L6 - NICOTINE Flashcards by Thomas Prud'homme

List short-term effects of tobacco.

Increased heart-rate, blood pressure and breathing rate
CO blocks O2 from getting into bloodstream
Stimulates nausea
Bad breath
Stimulates neurochemical systems
- Dopamine
- Norepinephrine (appetite suppression)
- Acetylcholine
- GABA
- B-Endorphin
- Glutamate
- Serotonin

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Associate the follow neurotransmitters with a state/function:
- Dopamine
- Norepinephrine
- Acetylcholine
- GABA
- B-Endorphin
- Glutamate
- Serotonin

Dopamine -> reward
Norepinephrine -> arousal
Acetylcholine -> arousal
Glutamate -> learning
GABA -> reduction of anxiety
B-Endorphin -> reduction of anxiety
Serotonin -> mood

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List long-term effects of tobacco.

Tobacco addiction
Emphysema and bronchitis
COPD
Heart and artery disease
Cancer of lung, bladder, pancreas

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Name three major coindicent long-term effects of adolescent tobacco use. List their implications.

Altered trajectory of normal brain development:
- Dendritic remodeling
- Lower gray matter volume in thalamus and amygdala
- Aberrant functional connectivity between dlPFC and amygdala and striatum
- Modified reward system
- Changes in 5HT synaptic function
Diminished cognitive function, persisting into adulthood:
- Reduced attention span
- Poorer memory
- Lower inhibitory control
Greater mental health problems
-Increased anxiety and depressive-like behaviour
-More severe tobacco dependence

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True or false: there is consensus about the relationship between adolescent tobacco use and its consequences in adulthood.

False.

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True or false: nicotine has behavioural implications.

True.

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In what organ is nicotine from smoked tobacco entering the bloodstream?

Lungs.

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True or false: nicotine is toxic at high concentrations.

True.

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Provide a hormonal basis for the tranquilizing effects of nicotine.

Decreases CORT.

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To what receptors bind nicotine?

Nicotinic acetylcholine receptors (nAChR).

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How many subunits does a nAChR have? What are the two types of subunits?

Alpha and beta.

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How many isoforms of nAChR subunits are there?

9 for alpha and 3 for beta.

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What are the most abundant nAChR subtypes in brain?

α4β2 and α7.

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True or false: nicotine has equal affinity for α4β2 and α7.

False: highest affinity for α4β2.

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How do you call nAChRs made up only of one type of subunit? Made of different types?

Homomeric vs heteromeric.

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Where are nAChRs mostly located?

Thalamus, but also basal ganglia, frontal and insular cortices.

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What NTs are binding nAChRs?

Acetylcholine and nicotine (presynaptically).

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What are the three states of nAChRs?

Closed.
Open.
Desensitized.

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Which state of nAChR is the most prevalent between open and desensitized?

Desensitized.

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Describe implications of nAChR desensitization.

Acute effects are limited.
Reduced satisfaction.
Facilitates the emergence of withdrawal symptoms.
Chronic nicotine use leads to neuroadaptive changes: upregulation of nAChRs.

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What specific nAChR has been found in higher densities in living human smokers? In what parts of the CNS?

Beta2 nAChR. In the striatum, cerebellum, and cerebral cortex compared to nonsmokers.

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With what aspects of tobacco consumption are the adaptations in β2 nAChRs thought to be involved?

In tobacco addiction, tolerance and dependence.

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What behavioural tests support the evidence that nicotine is addictive?

Self-administration and CPP (conditioned place preference).

What is the effect of nicotine on DA release in the NAcc?

Very intense peak (very addictive).

On what cell types are nAChRs found in the VTA?

Dopaminergic. GABAergic. Glutamatergic.

Which nAChR regulates many of addiction-relevant behavioural responses to nicotine? How is it experimentally supported?

Alpha4beta2 nAChRs: -Alpha4 subunit KO decreases self-administration. -Genetically-modified alpha4 subunit for increased sensitivity to nicotine increases self-administration.

Where is nicotine mostly metabolized?

Liver.

By which enzyme is nicotine mostly metabolized?

Cytochrome P450 enzymes (CYP2A6).

What is the implication of the half life of nicotine being only 2 hours?

Explains recurrent smoking in a single day.

What is nicotine's principle metabolite?

Cotinine.

Why are smokers carefully balancing their nicotine consumption?

Narrow window between withdrawal and OD.

Why are smokers almost certainly smoking in the first minutes of waking?

Nicotine is most likely out of their blood (4h>). They therefore have to smoke to avoid withdrawals.

List primary (4) and secondary (4) risk factors for TUD.

Primary: - Acute withdrawal syndrome - Negative affect (mood) - Positive effects (satisfaction) - Conditioned cues Secondary: - Stress - Antinociception (pain relief) - Weight control - Cognitive enhancement

List 5 neurotransmitters regulated by nicotine.

DA NE 5-HT ACh Glu

What is one simple behavioural treatment for TUD that tends to be underrated?

Brief advice from physician or other health professional

Provide four behavioural treatments for TUD.

Motivational interviewing Coping skills Community support groups Rapid smoking

What are the four broad classes of TUD pharmacotherapies? Give an example for each.

Slow-acting NRT: patch Fast-acting NRT: gum Antidepressant: SR bupropion Nicotinic partial agonist: varenicline

What is the most efficient pharmacotherapy for TUD?

Varenicline (nicotinic partial agonist)

Each of the four broad classes of TUD pharmacotherapies is associated with which respective predominant side effect?

Slow-acting NRT: local irritation Fast-acting NRT: oropharyngeal irritation Antidepressant: insomnia (activation) Nicotinic partial agonist: insomnia

Varenicline acts on which receptor?

alpha4beta2-selective nAChR partial agonist

Up to how many weeks is varenicline preventing smoking relapse?

24 weeks

Why does it make sense that the side effects of nicotine are nicotine-like?

Varenilcine binds to alpha4beta2 (but partial effects).

True or false: varenicline has no behavioural side effects.

False: no scientific consensus. Reports of neuropsychiatric treatment-emergent adverse effects.

What treatment between varenilcine and bupropion has the highest rate of continuous abstinence in clinical studies?

Varenicline, significantly.

From studies on the pharmacogenetics of smoking cessation, what treatments can we expect to be particularly efficacious for slow metabolizers and normal metabolizers?

- For slow metabolizers (low CYP2A6 activity), nicotine patch and varenicline are expected to be equally efficacious. - For normal metabolizers, varenicline is expected to be more efficacious than nicotine patch.

True or false: quitting smoking in MI populations leads to better psychiatric and substance use disorder outcomes.

True.

True or false: rates of tobacco smoking in MI populations are higher AND rates of quitting smoking are significantly lower.

True.

Name four broad risk factors that make Sz vulnerable to TUD?

Biochemical Genetic Behavioural Neurocognitive

What is the most significant biochemical difference between Sz and neurotypical smokers?

Lower density of beta2*nAChRs in Sz smokers.

Different densities of beta2*nAChRs in Sz smokers were observed in which brain areas?

-Parietal cortex -Frontal cortex -Thalamus -Striatum -Hippocampus

Based on previous case reports, why would it be counter-intuitive to prescribe varenicline to a neuroatypical individuals? Is this reluctancy founded?

There are reports implicating varenicline in treatment-emergent adverse events such as suicidality, homicidality, psychosis and mania. However, recent studies have shown that varenicline seemed safe and efficacious in both Sz and bipolar populations.

Name three research findings that attest varenicline's efficacy for smoking cessation in Sz populations.

- Increased abstinence - Varenicline effects do not seem to generate different positive or negative effects from control - Works for replase-prevention

Provide 4 reasons that might explain why co-use of tobacco and cannabis is so high.

- Both are smoked products, cross cuing - Substitution effects (one can temporarily replace the other) - Interaction between endocannabinoid and nicotinic receptor systems - Common social determinants

Why an association between tobacco use and transition to psychosis is presumed?

-Majority of early psychosis patients smoke tobacco -In average, psychotic patients have been using tobacco 5.3 years before before the onset of their illness.

Why is the relationship between Sz populations and cannabis unexpected?

Tobacco co-morbidity is generally associated with other substance use disorders (SUDs). However, it does not seem like it is the case for cannabis: Sz with current cannabis dependence history smoke less tobacco than Sz with no history of cannabis dependence.

Provide two possible mechanisms that could explain why Sz individuals tend to be cannabis-abstinent.

-Increase in tobacco use with cannabis abstinence in SZ versus CTL subjects could represent compensation -Sz patients might be more neurobiologically sensitive to cannabis, supported by selective improvements in neurocognition in SZ versus CTL subjects with cannabis abstinence

For what purpose has rTMS been advised for Sz tobacco-smokers?

rTMS reduces tobacco cravings in patients with schizophrenia.