low efficacy stimulants - nicotine Flashcards
what is the major psychoactive component of tobacco?
nicotine
what are routes of admin of nicotine?
Buccal (chew)
Intranasal (snuff)
Oral (Lozenge)
Transdermal (patch)
Nasal spray
Inhalation (cigarettes/ vapes) - COMMON
what are the different exposures to nicotine?
- first hand - inhaled by smoker
- second hand - exhaled by smoker or released from a burning cig
- third hand - residue that sticks to surfaces and dust after the smoke clears
which of different exposures are indirect exposure?
- second hand
- third hand
since nicotine is lipid soluble, what does it mean about absorption?
it is readily absorbed by the body through lungs, mucous membrane, skin, & less extent through GI tract
is nic administered through IV?
no
how much mg of nic is in a cigarette and how much reaches the blood stream?
in cig: 6-11 mg
in blood: 3mg
what can the smoker’s do that affects the absorption?
the user can titrate (adjust) dose of nicotine by inhaling more frequently or deeply
what is nicotine absorption dependent on?
pH - the environment that nicotine passes through changes the absorption rate
cigarette smoke is acidic, so less nic is absorbed. the pH of mouth can alter absorption nicotine
what can nicotine permeate? in how long, and where are peak levels seen?
permeates BBB
reaches brain 7-20 seconds following a puff
reaches peak levels in lungs, blood, and brain in 1o minutes
does nic reach the blood as fast as the brain?
no, it reaches brain first and there’s a slow increase in blood concentration
what affects plasma nicotine levels?
nicotine concentration in the cartridge, rate of puffing, and puff duration.
why is smoking during pregnancy bad for you?
- chemicals in cigarettes pass through placenta and reach all the organs of the developing fetus, including the brain
- prenatal exposure had long lasting effects on neurobehavioral development
what metabolizes nicotine, where does it occur, and what is the active metabolite formed?
metabolizing enzyme: CYP2A6
location: liver
metabolite: cotinine, a partial agoninst
where do we see increased CYP2A6 and what does that indicate?
it is increased in estrogen, so faster nicotine metabolized in women than men.
what inhibits CYP2A6 activity and what does it do?
methanol
it causes a slower conversion to cotinine
what is true with individuals with low CYP2A6 activity?
they have slow nic metabolism so..
- they are less likely to be smokers
- smoke less
- have greater success stopping
what is the half life of nic and cotinine?
nic: 2hr
cotinine: 16 hr
how do individuals avoid withdrawal symptoms?
they smoke repeatedly throughout the day
what are the methods of excretion of nic?
urine and breast milk
what neurotransmitter does nicotine and cotinine interact with?
acetylcholine
what occurs when nic/cotinine interact with the acetylcholine?
- neurons with cell bodies in BASAL FOREBRAIN projects to neurons in CEREBRAL CORTEX and LIMBIC SYSTEM
affects attention, learning, memory
- neurons with cell bodies in BRAINSTEM (PPN/LTD) project throughout the BRAINSTEM and CEREBELLUM
affects movement, breathing, heart rate
what is the synthesis, storage, and breakdown of the Ach system?
- choline and acetyl coA are combined by choline acetyltransferase (ChAT) to for acetylcholine
- Ach is moved into synaptic vesicles for storage by the vesicular Ach transporter (VAchT), embedded in the vesicle membrane
- The enzyme acetylcholinesterase (AChE), breaks Ach down to choline and acetate.
Choline is transported back into the cell for reuse
**There is NO reuptake transport for Ach!
Ach binds to 2 families of cholinergic receptors, what are they?
- nicotinic receptors (nAchR)
- muscarinic
what are the characteristics of the nicotinic receptors?
- many types but all of them are excitatory
- so when they are bound to, an ion channel is opended and positivelu charges cations flow into the postsynaptic neuron
what are the characteristics of the muscarinic receptors?
- G proteined coupled
- excitatory: M1, M3, M5
- inhibitory: M2, M4
what is the mechanism of nicotine at Ach nicotinic receptors?
- acts as a full agonist
- produces rapid influx of positively charged ions into the neuron, produces rapid excitatory responses
what is the mechanism of cotinine at Ach
nicotinic receptors?
- acts as a partial agonist
- activates the receptor to a lesser degree than nicotine so less excitatory responses are produced
what does high doses of nicotine lead to?
it causes persistant activation of nicotinic receptors (nAChR) and continuous depolarization of the cell.
Continous depolarization results in a DEPOLARIZATION block, so the cell cannot reset after the action potential occurs and it can’t fire again until nicotine is removed.
so instead of stimulant actions, it produces depressant actions
how does nicotine alter the activity of dopamine neurons?
it increases dopamine release in the mesolimbic pathways which accounts for its addictive properties
where does the mesolimbic pathway start and end, what role does it play in addiction, and what occurs when nicotine is present?
starts: VTA
ends: nucleus accumbens
key role: reinforcement
Binding of nicotine to High-affinity nicotinic receptors in the VTA stimulates burst firing of DA neurons, increasing DA release in the nucleus accumbens
what is seen in tobacco smoke? what does this cause
chemicals that inhibit mao which causes the dependence from chronic use
why is the mao inhibition so critical?
MAO is the enzyme that breaks down neurotransmitters like dopamine, serotonin, and NE.
This means you have a double-hit or even greater increase in mesolimbic dopamine because nicotinic receptor stimulation increases DA release, and MAO inhibition/ blockade prevents that DA signal from ending. Thus DA exists in the synapse for longer!
where are nicotinic receptors found?
CNS: hippocampus, cerebral cortex, basal ganglia, VTA & nucleus accumbens
PNS: at neuromuscular junctions
what systems does smoking activate?
sympathetic and parasympathetic systems (autonomic nervous system)
what does release of NE and EPI from adrenal glands contribute to?
the arousing effects of nicotine
in non smokers, what behavioral effects do we see after nicotine use?
arousal
anxiety
tension
lightheadedness
dizziness
nausea.
in smokers, what behavioral effects do we see after nicotine use?
- calm/relaxed state
- relief from withdrawal
mild euphoria
what are the acute effects of nicotine?
- General stimulant/ arousal effects
a. Increased heart rate and blood pressure,
alertness, appetite suppression - Carbon monoxide (in smoked form) reduces oxygen transport to heart and other organs
- Vasoconstriction
-Can have calming (anxiolytic) effects in some individuals
- Mild euphoria (relief?)
- Cognitive enhancements
- Antidepressant effects
what are the benefits of nicotine in learning, memory, and attention>
Abstinent smokers given nicotine show enhanced cognitive & motor performance
Nicotine has positive influence on cognition & motor function, even in non-smokers
in what diseases does nicotine reduce symptoms in?
- ADHD
- tourette’s
how is nicotine benefital to alzeimer’s?
- Acetylcholine neurons die in Alzheimer’s disease
- Patients showed increased capacity for learning verbal material following nicotine use
how is nicotine benefital to parkinson’s?
- Dopamine neurons die in Parkinson’s disease
- Nicotine users have lower incidence of Parkinson’s disease
- Nicotine is neuroprotective for dopamine neurons
is nicotine a scheduled drug?
nooo
what does chronic exposure to nicotine do?
induces depended and tolerance
what is true about nicotine acute tolerance?
it can occur DAILY
During the night, individual undergoes mild withdrawal symptoms. At the same time, tolerance from the previous day dissipates.
Individual wakes in the morning with strong urge to use tobacco products.
Acute Tolerance reflects desensitization of nAchR
what does chronic nicotine use do in the synapse?
causes downregulation of nAchR in the synapse
what is nicotine seen to be in terms of addictiveness?
be one of the MOST addictive drugs!
chronic uses results in tobaco use disorder
what type of dependence do we see for nicotine chronic users?
Physical dependence occurs, where body expects (and “needs”) nicotine to avoid unpleasant withdrawal effects
what does a long withdrawal from nicotine result in and is the most intense?
abstinence syndrome
what are the 3 types of symptoms associated with trying to quit?
- affective symptoms
a. anxiety, irritability, depressed mood,
anhedonia, insomnia, restlessness,
hyperalgesia. - somatic symptoms
a. tremors, bradycardia, nausea, hunger and
weight gain - cognitive symptoms
a. difficulty concentrating (attention issues) &
impaired memory
when does abstinence syndrome occur>
symptoms peak 24–48 hr after quitting and subside within 2–4 weeks.
what prevents withdrawal symptoms?
- nicotine replacement gum
- patches
what causes abstinence syndrome, from a biological perspective?
- Resensitization of the desensitized nAChRs (no more depolarization block)
- Return to normal levels of nAchR
- Nicotine withdrawal leads to hyperactivity of the habenula, a brain region that shuts down the mesolimbic dopamine system!
