What is the pathophysiology of nicotine addiction?

Updated: Jul 16, 2018
  • Author: R Gregory Lande, DO, FACN; Chief Editor: Glen L Xiong, MD  more...
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Nicotine exerts its neurophysiologic action principally through the brain’s reward center. This neuroanatomic complex, otherwise known as the mesolimbic dopamine system, stretches from the ventral tegmental area to the basal forebrain. The nucleus accumbens, a dopamine-rich area, is an intersection where all addictive behaviors meet. The release of dopamine at this site promotes pleasure and reinforces the associated behaviors, such as the use of alcohol and drugs, to replicate the positive experience.

Other factors may also promote nicotine dependence, such as nicotine’s reduction in the monoamine oxidase inhibitor enzyme. This enzyme is involved in the metabolism of catecholamines, including dopamine. The net effect would be a lingering presence of the stimulating dopamine at the nucleus accumbens. [7]

A closer inspection of nicotine’s neurophysiology reveals a much more complex system. In particular, researchers continue to study the brain’s neuronal nicotinic acetylcholine receptors (nAChRs).The nAChRs play a central role in nicotine’s widespread influence on brain chemistry.

Researchers have identified several nAChR subtypes, broadly classified in terms of alpha and beta subunits; the alpha-4 and beta-2 subunits are the most widely expressed in the brain. Acting through the nAChRs, nicotine influences glutamate, gamma-aminobutyric acid (GABA), acetylcholine, dopamine, norepinephrine, and serotonin. [8]

Nicotine also releases corticosteroids and endorphins that act on various receptors in the brain. Nicotine use results in more efficient processing of information and reduction of fatigue. In addition, nicotine has a sedative action, reduces anxiety, and induces euphoria. Nicotine effects are related to absolute blood levels and to the rate of increase in drug concentration at receptors.

Nicotine stimulates the hypothalamic-pituitary axis; this, in turn, stimulates the endocrine system. Continually increasing dose levels of nicotine are necessary to maintain the stimulating effects. With regards to dependence, some experts rank nicotine ahead of alcohol, cocaine, and heroin. A teenager who smokes as few as 4 cigarettes might develop a lifelong addiction to nicotine.

Small, rapid doses of nicotine produce alertness and arousal, as opposed to long-drawn-out doses, which induce relaxation and sedation. Nicotine has a pronounced effect on the major stress hormones. It stimulates hypothalamic corticotropin-releasing factor (CRF), and it increases levels of endorphins, adrenocorticotropic hormone (ACTH), and arginine vasopressin in a dose-related manner. Corticosteroids also are released in proportion to plasma nicotine concentration.

Nicotine alters the bioavailability of dopamine and serotonin and causes a sharp increase in heart rate and blood pressure. It acts on brain reward mechanisms, both indirectly (through endogenous opioid activity) and directly (through dopamine pathways).

A cigarette delivers 1.2-2.9 mg of nicotine, and the typical 1 pack–per-day smoker absorbs 20-40 mg of nicotine each day, raising the plasma concentrations to between 23-35 ng/mL. Nicotine addiction results from positive reinforcement (with the administration of nicotine) and withdrawal symptoms that start within a few hours of the last cigarette.

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