8. Nicotine

Nicotine

The psychoactive ingredient in tobacco (natural source)

Dried tobacco leaves

Contain 5% nicotine

Tobacco smoke

complex mixture

Tar

carries nicotine to lungs;

Cigarettes

20th century, due to new curing methods and invention of cigarette machine

U.S. tobacco use

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

3rd most widely consumed recreational drug

Nicotine

Tobacco use kills

9 million/year

Smoking / vaporizing ("vaping")

- Nicotine carried on tar or other particles

- Absorbed via lungs

- Provides highest blood nicotine

Nicotine by mouth (chew, dip, snus)

Absorbed by membranes in mouth

Nicotine by nose (snuff)

Absorbed by membranes in nose

Teens are more likely to use

e-cigarettes than cigarettes

Electronic nicotine delivery systems (ENDS)

Are electronic devices that vaporize

Smoking/vaping

gives fast onset and short duration.

Smoking/vaping causes nicotine to hit brain very fast:

7 seconds

Nicotine is mostly metabolized into

cotinine by acytochrome P450 enzyme

Half-life of nicotine averages

At 2 hours but varies among individuals.

People with reduced nicotine metabolism

Are less likely to become smokers

Nicotine is an agonist at nicotinic acetylcholine receptors (nAChRs), which are ionotropic receptors found in the:

- Brain and spinal cord

- Autonomic nervous system

- (neuromuscular junction, NMJ)

Nicotine effects on arousal

- Stimulant

- misidentify IV nicotine as cocaine

- see cross-substitution with cocaine

Nicotine enhances locomotor activity in animals

This effect shows sensitization

Acetylcholine (ACh)

Is implicated in cortical function related to sustained attention and memory

Nicotine can enhance

performance of attention-demanding tasks

Rat studies also show

enhanced performance on cognitive tasks with nicotine

Nicotine effects on mood

- Relaxing, alleviates stress, helps concentration...

But this has been hypothesized to be partially associated with relief from withdrawal

- smoke denicotinized cigarettes

A high dose of nicotine

Produces unpleasant symptoms. Largely due to autonomic actions of nicotine. But strong tolerance to these actions.

Lethal dose of nicotine (rare) -

kills through depolarization block of muscles involved in respiration

Withdrawal symptoms from nicotine are

opposite to acute drug effects

Regular smokers feel

irritability, stress, difficulty concentrating when they don't smoke

Nicotine tolerance- Acute tolerance

develops over the course of the day -- due to desensitization of nicotinic receptors (nAChR)

Nicotine tolerance- Chronic tolerance

lasts long after smoking cessation

Nicotine tolerance- Pharmacodynamic tolerance:

nAChRs have decreased function

Smoking during pregnancy causes

low birthweight

Half of all lifetime smokers

die prematurely

Negative effects of chronic use

Increased risk for lung diseases, but also cardiovascular diseases and cognitive deficits.

ACh: Synthesis

The precursor for acetylcholine (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 neurons in multiple brain systems, including:

- Striatum

- Basal forebrain

- Dorsolateral pons

ACh: Synaptic transmission

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

Receptor agonists

- Muscarine

- Nicotine

mAChR antagonists

Post-surgery nausea and vomiting, motion sickness, and seasickness

Drugs affecting ACh release

Botulinum toxin (Botox®)

• Blocks ACh release

Black widow spider venom

• Causes massive ACh release

AChE blockers

- Physostigmine (reversible)

- Nerve gases, insecticides (irreversible)

AChE blockers used to treat

- myasthenia gravis

- Synthetic analogs of physostigmine

Muscarinic ACh receptors (mAChRs)

Metabotropic (GPCRs)

Nicotinic ACh receptors (nAChRs)

Ionotropic (ion channels)

Muscarinic ACh receptors

- (M1-M5)

- Gq or Gi

Nicotinic ACh receptors- Pentameric (5 subunits) ligand-gated cation channel

In brain and muscle

Brain nAChRs

Consist of 2 α subunits and 3 β subunits (e.g., 2α4/3β2)or 5 α subunits.

- higher affinity

Muscle nAChRs

2 ACh binding sites

Nicotinic ACh receptors

Cation channel

Postsynaptic

rapid depolarization (EPSPs), whichcan increase neuronal firing or contract muscle

Presynaptic (axon terminal):

enhance release of neurotransmitters

Desensensitization:

nAChRs desensitize with continuous exposure to agonist (the channel closes); this is reversible. Causes acute tolerance to nicotine

Nicotine reinforcement in animals

Nicotine is self-administered by animals.

4Nicotine increases firing activity ofDA cells in VTA..

and causes more DA release at terminals in nucleus accumbens

α4β2-containing receptors

involved in rewarding effects of nicotine

α7-containing receptors

involved in cognitive (attention) effects of nicotine

Nicotine reinforcement: Contribution of α4β2 nAChRs in humans

Smoking occupancy of α4β2 nAChRs

Nicotine reinforcement: Contribution of α4β2 nAChRs in mice

IV nicotine self-administration impaired in mutant mice with genetic knockout of either α4, α6, or β2 but not α7

Nicotine effects on attention: Contribution of α7 nAChRs

α7-containing receptors are important for nicotine effects on attention

Menthol effects on nicotine

- Menthol intensifies nicotine withdrawal symptoms

- Menthol increases α4β2 nAChRs (even without nicotine)

Quitting smoking

- 70-75% like to quit

- 40-45% attempt to quit

- < 10% of attempts are successful

Treatment options

psychological (cue-induced craving) and pharmacological (dependence)

Nicotine replacement therapy (NRT)

helps with dependence/withdrawal

Other therapies target withdrawal AND craving

Buproprion: weak nAChR antagonist

Varenicline: - partial agonist at α4/β2

Most effective treatment