W 6 - Nicotine Flashcards
What are the forms of nicotine?
o Smoking tobacco
• Cigars, pipes ect
o Smokeless tobacco
• Snuff, chewing tobacco ect
How is nicotiine absorbed through smoking?
o 90% absorbed through the mucuous membrane in the lungs
o Directly to the heart and reaches brain in 7 sec
o Amount absorbed is determined by:
• How a cigarette is smoked
• vol of smoke
o Some nicotine absorbed through the mouth
o NOTE: alkaline so absorbed fast through mucous membranes
o Snuff
o Most nicotine absorbed through nasal cavity membranes
o Nasal Spray
o Most similar to smoking route of administration and absorption
What is the absorption when nicotine taken orally?
• Not as good as smoking because not readily absorbed through mucous membrane
• Chewing = tobacco absorbed through mouth membranes
• Ingestion = tobacco rarely swallowed
o Poorly absorbed
o Most metabolized in liver
o Usually induces vomiting
• Nicotine Gum
o Nicotine levels rise and fall with chewing
o Peak © approx. 1/3 that of smoking
What is the absorption when Nicotine taken transdermally?
• Patches
o Slow build up of nicotine
o Constant level of nicotine maintained for hours
What is the time of distribution of nicotine, and where is it concentrated?
- Depends on route of admin and time of admin
* Nicotine leaves the brain approx. 30 min and concentrates in liver, kidneys, salivary glands and stomach
Where is nicotine found?
• Nicotine crosses most barriers and is found in sweat, saliva, breast milk and placenta
How is nicotine extreted in the kidney’s?
o Depends on pH – i.e. 30-40% excreted in pH<7
How is nicotine metabolized/excreted in liver?
o Metabolized to:
• Cotinine (~80%)
• Nicotine - `/-N-oxide
What is the half life of nicotine
- Half life ~90-150 mins in adults
* Minimal day-to-day accumulation
What does metabolism depend on?
• Metabolism depends on:
o Gender
o Smoker vs non-smoker
o Genetics (e.g. CYP2A6 gene expression)
• If there is mutation then have people who are slower at metabolizing – protective (doesn’t need to smoke as much)
What are the physiological effects of nicotine?
• ↑ Heart Rate
• ↑ Blood Pressure – narrower vessels
• Vasoconstriction in skin
o Decreased skin temperature
o Cold Touch
o Because doesn’t have good blood supply to skin – aging and wrinkles
o Decreased blushing
• Inhibits stomach secretion – over long period of time can stimulate
• Stimulates bowel activity – laxative effect
What types of receptor sites does nicotine target?
Cholinergic
What are the types of receptor sites, and what are they named after?
- Named after agonists (activates receptor)
- Muscarinic
- Nicotinic (cHChR)
What is an agonist
Naturally occurring in the body
What is muscarinic receptors stimulated and blocked by?
o Stimulated by muscarine; blocked by atropine
What are nicotinic receptors?
- Mainly ionotropic - entry and exit of ions (Na+, K+, Ca2+ ions) - allows entry into cell when it binds
o Stimulated by nicotine
o Blocked by curare (neuromuscular), mecamylamine (neuronal)
o Body regulates homeostasis but by taking nicotine disturb balance
What are the three states of nChRs
- Basal state: closed ion channel at rest; high affinity for antagonists
- Active state: open channel; low affinity for agonists and antagonists
- Desensitized state: closed channel; insensitive to agonists/antagonists
What is the effect of nicotine on receptors?
o At low doses nicotine stimulates nicotinic cholinergic receptors
o At high doses it blocks these receptors
Where are nicotinic receptors located?
PNS and CNS
Whare neurotransmitters do nicotinic receptors release when stimulated
Dopamine (DA ) and norepinephrine (NE)
What does nicotine also stimulate the release of?
o Serotonin
o Beta-endorphin
o Hormones
What is the Nucleus Accumbens
reward centre
→ General the area of the brain that is effected in addiction
What is the Mesolimbic reward pathway
• Dopamine brought to NAc from VTA (ventral tegmental area)– this connection bringing in dopaminergic neurons is mesolimbic reward pathway
What happens to dopamine in withdrawal? - In mesolimbic reward pathways?
- Dopamine goes below normal in withdrawal – cravings
* Need to take drugs to feel ‘normal’
What happens in NcA?
- Ventral Striatum processes withdrawal and motivation
* Dorsal Striatum = habit forming behaviours
What type of control is done on NcA?
- Ventral Striatum processes withdrawal and motivation
* Dorsal Striatum = habit forming behaviours
What happens in people who take drugs? What is this called?
top down control from cortex to NA is weakened
• Can understand that behavior is not good for them but continues to do it
—> Increased impulsivity
What happens to cause compulsivity in drug takers?
- Habit – pleasurable and rewarding behaviours become a habit and start being controlled by dorsal striatum
- Control of DS by cortex is weakened – start compulsivity
- Something that starts recreational can start to become compulsive
What type of ion channels are nicotinic receptors (nAChRs)?
• nAChRs are pentarmeric legand-gated ion channels consisting of different combinations of a2 – a10 and B2 – B4 subunits
What are nicotine and acetylcholine
ligands to nAChR
Where are nAChRs distributed
widely distributed in the brain including the NAc, VTA, prefrontal cortex and amygdala
What are the effects on the PNS?
- Nicotinic receptor sites located at neuromuscular junctions of striated muscles
- Nicotine stimulation = muscle tremors
- Nicotine causes release many neurotransmitters that affect the PNS, e.g. adrenaline/epinephrine (E)
What are the effects on the CNS?
• Direct effect on synapses
• Release of adrenaline from various sites (synapses and adrenal glands)
• Stimulation of reticular activating system
o All result in increased arousal
What are the neurological effects?
• Stimulation of medulla – increased respiration
• Inhibition of reflexes due to stimulation of inhibitory cells in spinal cord
• Vomiting centre also stimulated
• Release of NE and DA - & stimulation of systems that use these NTs (e.g. reward system)
o Increase in DA activity in Nacc; correlates with rated pleasure
o nAChRs with alpha2, alpha4 & beta2 subunits appear to mediate nicotine reinforcement
• Serotonin systems also affected – antidepressant action
What are the subjective effects of nicotine?
o Acute effects
• Pleasurable (by smokers)
o Chronic effects
• Stress, decreased well being ratings
What are the effects on sleep?
o I.V. nicotine – REM sleep in cats but not humans
o Withdrawal may affect sleep (increased REM)
What do the effects on performance depend on?
- Smokers vs non-smoker
- Withdrawal
What are the general effects of nicotine on performance?
• Increased speed & accuracy of vigilance, attention & information processing
o Increased short-term episodic memory, but not LTM
o Increased alerting attention accuracy (vigilance)
o Increased speed of alerting and orienting attention and working memory (N-back task RT only) – motor system
• Faster motor reaction time – e.g. finger tapping speed; faster RT on N-back task
What are the effects on cognitive functioning?
• Effects of smoking similar to arousal – thus effect on learning
• Immediate recall impaired, but later recall improved
• Alzheimer’s disease
• Contentious area of research: many other studies show null or negative effects of nicotine on cog function
Animal Studies
What were the findings of SMA in rats?
• SMA in rats usually depressed initially, but increased after 7 days
o Initial decrease SMA due to increased Ach – then tolerance
o Increased adrenalin produces SMA similar to amphetamines
What are the conditioned responses to nicotine?
• Nicotine and amphetamine effects on conditioned behavior are similar:
o Nicotine seems to slow high rates of behavior and increase low rates of behavior
o Does not increase punished responses
o Withdrawal can disrupt shock-avoidance behavior
What may the conditioned responses be due to?
catecholamine release associated with nicotine, though nAChRs important (effects blocked by mecamylamine)
What is the self-administration in animals
• Most animals do not self-administer nicotine
• Monkey research
• Reinforcement depends on:
o Forces consumption
o Paired stimuli
o Reinforcement schedules which impose abstinence between administration
• Nicotine can also serve as a punisher
What is the self-administration in humans?
- Reinforcing in humans
* Self-administration is less frequent with higher doses and more frequent with lower doses
What are the theories of self-administration in humans?
- Maintain constant nicotine level – not true as doesn’t remain constant
- Trying to achieve high doses (bolus)
- Situation & expectations
- Dual reinforcement model
a. MOST LIKELY EXPLANATION
b. States that you have neurological and social cues which causes individual to engage in behavior
What are the discriminitive properties of nicotine?
• 0.2 mg/kg can be successfully discriminated – does not generalize to adrenalin, pentobarbital, caffeine
Do the effects generalise?
• May partially generalize to amphetamines & cocaine
o Suggested to involve cortex more so than reinforcement systems
• Low doses of ethanol can block nicotine discrimination in rats but not humans; caffeine potentiates nicotine discrimination in rats
• Humans can discriminate different doses in an identical cigarette; detect nicotine in nasal spray
What is the tolerance of nicotine?
• Develops to nausea produced by stimulating the vomit centre of the brain
What are the withdrawal symptoms of nicotine?
• Symptoms: Decrease HR; increased eating; decreased concentration; increased waking during sleep; cravings; anxiety; depression; aggression; depression; nervousness; headaches; nausea
When do withdrawal symptoms develop, how long do they last?
- Develop over 1st 3 days abstinence, peak – 1 wk then decrease
- Most symptoms disappear > 1 month; cravings may persist & triggered by cue exposure
What regulates the severity of withdrawal?
• Severity not related to dose, length of smoking, previous attempts to quite, age, gender, alcohol or caffeine
Fast metabolizers; more severe withdrawal
What is the treatment for nicotine addiction?
• 2/3 adult smokers want to quit; only 1/10 attempters succeed • Nicotine replacement therapy o Patches o Gum o Nasal spray • Pharmacotherapies o Buproprion (Zyban) o Varenicline (Champix0 • The future: nicotine vaccination? o TA-NIC & NicVAS clinical trials
