Psychopharmacology Week 6: Nicotine

Psychopharmacology of Addictive Behaviour - Week 6: Nicotine

Nicotine: A chemical compound (shown as a diagram). The only natural source of nicotine is tobacco ( Nicotiana rustica and Nicotiana tabacum).
Tobacco preparation: Leaves are harvested and dried; different processing methods produce smoking tobacco, chewing tobacco, tobacco snuff, and smokeless tobacco.
History of tobacco and nicotine: Indigenous people of North and South America were the first to use tobacco. Columbus introduced it to Europeans in 1492. Jean Nicot sent tobacco to Paris in 1560, which led to it being seen as a cure for various diseases. King James I launched an anti-smoking campaign in 1604. John Rolfe established tobacco production in Virginia, making it a crucial English colony. Nicotine was extracted from tobacco in 1828. Cigarettes gained popularity, particularly among women in France during the 1840s. WWI and WWII saw a surge in cigarette use, with increased tobacco company marketing. The 1950s marked a growing awareness of health risks, leading to the promotion of lower tar and filtered cigarettes. The 1964 U.S. Surgeon General's Report linked smoking to cancer; health warnings were added to cigarette packets in 1966. In 1971, cigarette advertising was removed from U.S. TV. The 1980s and 1990s saw the strong competition between big tobacco products like Marlboro and Coca-Cola. Electronic nicotine delivery systems (ENDS) emerged in recent times (2020s)

Administration, Absorption, Distribution & Excretion of Nicotine

Oral Administration (chewing tobacco/snuff): Nicotine is absorbed through mouth membranes (cheek and tongue). Swallowing is less frequent. It is not readily absorbed via digestion. Nicotine is rapidly metabolized in the liver during first-pass metabolism, often leading to vomiting as a body defence against poisoning. Nicotine levels fluctuate during chewing.
Inhalation (smoking): Approximately 90% of nicotine is absorbed from smoke and ash particles into the lungs. This results in fast absorption into the heart and then the brain. Peak concentrations are reached within 15 seconds and maximum within a minute. Duration of absorption depends on smoking habits more so than total volume of smoke inhaled.
Inhalation (snuff): Nicotine is primarily absorbed through nasal membranes. Smoking patterns are highly similar.
Transdermal (patches): Patches result in slow build-up of nicotine and maintain constant levels over hours.
Distribution: Nicotine reaches the brain rapidly (15-30 minutes), concentrating in the liver, kidneys, and salivary glands. It crosses many barriers and is found in sweat, saliva, breast milk, and the placenta.
Excretion: The amount of nicotine excreted through urine correlates directly with urine acidity. The liver is the main site of nicotine metabolism.
Metabolites: Cotinine (approx 80%) is a major metabolite and Nicotine-1-N-oxide are among the metabolic products. Different genes that influence CYP1A2 enzyme expression affect the overall excretion rates.
Half-life: Nicotine half-life is in the range of 90-150 minutes for adults.

Effects of Nicotine

Neurophysiological: Nicotine affects cholinergic receptor sites (muscarinic and nicotinic). Low doses stimulate nicotinic receptors, while high doses block them. Nicotinic receptors are also found in the central nervous systems (PNS and CNS) and synapses in the brain that use dopamine (DA) and noradrenaline (NE), stimulating them to release these neurotransmitters. Further, Nicotine affects serotonin and beta-endorphin release. It interacts with the reticular activating system, thereby increasing alertness.
Peripheral Nervous System: Nicotine receptors are found at nerve-muscle junctions in skeletal muscles. Stimulation of these receptors can cause muscle tremors. Nicotine activates the release of adrenalin/epinephrine, impacting the sympathetic nervous system, which leads to physiological changes like increased heart rate, blood pressure, and vasoconstriction in the skin, among others.
Central Nervous System: Nicotine interacts directly with brain synapses and stimulates the release of adrenalin from various sites in the brain. It also activates the reticular activating system further influencing arousal levels. Effects in the brain stem promote an increase in respiration, while those in the midbrain trigger the reward system. The release of dopamine and norepinephrine are increased in the mesolimbic reward pathway, an area known to participate in reinforcement. Also, nicotine interacts with serotonin systems further impacting behaviours like mood and depression.
Mood & Sleep: Nicotine initially affects mood positively. However, chronic use can induce stress and lower well-being ratings. Nicotine can trigger REM sleep in cats, but the effect on human sleep is less straightforward. Sleep deprivation can affect the effect of nicotine.
Performance: Effects vary depending on whether participants are smokers or not ("withdrawal studies"). Nicotine boosts vigilance, attention, and processing speed. It partially but not wholly affects short-term memory, but it does not impact long term memory. Nicotine generally facilitates motor functions with improved reaction times. Effects on cognitive functions such as learning might depend on the timing of tasks (recall/learning).

Conditioned Responses, Tolerance and Withdrawal, Self-Administration, and Discriminative Properties

Conditioning: Nicotine's effect on behaviour is similar to that of amphetamines; it tends to slow high rates of behaviour and increase responses to low rates of behaviour. Withdrawal symptoms, when it is abruptly discontinued, include disruptions in shock-avoidance behaviours. Catecholamine release impacts those responses.
Tolerance: Tolerance develops to the initial nausea induced by nicotine due to its action on the vomit center in the brain. Withdrawal symptoms often peak around one week after cessation. Many factors influence its severity including prior duration, attempts to quit, age, gender, and other substances like caffeine.
Self-Administration: While some animals do not self-administer nicotine, monkeys do, but reinforcement depends on factors including forced consumption, paired stimuli, and schedules that enforce abstention between consumption.
Discriminative Properties: Nicotine (0.2 mg/kg dose in animals) is successfully discriminated from other stimulants like adreanaline, pentobarbital, and caffeine. The effect is not fully generalized to amphetamines or cocaine, although partially observed. Alcohol can block nicotine perception in rats, but humans can still discern nicotine doses in identical cigarettes or nasal sprays.

Harmful Effects of Nicotine

Heart Disease: Nicotine increases the workload on the heart. Combined with carbon monoxide's effect of reducing blood oxygen carrying capacity and an increased need for oxygen, this creates increased workload and strain on the heart. Consequently, a risk of atherosclerosis arises.
Lung Diseases: Smoking damages the cilia and phagocytes in the lungs. This diminishes their ability to remove irritants like ash and tar, leading to increased susceptibility to lung diseases such as bronchitis and emphysema. Further, infections, including bacterial and viral forms, are more easily acquired.
Cancer: Smoking increases the risk of cancers in the mouth, nasal and sinus areas, lungs, kidneys, bladder, and stomach. Exposure to asbestos (or other carcinogenic elements) may further increase risk. Cessation of smoking can reduce risk.
Reproduction: Nicotine is associated with fertility issues in both men and women, increases the likelihood of birth defects, premature birth, low birth weights, and spontaneous abortions.
Passive Smoke: Secondhand smoke is another source of carcinogenic exposure, with a disproportionately high concentration found in side-stream smoke (from the end result of a cigarette or a smoke). It causes increased risk for lung cancer, and various other lung and respiratory issues; also nasal cancers, bronchitis, pneumonia, and SIDS (sudden infant death syndrome), and some tumors.

Treatment

Nicotine Replacement Therapy (NRT): Several different forms (patches, gum, nasal spray) are available, and are often associated with improved success rates among smokers attempting cessation.
Pharmacotherapies: Medications like Bupropion, Varenicline are also used alongside NRT to aid in quitting smoking.
Nicotine Vaccination: This area remains promising as a potential new treatment for those wishing to quit.