Chapter 13: Nicotine and Caffeine

Vaping

main difference between smoking and vaping: how the nicotine is delivered

burning end of cigarette reaches temperatures of up to 900 degrees Celsius (creates tobacco smoke)

combustion --> generates carcinogenic chemicals

Vaping DOES NOT involve combustion: heats ingredients into a vapor

dramatically reduces release of harmful chemicals

Vaping epidemic

outbreak of lung injury associated with use of vaping: caused by vitamin E acetate

vape smoke damages DNA and reduces repair activity in lung, heart, bladder

Nicotine

alkaloid produced in the roots and concentrated in the leaves as a potent antiherbivore

typical cigarette: 10mg of nicotine

no more than 1-3mg actually reaches smoker's bloodstream

CNS stimulant effects are felt within 7-10 seconds

metabolite: cotinine (basis for urine drug screen)

Basic Pharmacology and Mechanisms of Action of Nicotine

Most nicotine is metabolized to cotinine by CYP2A6

basis for urine drug screens

half-life of nicotine: 2hrs

half-life of cotinine: 15hrs

Individual variability in CYP2A6 function

low CYP2A6 activity --> reduced nicotine metabolism

less likely to become smokers

slow breakdown of nicotine is protective against smoking

Receptors

activates nicotinic cholinergic receptors (nAChRs)

ionotropic receptors (pentamers)

alpha4beta2 receptors are rare (very highly expressed on DA neurons in the VTA) --> rewarding effects

KO mice lacking alpha4 or beta2 subunit DO NOT self admin nicotine

High doses of nicotine --> persistent activation of nicotinic receptors

continuous depolarization of postsynaptic cell --> depolarization block

cell cannot fire again until nicotine is removed

biphasic effect: begins with stimulation --> turns to blockade

toxicity at high levels of nicotine

Behavioral and Physiological Effects of Nicotine

Effects

Effects on smokers

produces a calm, relaxed state

partly as relief from nicotine withdrawal symptoms

Effects on nonsmokers

heightened tension or arousal, light-headedness, dizziness, nausea

tolerance with repeated use (receptor desensitization)

Nicotine enhances working memory and attention

rats given nicotine show improvement on the 5-CSRTT

improved performance with acute AND chronic nicotine admin

poorer performance during withdrawal from chronic nicotine

nonsmokers given nicotine show enhanced performance on many kinds of cognitive and motor tasks

nicotine withdrawal: restlessness, irritability, increased appetite, insomnia, difficulty concentrating

Do different nAChRs have a role in attentional performance?

a7 subunit antagonist dose-dependently blocks influence of nicotine on omission errors

a7-containing nicotinic receptors mediate ability of nicotine to enhance attentional function

a7 agonists to improve cognitive performance

Mesolimbic DA pathway: key role in reinforcement

6-OHDA lesions in NAcc BLOCK nicotine self admin

nAChR antagonists in VTA block self admin

DA receptor antagonists in NAcc block self admin

IP Nicotine --> doubling of firing rate of VTA DA neurons and enhanced DA release in NAcc

Rats inhaling tobacco smoke

TS stimulates DA neurons

Mecamylamine (nAChR antagonist) blocks effects of TS

Tobacco smoke: contains other compounds that inhibit MAO A and B in brain and other organs

MAO inhibition --> reinforcing effects of smoking

Nicotinic receptors: abundant in the autonomic ganglia

Smoking activates BOTH sympathetic and parasympathetic systems and adrenal medulla

Parasympathetic activation: most pronounced effects in stomach --> increases HCL secretion and increased bowel contraction

Sympathetic activation leads to physiological arousal: tachycardia and elevated blood pressure

Adrenal medulla: catecholamine secretion

Accidental poisoning from swallowing, contact with tobacco in the field, insecticides that contain nicotine

Symptoms: nausea, excessive salivation, vomiting, diarrhea, mental confusion, cold sweat

untreated fatal dose: respiratory failure due to depolarization block of diaphragm

Self Admin Studies of Nicotine

Difficulties with nicotine self admin

nicotine on its own is reinforcing only in the right dose

high doses are aversive because of side effects

self admin is not as strong as opioids or psychomotor stimulants

reinforcement by smoking is more than just the delivery of nicotine (secondary reinforcers)

Aversive effects of nicotine: mediated by alpha5 subunit

alpha5 KO mice administer successively greater amounts of nicotine as the dose per infusion increases

WT mice plateau at a relatively low level of intake because of the aversive effects of nicotine at high doses

Tolerance of Nicotine

Acute tolerance

cigarette smokers undergo acute tolerance during the course of the day

related to desensitization of nicotinic receptors

desensitization of VTA DA neurons to continuous nicotine exposure

remove nicotine (during sleep) --> resensitization

24-hour period: regular smoker undergoes repeated elevations and drops in plasma nicotine levels

early in the day: mood may be elevated above baseline level

later peaks in nicotine may be only enough to maintain neutral mood (avoid withdrawal symptoms)

nAChRs resensitize significantly overnight --> allows cycle to repeat every day

Chronic tolerance

Withdrawal symptoms when pump runs out of nicotine or if a nicotinic receptor antagonist (mecamylamine) is given

brain reward function is reduced during nicotine withdrawal

increased threshold for ICSS

may be present during tobacco withdrawal in humans

withdrawal symptoms mediated by reduced DA activity in NAcc and increased CRF in amygdala

Cigarette Smoking and Vaping

Nicotine-dependent people: brief abstinence (few hours) --> craving

correlates with a drop in blood nicotine levels

withdrawal is relatively short

most symptoms are gone by four weeks

not just nicotine abstinence syndrome that makes it hard to quit

SECONDARY REINFORCERS: Sensory stimuli associated with the act of smoking become conditioned to the reinforcing effects of nicotine

Nicotine replacement therapy

relieves withdrawal symptoms

delivered in safer ways than smoking (gum, lozenge, patch)

Bupropion: initially developed as an antidepressant

DA and NE reuptake inhibitor (NDRI): may also stimulate DA and NE release)

weak antagonist at nAChRs

similar structure to stimulants

reduces cravings and withdrawal

Varenicline (Chantix)

partial agonist at high-affinity alpha4beta2 nicotinic receptors in the VTA and other brain areas

moderate amount of receptor activation

reduces nicotine cravings and adverse withdrawal symptoms

more effective than buproprion

Caffeine

consumed orally

completely absorbed from GI tract in 30-60 minutes

converted to a variety of metabolites by the liver (CYP1A2)

95% are eliminated through the urine

average plasma half-life: 4hrs

Behavioral and physiological effects

In lab animals --> biphasic effects

low doses --> stimulant

high doses --> reduced activity

In humans

low doses --> positive subjective effects

feelings of well-being, increased energy, increased alertness, enhanced sociability

high doses --> anxiogenic

Cognitive effects

Autonomic effects: increased blood pressure and heart rate, increased urine output

chronic caffeine use --> tolerance

Can produce a mild form of dependence

Caffeine withdrawal: sleepiness, headache, irritability, intense craving

relief from withdrawal is a major factor in chronic coffee drinking

Acute caffeine

increased blood pressure and respiration rate

enhanced water excretion (diuresis)

most evident in non-regular caffeine drinkers

Caffeinism: 1000mg+ per day

restlessness, nervousness, insomnia, tachycardia, GI upset

difficult to distinguish from a primary anxiety disorder

individuals experience very strong withdrawal symptoms and craving when usage is reduced

Therapeutic uses

potentiates analgesic properties of aspirin and acetaminophen

included in some OTC pain medications

effective in treatment of apnea in premature newborns: regularizes breathing

Mechanisms of Action of caffeine

does not directly influence catecholamine systems

Caffeine's biochemical effects

inhibition of PDE

blocks GABAA receptors

Stimulates Ca++ release within cells

Blockade of A1 and A2A receptors

only partial blockade of A1 and A2A adenosine receptors has effects that operate at doses found in a cup of coffee --> mild stimulant effects

Adenosine

in the brain, has NT like function

modulator in inducing drowsiness and sleep

stimulant properties of caffeine depend on antagonism of adenosine receptors in the brain, especially the striatum

Caffeine and DA: caffeine removes the "brake" on DA signaling that is normally mediated by adenosine

striatum expresses high levels of A2A receptors

adenosine inhibits D2R signaling

coexpressed with postsynaptic D2 receptors

in striatal neurons, A2AR agonists decrease D2R agonist binding

caffeine-induced increased in locomotor activity and arousal are absent in A2A R KO mice

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