Nicotine

history of nicotine

originated in the Americas and spread across the world

been in use for thousands of years

medicinal uses

disinfection, teeth whitener, local pain relief

nicotine use in the US

widespread use that peaked in the 1950s

use has been declining due to adverse health effects and laws

• 20% of American have smoked in the past month

• of them, 60% smoke daily (addiction)

• of them 40% smoke > 1 packs per day

huge causal factor of death

adverse health consequences of smoking

linked to many different chronic diseases and cancers

• women have lower risk of cancer

health consequences persist at lower incidence even after quitting

women’s consequences have lagged men’s due to later timeline for social acceptance

HUGE financial cost to society

overall diminished health

adverse effects of second hand smoke

causally linked to many adverse health effects with a large financial cost

living with someone who smokes > 2 packs a day is the equivalent to you smoking 3 cigarettes a day

other reasons why nicotine is a carcinogen

there are many other chemicals found in cigarettes that are carcinogens

alternative delivery systems

e-cigarettes and waterpipes

is it harm reduction through filtering or a gateway to nicotine dependence

flavored vapes are banned due to this concern about gateway

how does nicotine poisoning occur

most common poisoning in young children is via eating cigarettes or liquid nicotine

most common poisoning in adolescents and adults is vaping and liquid nicotine

nicotine poisoning symptoms

early: nausea, vomiting, tremor, anxiety, tachycardia, hypertension, tachypnea

later: hypotension, bradycardia, hypopnuea

severe: respiratory failure

adult LD₅₀: ~0.5-1 mg/kg

child LD₅₀: 0.1 mg/kg

absorption of nicotine

cigarettes provide rapid absorption compared to oral absorption (snuff, snus, nicotine gum, chewing tobacco)

oral absorption is pH dependent with alkaline nicotine absorbed quicker

smoked nicotine concentrations

increase rapidly and decrease quickly (short half-life)

individuals titrate their concentration via recurrent use

blood carbon monoxide concentrations

carboxyhemoglobin levels follow the trends of nicotine levels as it measures the level of burned material

this level is higher than the OSHA permissible amount

metabolism of nicotine

nicotine is metabolized to cotinine which can remian in the blood for days and the hair for months

cotinine is used to monitor nicotine use

features of tobacco use disorder

positive effects:

• increased arousal, attention, learning, reaction time, problem solving

• decreased anxiety, stress, appetite

over time tolerance is built to the nausea

withdrawal: craving, irritability, depressed, insomnia, hunger, anxiety, difficulty concentrating

associated diseases: lung and cervical cancer

giving up social activites to smoke

rare failure to fulfill obligations

patterns of smoking

regular smokers:

• show escalation of use and increasing craving

chippers:

• show low (1-5 cigarettes per day) but constant use, show no withdrawal, often only smoke in certain situations, and lower craving

converted chippers: show an erratic pattern of use and several quit

craving among regular smokers

many have morning cigarettes, smoke at night, and can’t quit

length of nicotine withdrawal

weeks (especially the craving)

both emotional and somatic signs can last for weeks

boundary model of tobacco use

users have a minimum intake due to withdrawal and maximum intake due to aversive effects

in the middle it depends on the day-to-day

alcohol and nicotine addiction

alcohol and nicotine addiction has a high coincidence

structure of nAChR relative to nicotine

widelty expressed in CNS pre and postsynaptic channels

nicotine activates at alpha2, 4, and 7 subunits and can bind at clockwise alpha to beta interfaces

exhibit rapid desensitization depending on the subunit composition

• chronic desensitization induces up regulation

5 subunits form homopentameric and heteropentameric receptors

• important are alpha₇, and alpha₄-beta₂ type 

effects of nAChR activation

cys-loop family cation conducting LGIC (Na⁺, K⁺, Ca²⁺)

causes cation entry → depolarization → Na⁺_VG channel opening

presynaptic Ca²⁺ influx increases neurotransmitter release

postsynaptic Ca²⁺ influx alters gene expression via Ca²⁺ mediated kinase II (CAMKII)

why doesn’t acetylcholine activation of nAChRs cause desensitization

it is rapidly broken down by acetylcholinesterase in the synapse leading to a transient pulsatile effect that doesn’t trigger desensitization

proof of nicotines rewarding and reinforcing effects

• decreased ICSS threshold

• typical rewarding self-administration dose-response curve

• animals will administer a lot of nicotine to reach desired concentration (“load up”) and then maintain this concentration "(“settle down”)

sensitization effect of nicotine

chronic nicotine sub cutaneous administration sensitizes rats to the locomotor effects

nAChR in the reward pathway proof

nicotine infusion increases dopamine levels in the nucleus accumbens and ventral tegmental areas, shown via microdialysis

nicotine is more potent in the NAc than the VTA

less nicotine administration in 6-OH DA lesioned NAc

beta-2 subunits are shows to mediate self-administration as it is lost in knock-outs

neurocircuitry of nAChR reward

activation of alpha₄-beta₂ receptors on DA neurons causes cation conduction (reward!)

activation of alpha₇ nAChRs in the glutamate terminal to VTA increase glutamate release causing DA activation ** and LTP at the synapse

rapid desensitization at alpha₄-beta₂ receptors cause inhibition of GABA decreasing inhibition of DA

side note: there are similar effects on serotenergic neurons in the dorsal raphe → antidepressant effects?

escalating use is spurred by:

withdrawal paired with long access

measures of spontaneous nicotine withdrawal

• higher the dose the more severe the symptoms

• increased ICSS thresholds for (~4 days): dysphoric

  • osmosis mini pump used to administer and then removed to cause withdrawal

  • behavior normalized quicker

DA and CRF in precipitated nicotine withdrawal and dependent rats

when mecamylamine (charged nAChR antagonist) is injected dopamine levels deceased

• due to the desensitization of alpha₄-beta₂ receptors

additionally corticoreleasing factor (CRF) increased indicating a stress response

• CRF_R1 antagonists decreased nicotine self-administration in acute abstinence (lessened stress)

nicotine cues for releapse

1) drug cues

2) non-contingent drug administration

3) stress

all trigger craving

nicotine and the insula

insula lesions distrupt smoking addiction

• immediately quit, did not relapse, difficulty < 3/7, no urges

correlation is significant

transcriptional effects

nicotine mediated Ca²⁺ entry has long term downstream transcription effects that are significant in chronic use

risk for tobacco addiction

CHRNA5 (alpha₅ subunit) polymorphism is associated with nicotine dependence - revealed through genome wide association studies

CHRNA5 knock-outs show an increase in nicotine administration

other genes are associated