Nicotine Addiction Flashcards
Tobacco Overview (4)
- Leaves of Nicotiana tobacum cured and (usually) smoked (potent poison for bugs/keeps them away)
- Indigenous to North America
- Given to C Columbus when lander in San Salvador in 1492
- Smoked by natives for medicinal, ceremonial purposes (~1 B.C.) (enhancing fertility, predicting weather,conducting war councils, enabling vision quests, making peace)
Tobacco history (4)
- Jean Nicot de Villemain introduces tobacco to France, promotes importation and cultivation (1556)
- Chewed recreationally, used for ailments (e.g. headaches, colds) in Europe (1500s)
- Tobacco becomes major cash crop of American colonies, spurring demand for slave labor (1600s)
- No society that has adopted tobacco has ever given it up
Smoking - why is it important? (10)
- Tobacco addiction is the LEADING preventable cause of death in Western societies
- 1.3 Billion smokers worldwide +contributes to appx 5 million death a year (WHO)
- Half of all smokers die prematurely as a consequence of their addiction
- WHO data shows that Europe still has the highest overall smoking rates
- UK rates have fallen to 14.1% (2020)
- Service cost over £61 million last year (UK)
- Smoking prevalence is linked to socio-economic status and vulnerable
populations - Non smokers exposed to environmental tobacco smoke have a sig. higher risk of developing cancers +pulmonary diseases
- Children exposed to second hand smoke develop a variety of respiratory disorders +morbidity.
- Only 3-5% of smokers who want to quit succeed without NRT and only 1/3 succeed with them
Hazardous components in cigarette smoke (8)
Nicotine
N-nitrosamines - carcin.
Benzene - carcin.
aromatic amines - carcin.
Acetaldehyde - animal carcin + maybe human
1.3-Butadiene - carcin. +tetratogen
Acrolein - carcin. + dna mutagen
Polyaromatics - carcin. + dna mutagen
What is the major component causing addiction? (2)
major if not sole compound responsible for driving the addiction to smoking and thus a formidable obstacle to the prevention of tobacco related deaths is
NICOTINE
Nicotine mimics some of the actions of acetylcholine
Nicotine action - pharm targets (3)
1) has pyrrolidine + pyridine ring
2) acts on nAChr (ligand gated ion channels = depol.)
3) Ach also binds to nAChr but also muscarinic r (GPCR)
Nicotine absorption (4)
- Nicotine is readily absorbed through intact skin.
- Nicotine is well absorbed in the small intestine but has low bioavailability (30%) due to first-pass hepatic metabolism.
- Nicotine is rapidly absorbed across respiratory epithelium.
- Passes freely through the BBB and reaches brain in 11 secs = highly addictive
Nicotine metab. (4)
liver metbolises it using CYP enzymes
= 70-80%: cotinine
approx. 10%: other metabolites
= excreted in urine
=10-20% unchanged in urine (not in liver)
Nicotine excr.
Half-life:
Nicotine t½ = 2 hr
Cotinine t½ = 19 hr - remains in body for longer
Excretion Occurs through kidneys (pH dependent;
with acidic pH)
Through breast milk
Nicotine pharmodynamics - body parts affected (9)
Nicotine binds to receptors in the brain and other sites in the body = effects every single organ in the body
-CNS
-PNS
-CVS
-GI system
-Exocrine glands
-Adrenal medulla
Other:
Neuromuscular junction
Sensory receptors
Other organs
Nicotine has predominantly stimulant effects
Clinical effects of smoking: (9)
heart attacks
cancers (larynx, oral, esophageal, lung, pancreatic, bladder, kidney, cervical)
stroke
doubles cataracts risk
circ diseases
stomach ulcers
Asthma, COPD
impotence
unborn babies: preemie, lowbirthweight, stunted dev., infant death
CNS effects (4)
Central nervous system
– Pleasure
– Arousal, enhanced vigilance (at low doses, at high doses anxiety)
– Improved task performance at low doses
– Anxiety relief (perceived benefit) (does cause muscle relaxant so maybe true)
CVS effects (5)
Cardiovascular system
– inc. HR
– inc. CO
– inc. BP
– Coronary vasoconstriction
– Cutaneous vasoconstriction
Other (7)
– Appetite suppression (sympathetic) -withdrawal
– Increased metabolic rate(sympathetic)
– Skeletal muscle relaxation
– Vomiting, nausea, headache (tolerance)
– Slow stomach secretions
– Laxative
– Constricts blood vessels, wrinkles
Neurochemical + related effects- r’s (7)
- Dopamine= Pleasure, reward
- Norepinephrine=Arousal, appetite suppression
-Acetylcholine=Arousal, cognitive enhancement
-Glutamate=Learning, memory enhancement
-Serotonin=Mood modulation, appetite suppression
-beta-Endorphin=Reduction of anxiety and tension
- GABA= Reduction of anxiety and tension
Nicotinic Acetylcholine
Receptors (nAChRs) (5)
- Ligand-gated ion channels (mostly Na+/K+ )
- Widespread in the CNS
- Ach= the endogenous ligand
- The major role in mammalian CNS is to influence neurotrans release
nAChR structure (4)
- Pentamer
– 5 polypeptide subunits
– 9 subtypes (alpha1, 2, 3, 4..7, beta1, 2 etc)
– Potential for 59 = 2 million diff. assemblies - Nicotine is a potent agonist at the nicotinic alpha4beta2r
- Nicotine dependence is modulated primarily through alpha4beta2 nAChr
beta2-subunit k/o mice - self admin (2)
– normal mice in chamber w/ lever - injection of nicotine = press level(self-admin) (high DA)
- beta2-subunit k/o mice =mice do not self-administer nicotine: nicotine doesn’t produce reinforcing effect (less da is released).
3 drugs on DA neurotransmission levels (4)
Meth: highest
Coke: slightly less
nicotine: much less
Cholinergic system (4)
1) Cholinergic neurons
2) project on nucleus basalis/ striata/ septum of hippo/ SN-Th
3) = ACh release
4) Ach binds + acts on NAChr’s
NAChr’s in the brain (6)
alpha-4beta-3 and alpha7 in each
prefrontal cortex - DM +craving
Hippo: reward related learning + context info processing
Striatum: Reward, motivation, Habit
Amygdala: Emotional response stress
VTA + SnC : Reward + emotions
Reinforcing effect of nicotine: “reward” pathway (4)
Nicotine interacts with the ‘reward’ pathway
Nicotine releases da in the nucleus accumbens + dorsal striatum in vitro and in vivo
nAChRs are found on both cell bodies and axon terminals of da neurones
Can also modulate GABA and glutamate release
image
nAChRs: functional states (3)
Three states of the nAChR ion channels:
– closed (at rest) - not stim. by anything
– open ( binding = cations flow into the cell - depol.)
– desensitised (closed and not responsive to agonists after contin. stim = x depol (tolerance)) - can be activated just needs a lot more
Receptor activation (6)
1) Ach (or nicotine) binds to the receptor and stabilises the open state of the ion channel for several ms
2) Cations (Na+ and K+) enter and depolarise the cell= initiating cellular response
3) variety of neurotrans released in the CNS
(as presynaptic), nAChRs are present on various types of neurons.
4) ACh is rapidly broken down by acetylcholine-esterase
5)Nicotine has much longer duration of effect than ACh
6)Receptor becomes de-sensitised and unresponsive for a period of time
nAChRs with repeated
smoking (3)
B/w cigarettes nAChRs are mainly desensitised (acute tolerance)
Next cigarette activates a small pool of receptors that are still responsive, producing pleasurable effects
In chronic smokers (e.g. with daily smoking for 6 months or
longer):
– Tolerance
– Withdrawal syndrome on cessation of smoking
– Long-term desensitisation of nAChRs
– Increase in receptor density (upreg. of nAChRs) as a compensatory response to desensitisation of the large proportion the total no. of nAChRs receptors
Mechanism of dependence (α4β2*) studies (3)
rat brain treated w/saline (smokers = darker)
Upreg.of nAChRs as a compensatory response to desensitisation of nAChRs
increase in r’s associated w/craving + dependence
How do you upreg. more receptors?
either
1) incr. protein synth = transc. +translat = not here X
or
2)interfere w/reg. of r’s: nicotine inc. internalised r’s in vesicles to go to membrane to be used
Brain of Nonsmoker Versus Brain of
Smoker (2)
Autopsy studies comparing smokers to nonsmokers reveal up to 400% increases in brain nicotine receptors
Reversibility extent, time course, and variability is unclear
Cycles of pleasure and
withdrawal (6)
- Initial activation causes pleasure response but…
- Dopamine falls quickly over next 2hrs
- As levels fall the smoker feels displeasure/withdrawal
- The next cigarette reduces cravings and other withdrawal symptoms + produces some +ve effects
- This reinforces the compulsion to smoke
- Environmental cues are also important in producing addiction
Nicotine plasma concentration (7)
- Each cigarette delivers 1.2-2.9mg of nicotine
- A typical pack-a-day smoker absorbs 20-40mg of nicotine/day
- Half-life is ~ 2hours
- During a typical day, nicotine accumulates over 6-8 hours (3-4
half-lives) - The increment is 5-30ng/ml after each cigarette (depending on
how the cigarette is smoked) - More frequent smoking reduces fluctuations in nicotine plasma
concentration - The plateau (10-50ng/ml) is usually reached in the early
afternoon
Nicotine addiction cycle (5)
graph w/ uneven bell shaped curve
- jagged lines throuugh grey shape = fluctuatiosn of nicotine (DA)
- bottom solid line - threshold below which = withdrawal
- top solid line - threshold above which you get pleasurable effects
- grey shape = feeling neutral - neighter pleasure or withdrawal
Nicotine addiction types (2)
- Tobacco users maintain a minimum serum nicotine concentration in order to
– Prevent withdrawal symptoms
– Maintain pleasure/arousal
– Modulate mood - Users self-titrate nicotine intake by:
– Smoking/dipping more frequently
– Smoking more intensely
– Obstructing vents on low-nicotine brand cigarettes
Nicotine withdrawal pt1 (6)
- Nicotine plasma concentration significantly drops overnight, which leads to withdrawal symptoms in the morning in chronic smokers.
- Withdrawal onset is usually within a few hours after last cigarette
- Nicotine withdrawal syndrome includes: Mood changes
- 1st morning cigarette produces the most pleasurable effect – After an overnight abstinence more receptors become available for activation – It also relieves withdrawal symptoms
- The earlier the smoker begins to smoke after waking in the morning the more severe the dependence
- If abstinence continues, withdrawal symptoms peak at 24-48hrs and gradually subside over several weeks.
Withdrawal mood changes (6)
- dysphoria, depressive mood
– Irritability, frustration or anger
– Anxiety, restlessness
– Difficulty concentrating, impaired attention
– Hunger, increased appetite or weight gain
– Craving
- Some symptoms persist for months
– mild depression, dysphoria and anhedonia
Factors contributing to tobacco use: (3)
Environment
Tobacco advertising
Conditioned stimuli
Social interactions
Physiology
Genetic predisposition
Coexisting medical conditions
Pharmacology
Alleviation of withdrawal symptoms
Weight control
Pleasure
Contextual smoking (3)
Some places, times and situations are closely associated w/smoking and enhance craving:
– Morning coffee with breakfast
– Coffee shop
– Tea breaks
Genetics (3
- Heritability ~50% (range 28-84%)
- Effect of gene polymorphisms:
– People with defective alleles of CYP2A6 gene= slow metabol. of nicotine and lower rates of smoking + tobacco dependence.
– People with CHRNA4 gene polymorphism (gene coding for α4 subunit of the nicotinic Ach receptor) have higher rates of tobacco dependence
Habenular α5 nicotinic receptor subunit signalling controls nicotine intake - studies (6)
polymorph of alpha5 - inc. chances of nicotine addiction + lung cancer
ko mice - with self-amin test
Nicotine intake has bell-shaped conc curve - at a higher conc = aversion
Up-phase represents rewarding component, unaffected by deletion of alpha5
Down phase reflects the aversive effects of higher doses of nicotine, significantly greater responses in a5 KO
reintroduced alpha5 construct in diff parts of brain - expected results, until introduced in medial habenula =Identification of novel pathway that transmits inhibitory motivational signal which limits nicotine intake (opposes mesoaccubens reward)
Smoking and Mental Health (4)
People with psychiatric disorders and substance use disorders have 2-4x higher rates of smoking (range 41% and 67% respectively) than the general population
- 40-88% of patients with schizophrenia smoke
- Higher rates of depression in smokers
- Higher rate of smoking in substance abusers
Smoking: any health benefits? (3)
- Possibly reduces symptom severity in schizophrenia (self-medication hypothesis)
– There is deficient endogenous central nicotinic neurotrans in
schizophrenia = causes a disruption of sensory gating (a possible mechanism for delusions)
– Exogenous nicotine partly compensates for this deficiency.
– Schizophrenic patients smoke larger amounts of cigarettes per day and
extract more nicotine from them – sig. health risk.
– Therapeutic use of safe forms of nicotine in schizophrenia has been
proposed. - Reduces risk of Parkinson’s disease
– Lower incidence of PD in smokers
– Benefit correlates with the intensity and duration of smoking.
– Does not appear to be due to publication bias
– Nicotine neuroprotective for nigrostriatal neurons - Does it reduce prevalence of Alzheimer’s disease?
– After controlling for tobacco industry affiliation, smoking has been found to
increase the risk of Alzheimer’s disease,
Tobacco dependence:
A 2-PART PROBLEM (2)
Tobacco Dependence: Treatment should address the physiological
and the behavioural aspects of dependence
Physiological: The addiction to nicotine -Treatment =Medications for cessation
Behavioural: The habit of using tobacco- Treatment
=Behaviour change program
