Nicotine

Question 1

How does smoking effect the body

Answer 1

Tobacco addiction is the leading cause of preventable death in the western world.

Tobacco harms all parts of the body- it increases the liklehood of developing stroke.
Lung cancer
COPD
Blood and kidney cancers
reproductive system
increased risk of premature birth during pregnancy.

Question 2

What are the hazardous chemicals in cigarettes

Answer 2

Nicotine: addictive, increases heart rate, blood pressure, blood glucose, the lethal dose is 500-1000mg

acetylaldehydes: human and animal carcinogen
N-nitrosamines- human carcinogen
benzene: known human carcinogen

SMOKING is addictive due to the presence of NICOTINE

Question 3

Which neurotransmitter does nicotine mimic?
& what is the structure of nictotinic acetylcholine receptors

Answer 3

Nicotine mimics the activity of Ach.
Ach binds to nicotinic acetylcholine and muscaranic receptors .

nicotinic acetyl choline receptors have a pentameric structure:
-5 receptor subunits-
-4 transmsmbrane domains
- come together to form a central pore.

Question 4

Describe nicotine absorption

Answer 4

-Nicotine is absorbed well through intact skin.
- Is well absorbed by the gut- but it has a low bioavailability.
-Rapidly absorbed through respiratory epithelium
- Passes through the blood brain barrier in 11 seconds

Question 5

Describe the metabolism & excretion of Nicotine

Answer 5

Nicotine is mainly metabolised in the liver to Cotinine (inactive metabolite) and other metabolites ( nicotine-oxide)

The half life of nicotine is 2 hrs
The half life of cotinine- 19hours ( useful marker to second hand smoke)

rapid metabolism of nicotine underlies tobacco users need for frequent administration

• Nicotine is excreted through the kidneys
• also accumulates in the brain

Question 6

Nicotine pharmacodynamics

Answer 6

Pharmacodynamics refers to the effects of nicotine on the body

Nicotine binds to its receptors all over the body and has a stimulatory effect.

-CNS:
arousal, inc vigilance(low doses) and anxiety at high doses
Improved task performance
anxiety relief

-Cardiovascular system:
- Inc heart rate
-Inc cardiac output
-Inc blood pressure
- coronary vasoconstriction

-Other:
- appetite suppression
- inc. metabolic rate

Question 7

What are the neurochemical effects of nicotine on the body

Answer 7

-Dopamine: pleasure and reward
-Norepherine: arousal and appetite surpression
-Acetylcholine: arousal and cognitive enhancement
- Glutamate: learning and memory enhancement
-Seratonin: mood modulation and appetite surpression
- B endorphins: reduces anxiety and tension
- GABA: reduces anxiety and tension

Question 8

Nicotine pharmacology: Structure of nAchR

Answer 8

The nAchR has a pentameric structure- 5 subunits- 9 different types
- 4 transmembrane domains
- Na+/K+ ion channel

• Nicotine is a potent agonist at the a4b2 receptor
  -It is through this ion channel- dependance occurs through this ion channel-

study: B2 knock out mice: do not produce reinforcing effect (less dopamine is released, so less of a reinforcing effect) - mice did not self administer nicotine

how did we measure the extent of the B2 rewarding effect in knock out mice- using mice self administration model.

how did we measure the dopamine levels in normal and B2 KO mice: Microdialysis (probe in the brain) - measure the levels of dopamine.

Question 9

Where is dopamine released from

Answer 9

In the mesolimbic pathway: functions of reward and motivation

Dopaminergic neurons originate in the VTA (midbrain) and they project to the
1. Nucleus accumbens (basal ganglia–striatum)- reward
2. Pre-frontal cortex ( excecutive function and memory)
3. Amygdala (emotional centres)

Nicotine has an effect on dopamine levels - but not as much as cocaine or amphetamine

Question 10

Where are nAchR found

Answer 10

A4B2 and A7 nAchR are found in the
- Prefrontal cortex (decsion making and craving)
- Striatum (motivation+habit)
-Amygdala (emotional centre)
-Hippocampus: (memory, reward-related memory)
-VTA and substantia niagra: reward

Question 11

How does nicotine regulate the dopaminergic pathway

Answer 11

Nictotine causes the release of dopamine from dopaminergic neurones. Nicotine binds to nAchR on the cell body and synaptic terminals of dopaminergic neurones.
NaAchR can also modulate the release of GABA and Glutamate.

Question 12

What are the three states of NAchR

Answer 12

• Open state: Flow of Na+ and K+ ions
• closed state: no flow of Na+ and K+ ions
  -Desensitised state: Ion remains bound to the receptor but the ion channel does not open - and so you don’t get depolarisation

Question 13

What happens during receptor activation

Answer 13

Ach (or nicotine) binds to the receptor and stabilises the open state of the ion channel for several milliseconds.
Cations (Na+ and K+) enter and depolarise the cell initiating cellular response
A variety of neurotransmitters are released in the CNS as presynaptic nAChRs are present on various types of neurons.
ACh is rapidly broken down by acetylcholine-esterase
Nicotine has much longer duration of effect than ACh
Receptor becomes de-sensitised and unresponsive for a period of time

Question 14

What are the effects of acute and chronic cigarette smoking on nAchR- highlight the mechanism of dependance

Answer 14

Between cigarettes you may get the desensitisation of the nAchR (acute effects)

Chronic smoker:
The cessation of smoking leads to withdrawal symptoms.
Excess smoking can result in the long term desensitisation of the nAchR (A4B2)
As a result there is a significant upregulation of nAchR as a homeostatic compensatory response as a result of a latge proportion of desensitised nAchRs——-

Increases receptors are associated with craving and dependance

Question 15

In what manner is there the upregulation of receptors

Answer 15

Increased trafficking of internalised receptors in vesicles towards the cell membrane

Question 16

Describe the nicotine addiction cycle

Answer 16

Nicotine is taken- induces the release of dopamine and results in pleasurable effects.

Tolerance and physical dependance

Abstinence: produces displeaasure and withdrawal symptoms

Nicotine used to self medicate the withdrawal symptoms

• TOLERANCE develops - due to increased receptor desensitisation and an up-regulation of receptors with increased craving.

Question 17

Why do smokers describe the first cigarette of the day as the most pleasurable

Answer 17

when the first cigarette of the day is smoked, Nicotine binds to the nAchR and induces the release of dopamine and a pleasurable effects and some levels of tolerance develop. As the day progresses, a cigarette is smoked but nicotne accumulates and some receptors are desensitised - Nictotine is unable to bind to some of the receptors, thus the arousal and pleasurable effects are not to same extent as the first cigarette.

A higher conc. of nicotine is needed to induce the same effect- thus the threshold for pleasure and arousal increase throughout the day as the smoker becomes tolerant to the effects of nicotine.
later in the day each induvidual cigarette produces limited amount of pleasure and arousal

increased smoking leads to developing increased levels of tolerance. increased smoking is to only alleviate the withdrawal symptoms not induce pleasure

increased withdrawal symptoms between successive cigarettes

cessation of smoking overnight causes the resensitisation of receptors

Question 18

Characteristic of nicotine addiction

Answer 18

smokers maintain a serum nicotine concentration:

• prevent withdrawal symptoms
• Maintain pleasure/ arousal
  -modulate mood

how??
- indirectly mechanism:
-smoking or dipping more frequently
- smoking more deeply
-smoking more intensily

Question 19

When is nicotine withdrawal most common and what are the symptoms

Answer 19

Nicotine withdrawal symptoms are most common in the morning because plasma nicotine levels fall overnight and lead to withdrawal symptoms in the morning. More nAch receptors become avialabale in the morning receptors

Withdrawal symptoms:
-Mood changes: dysphoria and depressive mood
- Irratability
- Anxiety and restlessness
- Difficulty concentrating
-Hunger, increased appetite
-Craving

Question 20

What factors contribute to tobacco use

Answer 20

• Physiology:
  ^ Genetics:
  defective alleles of CYP2A6 - slow metabolism of nicotine - lower rates of smoking-( nicotine remains in the body for longer periods as it is not broken down - longer to develop tolerance)
• CHRN44 gene polymorphism: (encodes for the a4 subunit of nAchR) higher rates of tobacco dependance

^Coexisting medical conditions

• Pharmacology:
  ^Alleviate withdrawal symptoms
  ^Weight control- tobacco suppresses appetite
  ^pleasure
• Environment:
  ^Advertising
  ^social interactions
  ^conditioned stimuli

Question 21

which gene mutation significantly regulates nicotine intake

Answer 21

The CHRNA5 gene encodes the a5 subunit of the nAchR. (Associated with nicotine addiction and lung cancer)

IN CHRNA5 knockout mice, there was increased nicotine intake

why? Bec in CHRNA5 knockout —- the rewarding effects of nicotine were not affected. the inhibitory mechanism at higher doses of nicotine were abolished.

a5 subunit was reintroduced in the medial habenulla - inhibitory mechanism was restored.

Question 22

Which group of people is smoking common in

Answer 22

Smoking is common amongst patients with psychiatric disorders

• schizophrenic patients:
  schizophrenic patients have impaired nicotinic neurotransmission(delsuions). so nicotine functions to compensate for this deficiency. shizophrenic patients smoke larger amounts of cigarettes per day.

-substance abusers

Question 23

What are the health benefits of Nicotine

Answer 23

• Reduces the risk of parkinsons disease
• Lower risk of PD in smokers

Question 24

What should nicotine treatment address

Answer 24

Treatment should address the physiological and behavioural aspects of dependance.

• Physiological: addiction– treating addiction– medications for cessation
• Behavioural: the habit of using tobbaco—- behavioural change programmme