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Chapter 13: Nicotine and Caffeine - Coggle Diagram
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
nicotine withdrawal: restlessness, irritability, increased appetite, insomnia, difficulty concentrating
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
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
Tobacco smoke: contains other compounds that inhibit MAO A and B in brain and other organs
MAO inhibition --> reinforcing effects of smoking
Mecamylamine (nAChR antagonist) blocks effects of TS
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
coexpressed with postsynaptic D2 receptors
adenosine inhibits D2R signaling
in striatal neurons, A2AR agonists decrease D2R agonist binding
caffeine-induced increased in locomotor activity and arousal are absent in A2A R KO mice