nicotine addiction Flashcards
Give an overview of tobacco and its history
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)
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
Facts behind smoking
Tobacco addiction is the LEADING preventable cause of death in Western societies
1.3 Billion smokers worldwide and 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 significantly higher risk of developing cancers and pulmonary diseases.
• Children exposed to second hand smoke develop a variety of respiratory disorders and morbidity.
Only 3-5% of smokers who want to quit succeed without NRT and only 1/3 succeed with them
nicotine isn’t a carcinogen itself or toxic at concentrations they are used
Problem of nicotine and how its absorbed
nicotine isn’t a carcinogen itself or toxic at concentrations they are used
Nicotine mimics some of the actions of acetylcholine
structure of nicotine= pyrrolidine ring and pyridine ring
acts on nicotinic receptors
they are endogenous ligands (as acetylcholine acts on these receptors)
Ach also acts on muscarinic receptors
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
Nicotine is readily absorbed across intact skin. This allows for transdermal administration of nicotine as a therapeutic adjunct to tobacco cessation (Taylor, 2006).
Conversely, the bioavailability of nicotine in the gastrointestinal tract is limited. Absorption across the gastric mucosa is poor as a result of low gastric pH. In the small intestine, nicotine is well absorbed due to increased pH; however, the systemic bioavailability is low (30%) because it undergoes significant first-pass hepatic metabolism (Benowitz, 1992). Oral nicotine formulations (e.g., sublingual tablets and lozenges) are not subject to first-pass hepatic metabolism.
Metabolism of nicotine
Nicotine is metabolized extensively in the liver and to a lesser extent in the kidney and lung. Approximately 70–80% of nicotine is metabolized to cotinine, an inactive metabolite (Benowitz et al., 1983), and about 4% is metabolized to nicotine-oxide.
The metabolism of nicotine to cotinine is a two-step process likely involving CYP2A6 and aldehyde oxidase. Cotinine is further metabolized to 3′-hydroxycotinine, which undergoes renal elimination. However, nicotine, cotinine, and 3′-hydroxycotinine also undergo glucuronidation. A small fraction (10–20%) of an administered dose of nicotine is excreted as unchanged drug in the urine
Excretion of nicotine
Half-life Nicotine t½ = 2 hr Cotinine t½ = 19 hr Excretion Occurs through kidneys (pH dependent;h with acidic pH) Through breast milk
The half-life of nicotine in the body is approximately 2 hours. This rapid metabolism of nicotine to inactive compounds underlies tobacco users’ need for frequent, repeated administration of nicotine. With regular tobacco use, significant nicotine levels accumulate during waking hours.
The half-life of cotinine (nicotine’s major metabolite) is much longer (18–20 hours). For this reason, cotinine can be used as a more reliable marker of tobacco use and exposure to second-hand smoke.
Nicotine and other metabolites are excreted in the urine. Urinary excretion is pH dependent; the excretion rate is increased in acidic urine. Nicotine accumulates in breast milk (Hukkanen et al., 2005) and can be detected in the blood and urine of infants of nursing smokers
Describe the pharmacodynamics of nicotine
Nicotine binds to receptors in the brain and other
sites in the body.
CNS EFFECTS Pleasure Arousal, enhanced vigilance (at low doses, at high doses anxiety) Improved task performance at low doses Anxiety relief (perceived benefit)
OTHER Appetite suppression (sympathetic) Increased metabolic rate (sympathetic) Skeletal muscle relaxation Vomiting, nausea, headache (tolerance) Slow stomach secretions Laxative Constricts blood vessels, wrinkles
CVS EFFECTS Increased Heart rate Cardiac output Blood pressure Coronary vasoconstriction Cutaneous vasoconstriction
Nicotine primarily has stimulant effects
Nicotine pharmacodynamics refers to the effects that nicotine has on the body.
Nicotine is a potent agent that affects numerous organ systems, including the cardiovascular, endocrine, musculoskeletal, and neurologic systems, as shown in this diagram. Following absorption, nicotine binds to receptors in the brain and other sites in the body, inducing a variety of predominantly stimulant and, to a lesser extent, sedative effects
Describe some neurochemical and related effects of nicotine
On a neurochemical level, nicotine induces a variety of central nervous system, cardiovascular, and metabolic effects. Nicotine stimulates the release of many neurotransmitters, which have been associated with the following effects (Benowitz, 1999):
Neurotransmitter Effects
Dopamine Pleasure, reward
Norepinephrine Arousal, appetite suppression
Acetylcholine Arousal, cognitive enhancement
Glutamate Learning, memory enhancement
Serotonin Mood modulation, appetite suppression
-Endorphin Reduction of anxiety and tension
GABA Reduction of anxiety and tension
Nicotine induces a constellation of effects that reinforce tobacco use behavior.
What are nicotinic acetylcholine receptors and describe their structure
Ligand-gated ion channels (mostly Na+/K+ )
Widespread in the CNS
Acetylcholine (Ach) is the endogenous ligand
The major role in mammalian CNS is to influence neurotransmitter release.
Pentamer
5 polypeptide subunits
9 subtypes (a1, a2, a3, a4..a7, b1, b2 etc)
Potential for 59 = 2 million different assemblies
Nicotine is a potent agonist at the nicotinic 42 receptor
Nicotine dependence is modulated primarily through alpha4beta2 nACh receptors
In beta 2-subunit knock-out mice nicotine does not produce reinforcing effect (less dopamine is released and mice do not self-administer nicotine).
a4b2 nAChRs are important for nicotine dependence
mice experiments on alpha 4 beta 2 receptors
mice studies:
Nicotine does not activate VTA neurons of b2 KO mice
In these mice nicotine does not promote DA release in striatum
b2 KO mice do not self-administer nicotine
investigated nicotine adminstration of nicotine in normal mice with the a4b2 receptor and those without the b2
the more the mice got nicotine, the more they pressed the lever in normal mice
he observed the B2 knockout mice did not press the lever as much
suggesting nicotine was not reinforcing in the B2 receptor knockout mice
Describe the main acetylcholine pathways
Two main diffuse modulatory cholinergic systems – basal forebrain complex / septohippocampal pathway and nucleus basalis (cognitive function / Alzheimer’s disease) and motor control (striatal)
1) 1 cholinergic pathway includes cholinergic neurones (that release acetylcholine) with cell body in the nucleus basalis, with the neurones projecting to cortical areas of the brain where acetylcholine gets released
2) another one from the septum to the hippocampus (septohippocampal pathway)
3) substantia niagra to the thalamus
4) stratum also releases Ach
once Ach gets released in those brain regions, they act on nicotinic receptors and induce a pharmacological response
a4b2 receptors and alpha 7 are localised in the pre-frontal cortex, involved in executive decision making and craving
a4b7 are also in the NA and striatum, playing a role in reward and motivation+habit formation
a4b2 as well as a7 found in the hippocampus involved in memory. involved in reward related learning and contextual information processing
both a4b2 and a7 found everywehre
a7 particularly found in hippocampus
Describe the reward pathway- the reinforcing effect of nicotine
Nicotine interacts with the ‘reward’ pathway
Nicotine releases dopamine in the nucleus accumbens
and dorsal striatum in vitro and in vivo.
nAChRs are found on both cell bodies and axon terminals of dopamine neurones.
They can also modulate GABA and glutamate release
how does nicotine induce release of dopamine in nucleus accumbens
mesolimbic pathway consists of dopaminergic neurones projecting from the ventral tegmental area to the nucleus accumbens
a4b2 is located bot pre and post synaptically in dopaminergic neurones
but also localise post synaptically in the cell body of dopaminergic neruones in the ventral tegmental area
activation of those receptors by nicotine; either post-synaptically or pre-synaptically activate those dopaminergic neurones in the nucleus accumbens
glutamatergic neurones as well as GABAnergic neurones also contain nicotnic recpeotrs found pre synaptically and post synaptically
Describe the 3 different states nAChRs can be found in
Three states of the nAChR ion channels:
closed (at rest)
open (cations flow into the cell)
desensitised (closed and not responsive to agonists)
nicotinic receptors can be found in 3 states:
1) closing/resting state- nicotinic receptor not activated by any ligand. no influx of Na or K
2) activated by acetylcholine or an agonist, ion channel opens and positively charged ions come in- depolarisation (ACTIVE/OPEN state)
3) desensitized state- what happens when the nicotinic receptor is activated repeatedly. If you bombard nicotinic AchR with nicotine, it will close. So REPEATED activation of nicotinic receptors will close the channel. there will still be binding but no response
this is a homeostatic compensatory mechanism that opposes the CONSTANT pharmalogical effect of an agonist on the receptor. too much stress on the biological system will make it want to go back to normality.
this process is what results in nicotine TOLERANCE
How are nicotine receptors activated?
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
What happens to nAchRs with increased smoking
Between 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 (upregulation of nAChRs) as a compensatory response to desensitisation of the large proportion the total number of nAChRs receptors.
smoker smoking 10 cigs a day- so a lot of nicotine
as a result, most of their nicotinic receptors are desensitised
induces tolerance. greater concentration of nicotine needed for same effect
small pool of nACH will still be sensitised
greater dose needed to get the same release of dopamine
What is the mechanism of upregulation of a4b2 receptors to show dependence?
repeated administration of nicotine causes up-regualtion of nicotine dependence
experiment:
a4b2 nicotinic receptors in coronal brains of rats treated with saline+ those treated with nicotine for 2 weeks
massive upregulation of a4b2 in the brains of rats given nicotine EVERYWHERE- in striatum, thalamus, hippocampus,
in cortex of non-smokers you see lower levels of nicotinic receptors vs in smokers (look at coloured diagram on left in pre frontal cortex)
Brains of smokers vs non smokers
Autopsy studies comparing smokers to nonsmokers reveal up to 400% increases in brain nicotine receptors
Reversibility extent, time course, and variability is unclear
In smoker brains:
Increased receptors associated with craving and dependence
compensatory homeostaticmechanism- desenesitisation (closing)
this is stressful for biological system, by upregulating receptor numbers they can alleviate that stress. these are the cravings smokers have
Increased protein synthesis of nicotnic receptor? research has shown that repeated nicotine administration increases a4b2 receptors towards the cell membrane of the neurone. but mrna remains the same
cycles of pleasure and withdrawal with smoking
Initial activation causes pleasure response but…
Dopamine falls quickly over the next 2 hours
As levels fall the smoker feels displeasure or withdrawal
The next cigarette reduces the cravings and other withdrawal symptoms and produces some positive effects
This reinforces the compulsion to smoke
Environmental cues are also important in producing addiction
fall in dopamine causes mergence of withdrawal symptoms
causing dysphoria or aversion
slight anxiety, negative moods, hunger and irritability
motivational trigger to go and smoke again
leads to cycle
Plasma concentration of nicotine
Each cigarette delivers 1.2-2.9mg of nicotine
A typical pack-a-day smoker absorbs 20-40mg of nicotine each 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
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 addiction cycle
After smoking the first cigarette of the day, the smoker experiences marked pharmacologic effects, particularly arousal. No other cigarette throughout the day produces the same degree of pleasure/arousal. For this reason, many smokers describe the first cigarette as the most important one of the day. Shortly after the initial cigarette, tolerance begins to develop.
Accordingly, the threshold levels for both pleasure/arousal and abstinence rise progressively throughout the day as the smoker becomes tolerant to the effects of nicotine.
With continued smoking, nicotine accumulates, leading to an even greater degree of tolerance. As a result, the smoker experiences greater withdrawal symptoms between successive cigarettes. Late in the day, each individual cigarette produces only limited pleasure/arousal; instead, smoking primarily alleviates nicotine withdrawal symptoms.
Cessation of smoking overnight allows resensitization of drug responses (i.e., loss of tolerance). Most dependent smokers tend to smoke a certain number of cigarettes per day (usually more than 10) and tend to consume 10–40 mg of nicotine per day to achieve the desired effects of cigarette smoking and minimize the symptoms of nicotine withdrawal
Describe nicotine withdrawal
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
dysphoria, depressive mood
Irritability, frustration or anger
Anxiety, restlessness
Difficulty concentrating, impaired attention
Hunger, increased appetite or weight gain
Craving
First 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 24-48 hours and gradually subside over several weeks.
Some symptoms persist for months
mild depression, dysphoria and anhedonia
What factors contribute to developing a nicotine addiction
Some places, times and situations are closely associated with smoking and enhance craving:
Morning coffee with breakfast
Coffee shop
Tea breaks
Heritability ~50% (range 28-84%)1
Effect of gene polymorphisms
People with defective alleles of CYP2A6 gene have slow metabolism of nicotine and lower rates of smoking and tobacco dependence.1
People with CHRNA4 gene polymorphism (gene coding for α4 subunit of the nicotinic Ach receptor) have higher rates of tobacco dependence.
CYP2A6 responisble for coding p450
metabolism of nicotine is slow if that gene is defective
only small amount of cigs needed to maintain high levels of nicotine so less withdrwal and less dependence
polymorphism of this gene assocated assocatied w HIGHER tobacoo dependence
How does alpha 5 nicotinic receptor subunit control nicotine intake
Medial habenula to Interpeduncular nucleus via fasciculus retroflexus
Genetic variation in CHRNA5, the gene encoding the α5 nicotinic acetylcholine receptor subunit, increases vulnerability to tobacco addiction and lung cancer, but the underlying mechanisms are unknown. Here we report markedly increased nicotine intake in mice with a null mutation in Chrna5. This effect was ‘rescued’ in knockout mice by re-expressing α5 subunits in the medial habenula (MHb), and recapitulated in rats through α5 subunit knockdown in MHb. Remarkably, α5 subunit knockdown in MHb did not alter the rewarding effects of nicotine but abolished the inhibitory effects of higher nicotine doses on brain reward systems.
Effect of increased nicotine intake in alpha 5 knockout mice:
Nicotine intake has bell-shaped conc curve
Up-phase represents rewarding component, unaffected by deletion of a5
Down phase reflects the aversive effects of higher doses of nicotine, significantly greater responses in a5 KO
Effect of the rescue’ of α5* nAChRs in the habenulo-interpeduncular tract normalizes nicotine intake: dentification of novel pathway (habenulo-interpeduncular) that transmits inhibitory motivational signal which limits nicotine intake (opposes mesoaccubens reward)
Impact of smoking on mental health
People with psychiatric disorders and substance use disorders have 2-4 times 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
Potential health benefits of smoking?
Possibly reduces symptom severity in schizophrenia (self-medication hypothesis)
There is deficient endogenous central nicotinic neurotransmission in schizophrenia, which 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 – significant health risk.
Therapeutic use of safe forms of nicotine in schizophrenia has been proposed.1
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.2
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,
Explain how tobacco dependence is a 2 part problem-physiological and behavioural
Tobacco dependence is a chronic brain disease and is a condition that requires a two-prong approach for maximal treatment effectiveness.
Prolonged tobacco use of tobacco results in tobacco dependence, which is characterized as a physiological dependence (addiction to nicotine) and behavioral habit of using tobacco. Addiction can be treated with FDA-approved medications for smoking cessation, and the behavioral habit can be treated through behavior change programs, such as individualized counseling and group or online cessation programs.
The Clinical Practice Guideline for treating tobacco use and dependence (Fiore et al., 2000), which summarizes more than 6,000 published articles, advocates the combination of behavioral counseling with pharmacotherapy in treating patients who smoke.
