DBM - Chapter 13 - Nicotine, Caffeine, and Kratom

short-term vaping effects

pulmonary: increased flow resistance and reactivity

cardiovascular: increased heart rate, blood pressure, aortic stiffness

long-term vaping effects

pulmonary: higher airway resistance, airway obstruction and inflammation, COPD, chronic bronchitis, asthma

cardiovascular: increased atherosclerosis and aortic stiffness

nicotine metabolism

most (75%) metabolized to cotinine by CYP2A6

• half-life of nicotine: 2 hrs

• half-life of cotinine: 20 hrs

CYP2A6 expression increased by estrogen, inhibited by menthol

CYP2A6

main metabolic enzyme for nicotine

expression increased by estrogen, inhibited by menthol

individual variability:

• low CYP2A6 » reduced nicotine metabolism » less likely to become smoker

• slow breakdown of nicotine is protective against smoking

nicotine receptors

nicotinic cholinergic receptors (nAChRs)

⍺4β2 receptors » highly expressed on DA neurons in the VTA

• KO mice for ⍺4 or β2 subunit do not self-admin nicotine

depolarization block

high doses of nicotine » persistent activation of nAChRs

continuous depolarization » depolarization block » cannot fire again until the nicotine is removed

biphasic effect of nicotine

begins with stimulation » turns to blockade (depolarization block)

mechanism of toxicity at high levels of nicotine

nicotine effect on smokers

produces calm or relaxed state (partly relief from withdrawal)

withdrawal symptoms: restlessness, irritability, appetite, insomnia, difficulty concentrating

nicotine effects on nonsmokers

heightened tension/arousal, light-headedness, insomnia, difficulty concentrating

tolerance developed with repeated use » receptor desensitization?

animal study findings

enhanced working memory and attention

improvements on the 5-CSRTT of attention

• improved with acute or chronic nicotine admin

• poorer performance during withdrawal from chronic nicotine

non-smokers given nicotine showed enhanced performance on cognitive/motor tasks

⍺7 subunit

⍺7 antagonist (MLA) blocks nicotine’s effect on omission errors

• ⍺7-containing nAChRs mediate ability to enhance attention

• ⍺7 agonists to improve cognitive performance?

“low-attention” nicotine enhancement

subjects divided into “low” and “high” baseline attention performance » tested on ability to detect and correctly identify brief visual stimulus

received transdermal nicotine patch prior to testing » enhancement shown only if in low-baseline attention

mesolimbic DA pathway

plays key role in reinforcement

• 6-OHDA lesions in NAcc, nAChR antagonists in VTA, DA antagonists in NAcc » block nicotine self-admin

nicotine » doubling of firing rates in VTA DA neurons, enhanced DA release in NAcc

MAO and nicotine

tobacco smoke » contains compounds that inhibit MAO-A and MAO-B in brain and other organs

inhibition contribute to reinforcing effects of smoking?

sympathetic activation

activated by nicotine

produces tachycardia, elevated blood pressure

parasympathetic activation

activated by nicotine

most pronounced in stomach » increased HCl secretion and increased bowel contractility

adrenal medulla

activated by nicotine

increases catecholamine secretion

nicotine poisoning

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

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

nicotine self-administration

reinforcing at the right dose, high doses are aversive because of side effects

self-admin not as strong as opioids or psychomotor stimulants

reinforcement by smoking more than just delivery of nicotine

aversive effects of nicotine

mediated by ⍺5-nAChR subunit » highly expressed in interpenduncular nucleus

• KO mice administer successively greater amounts

• WT mice plateau at relatively low intake because of aversive effects

acute nicotine tolerance

cigarette smokers undergo over the course of a day

related to desensitization of nAChRs

24 hour period:

• repeated elevations and drops in nicotine levels

• early in the day, mood elevated above baseline

• later peaks only enough to maintain neutral mood

• nAChRs re-sensitize overnight » cycle repeats

tolerance and dependence in animals

withdrawal if pump runs out of nicotine or if nAChR antagonist (mecamylamine) given

brain reward function reduced during withdrawal

• increased threshold for ICSS

• reduced DA activity in NAcc and increased CRF in amygdala

nicotine replacement therapy (NRT)

relieves withdrawal symptoms

delivered in safer ways compared to smoking

increases likelihood of quitting smoking by 50-60% compared to placebo/no intervention

bupropion (Wellbutrin Zyban)

initially developed as antidepressant » DA and NE reuptake inhibitor (NDRI)

similar in structure to stimulants

reduces cravings and withdrawal symptoms

varenicline (Chantix)

partial agonist of ⍺4β2 nicotinic receptors » moderate activation

reduces nicotine cravings and withdrawal symptoms

more effective than buproprion

caffeine metabolism

converted to metabolites in the liver via CYP1A2

• paraxanthine (CNS stimulant) » metabolites excreted through urine (95%)

average plasma half-life about 4 hours (variable)

laboratory animal effects of caffeine

biphasic effects

low doses » stimulant effects

high doses » reduced activity

human effects of caffeine

low doses in humans » positive subjective effects

• well-being, increased energy, alertness, sociability

high doses in humans » anxiogenic

• people with panic disorder hypersensitive to anxiogenic effects

physiological effects of caffeine

cognitive effects

autonomic: increased blood pressure, heart rate, increased urine output

• chronic caffeine usage » tolerance, mild dependence

caffeine withdrawal

sleepiness, headache, irritability

intense craving

relief from withdrawal »> major factor in chronic coffee drinking

caffeine intoxication

consumption of high doses of caffeine » restlessness, nervousness, insomnia, tachycardia, muscle twitching, GI upset

• difficult to distinguish from primary anxiety disorder

• extremely high doses (3-5g) can produce severe toxicity or death

caffeine use disorder

1. difficulty reducing caffeine use

2. continued use despite knowledge of effects

3. withdrawal symptoms upon abstinence

therapeutic uses of caffeine

potentiates analgesic properties of aspirin and acetaminophen

• included in some OTC pain meds

effective in regularizing breathing in premies with apnea

epidemiological effects of coffee

3-5 cups of coffee/day » reduces vulnerability to obesity, type 2 diabetes, cirrhosis, cancer, Parkinson’s, and age-related dementia

mainly attributed to antioxidant and anti-inflammatory substances

biochemical effects of caffeine

inhibition of cAMP phosphodiesterase (PDE)

blocks GABA-A receptors

stimulates Ca²⁺ release within cells

blockade of A1 and A2A adenosine receptors

adenosine

NT-like function in the brain » sleep/drowsiness modulator?

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

caffeine and DA

caffeine may remove the “brake” on DA signaling

high levels of A2A-R in striatum » co-expressed with postsynaptic D2 receptors » form A2A-D2 hetero-tetramers

adenosine allosterically inhibits D2 signaling (NAM) » in stratal neurons, A2A agonists decrease D2 agonist binding » decrease DA affinity for its receptor

caffeine-induced increases in locomotor activity and arousal absent in A2A KO mice

kratom

tree in coffee family » mitragynine and 7-hydroxymitragynine

low doses » stimulant

high doses » sedative or narcotic

used to self-treat conditions such as pain, cough, diarrhea, anxiety, depression, opioid use disorder, opioid withdrawal

kratom method of action

bind to µ-opioid receptors AND act on NTs (5-HT, DA, NE, kappa opioid receptors)

structures do not resemble typical opioid like morphine