Unit 8: Nicotine

Nicotine Definition

The psychoactive ingredient in tobacco (natural source)

Dried tabacco leaves contain 5% nicotine

Tar: carries nicotine to lungs

Recent history of tobacco

Cigarettes became dominant form in the 20th century due ot new curing methods and invention of cigarette machines

U.S Tobacco use

About 20% of U.S adults are current users of tobacco products

Worldwide tobacco use

Nicotine is the 3rd most widely consumed recreational drug in the world

Kills about 9 mill/year

Pharmacokinetics: Smoking

Nicotine carried on tar or other particles

Absorbed via lungs

Provides highest blood nicotine

Pharmacokinetics: By mouth

Absorbed by membranes in mouth

Pharmacokinetics: By nose

Absorbed by membranes in nose

Teen nicotine statistics

Teens are more likely to use e-cigarettes than cigarettes

Electronic Nicotine Delivery System (ENDS)

Electronic devices that vaporize flavored liquid that often contains nicotine

Speed and onset

Onset: Fast

Duration: Short

Hits the brain in 7 seconds

Nicotine Metabolism

Mostly metabolized into cotinine by a cytochrome P450 enzyme

Half life averages about 2 hours but varies among individuals

people with reduced nicotine metabolism are less likely to become smokers

Nicotine mechanisms of action

Pharmacodynamic action: Nicotine is an agonist at nicotinic aceteylcholine receptors which are ionotropic receptors found in the brain and spinal cord

• autonomic nervous system, neuromuscular junction

Nicotine effects on arousal

Nicotine is a stimulants

Misidentify IV nicotine as cocaine

see cross substitution with cocaine

nicotine enhances locomoter activity in animals, and this effect shows sensitization

Effects on cognition

ACh is implicated in cortical function related to sustained attention and memory

Nicotine can enhance performance of attention demanding tasks

Rat studies show enhanced performance on cognitive tasks with nicotine

Effects on mood

Smoke deniotinized cigs

Nicotine toxicity

A high dose of nicotine produces unpleasant symptoms

Largely due to autonomic actions of nicotine, but strong tolerance to these actions

Lethal dose (rare): kills through depolarization block of muscles involved in respiration

Dependence and withdrawal

Withdrawal symptoms are opposite to acute drug effects

Regular smokers feel irritability, stress, difficulty concentrating when they dont smoke

Acute tolerance

Develops over the course of the day, due to desensitization of nicotinic receptors (nAChR)

Chronic tolerance

Lasts long after smoking cessation

Pharmacodynamic tolerance: nAChR have decreased function

Effects of chronic use

Smoking during pregnancy causes low birthweight

Half of all lifetime smokers die prematurely

Increased risk for lung disease but also cardiovascular diseases and cognitive deficits

ACh Synthesis

The precursor of ACh is choline, a vitamin found in many foods

Choline acetyl transferase (ChAT) is the enzyme that synthesizes ACh

ACh Degradation

Acetylcholinesterase (AChE) metabolizes ACh into choline and acetic acid

ACh central actions

ACh neurons in multiple brain symptoms

Striatum: regulate responses to DA

Basal forebrain: cognition

Dorsolateral pons: arousal/sensory

ACh synaptic transmission

Packages into vesicles by vesicular acetylcholine transporter (VAChT)

ACh undergoes rapid degradation/metabolism by AChE, converting it back to choline

Choline is then taken up by the choline transporter and reused to make more ACh

Receptor agonists

Muscarine (mAChR)

Nicotine (nAChR)

mAChR antagonist

Post surgery nausea and vomiting, motion sickness, seasickness

ex. dramamine

Drugs affecting ACh release

1. Botulinum toxin: blocks ACh release

2. Black widow spider venom: causes massive ACh release

AChE blockers

Physostigmine: reversible

Nerve gases and insecticides: irreversible

used to treat myasthenia gravis, synthetic anaolgs of physostigmine

Muscarinic ACh receptots

Metabotropic (GPCR)

selective agonist muscarine found in toxic mushroom

Nicotinic ACh receptors

Ionotropic (ion channels)

named after selective agonist nicotine

Muscarinic ACh receptors

5 types: M1-M5

coupled to Gq or Gi

Nicotinic ACh receptors

Pentameric (5 subunits) ligand gated cation channel

brain and muscle

Brain nAChRs

Consists of 2 a subunits and 3 B subunits or 5 a subunits

higher affinity

Muscle nAChR

2 ACh brinding sites: both need to be bound for channel opening

Cation channel

In periphery mostly Na channel; in brain, Na and Ca

Postsynaptic nicotine ACh receptors

rapid depolarization (EPSP) which can increase neuronal firing or contract muscle

Presynaptic nicotine ACh receptors

Axon terminals, enhance release of neurotransmitters

Densensitization nicotine ACh receptors

nAChR desensitize with continuous exposure to agonist (the channel closes) that is reversible. cause acute tolerance to nicotine

Nicotine reinforcement

Nicotine increases firing activity of DA cells in VTA and causes more DA release at terminals in nucleus accumbens

a4b2 containing receptors

involved in rewarding effects on nicotine

smoking occupancy of a4b2 nAChRs

a7 containing receptors

involved in cognitive (attention) effects of nicotine

important for nicotine effects on attention

Contribution of a4b2 nAChR in animals

IV nicotine self administration impaired in mutant mice with genetic knockout of either a4, a6, b2, but not a7

Menthol effects of nicotine

Menthol intensifies nicotine withdrawal symptoms

Menthol increases a4b2 nAChrs (even without nicotine)

Quitting smoking

Like to quit: 70-75%

Attempt to quit: 40-45%

Successful attempts: <10%

conditioned cues and habits have a critical role in smoking behavior

Treatment options

Psychological (cue induced craving) and pharmacological (dependence)

nicotine replacement therapy: helps with dependence/withdrawal, most OTC

Treatment options for withdrawal and craving

Buproprion: weak nAChr antagonist

Varenicline: partial agonist at a4/b2

• most effective treatment (3x quit rate)