the liver by cytochrome P450 enzymes (CYP2A6).
What is the half-life of nicotine in blood?
2 hours.
What is a major nicotine metabolite?
Cotinine.
T or F: Smokers will smoke arbitrary amounts on a daily basis.
False.
Individuals who use nicotine titrate serum concentrations within quite narrow limits.
How might a smoker’s pattern look like throughout the day? What might be the reasons behind that?
1) Individuals with tobacco addiction often smoke their first cigarette within 5 minutes of waking
2) Levels are then maintained throughout the day
→ They avoid levels that are too low to avoid withdrawal symptoms
→ They avoid levels that are too high to avoid aversive symptoms
When does the typical onset of nicotine withdrawal occur?
After 4 hours of last use.
List some symptoms of nicotine withdrawal.
1) Irritability
2) Anxiety
3) Depression
4) Impatience
5) Difficulty concentrating
6) Impaired performance
7) Insomnia
8) Increased appetite/weight gain
9) Cravings
T or F: Nicotine withdrawal symptoms are relatively easy to deal with.
False.
Withdrawal symptoms negatively reinforce nicotine use and make it difficult to quit.
What two tests can be used to diagnose TUD?
1) DSM-5 test
2) Fagerstrom test for nicotine dependence
T or F: People with psychiatric disorders have heightened vulnerability to the addictive properties of cigarette.
True.
Which psychiatric population often has TUB comorbidity?
Schizophrenic population.
What were electronic cigarettes originally developed for?
Smoking cessation
How is nicotine delivered through e-cigarettes?
Delivers a nicotine-containing aerosol to users by heating a solution typically made up of propylene glycol or glycerol (base) and nicotine
What factors can affect nicotine exposure when smoking e-cigarettes?
1) e-liquid [nicotine]
2) e-cigarette power
3) user consumption patters
Why might e-cigarettes be perceived as healthier compared to traditional cigarettes?
Nicotine is delivered to the upper and lower respiratory tract without any combustion, thus being perceived as a healthier alternative.
What are the compartments of an e-cigarette?
1) Mouthpiece
2) Cartridge
3) Coil (Heating element)
4) Rechargeable battery
Read slide 52.
almost there !!
T or F: JUUL e-cigarette contain low amounts of nicotine, making them the better option.
False.
JUUL e-cigarettes have a high level of nicotine: a single pod contains as much nicotine as a pack of 20 cigarettes.
What make JUUL pods so potent?
The use of nicotine salts, which are easier to inhale and more readily absorbed into the bloodstream.
List some toxic compounds found in e-cigarettes.
1) Nicotine
2) Propylene glycol
3) Acetaldehyde and formaldehyde (carcinogens)
4) Acrolein
5) Diacetyl
6) Diethylene glycol
7) Heavy metals: tin, lead, nickel
8) Cadmium
9) Benzene
Why might e-cigarettes be appealing to youth?
- flavouring
- discreteness
- accessibility
- perceived health
- targeted advertising
- unaware that they contain nicotine
Read slides 56-60.
slay mama
T or F: Reducing smoking does not lead to health improvements.
False.
Reducing smoking can lead to improved breathing and exercise tolerance.
T or F: Reductions in cardiac, pulmonary, and oncological disease are only seen when quitting smoking.
True.
T or F: Chronic smokers do not want to quit.
False.
~70% of people who use tobacco want to quit.
T or F: Most quitting attempts are successful.
False.
Even with current treatment options, most attempts end in relapse (77%).
How many attempts might it take to successfully quit tobacco use?
Up to 30.
List some behavioural treatments for TUD.
1) MI
2) Support groups
3) Hypnosis
4) Acupuncture
5) Relapse-prevention
6) Coping skills
7) Aversive therapy (not used)
List some pharmacotherapies for TUD.
1) Slow-acting nicotine replacement therapy
2) Fast-acting nicotine replacement therapy
3) Antidepressants
4) Nicotinic partial agonist.
Fill out the table for pharmacotherapeutic options
Good luck…
Why might NRT not be successful?
NRT does not replace the rituals linked to smoking.
Describe the MoA of Varenicline (Champix).
Varenicline is a a4b2 nAChR partial agonist.
Read slides 67-69
What is the main side effect of Varenicline?
Nausea
Explain the pharmacogenomics of smoking cessation. Which treatment options might be most beneficial?
The CYP2A6 gene is highly polymorphic, with many variants altering CYP2A6 function; individuals can be genotyped for these variants and grouped into CYP2A6 activity groups: fast, normal and slow metabolizers.
→ Treating normal metabolizers with varenicline may optimize quit rates
→ Treating slow metabolizers with nicotine patch may optimize quit rates
What is a novel therapeutic option for TUD?
Brain stimulation.
What is a novel therapeutic target for TUD?
Endocannabinoid system.
