Nicotine brain levels

Inhaled nicotine is efficiently delivered to the brain (see chapter by Benowitz, this volume) where it selectively interacts with its central targets, the neuronal nicotinic acetylcholine receptors (nAChRs). The multiple subtypes of uAChR (see chapter by Collins et al, this volume) all bind nicotine but with different affinities, depending on the subunit composition of the uAChR. Binding may result in activation or desensitisation of uAChRs, reflecting the temporal characteristics of nicotine dehvery and local concentration of nicotine. Another level of complexity of the actions of nicotine reflects the widespread and non-uniform distribution of uAChR subtypes within the brain, such that nicotine can influence many centrally regulated functions in addition to the reward systems. In this chapter, we address the consequences of nicotine interactions with nAChRs at the molecular, cellular and anatomical levels. We critically evaluate experimental approaches, with respect to their relevance to human smoking, and contrast the acute and chronic effects of nicotine. 

In the late 1990s, a new approach to nicotine addiction was introduced. It involves the use of an antidepressant known by its generic name as bupropion. Bupropion is believed to act like nicotine in that it apparently can boost brain levels of dopamine as well as norepinephrine. Some patients have successfully terminated drug therapy after a few months with no ill effects. 

By inhalation the nicotine in tobacco smoke reaches the brain in seven seconds. Brain levels thus rise rapidly, but then they fall rapidly because nicotine is quickly distributed to other sites of action. Nicotine is metabolized primarily in the liver and eliminated mostly in urine. 

Another efficient modality for smoking cessation is bupropion.The antidepressant activity of bupropion is achieved through its effects on the levels of dopamine and norepinephrine in the brain (the effects of bupropion are mediated by blocking the reuptake of both dopamine and norepinephrine ). These effects are thought to underlie its positive results in clinical trials of patients with tobacco dependence (bupropion about doubles long-term abstinence rates compared with placebo). Increased brain levels of dopamine and norepinephrine would be expected to counteract the deficiency of these neurotransmitters during nicotine withdrawal and thereby aid in smoking cessation. 

Other claims for megadoses of nicotinic acid or nicotinamide, such as the claim that abnormalities associated with schizophrenia, Down s syndrome, hyperactivity in children, etc. can be reduced, have so far failed to win general acceptance. Clearly niacin deficiency or dependency can exacerbate some types of mental illness such as depression or dementia. There have been a number of attempts to treat depression with tryptophan or niacin, or both, on the basis that the correction of depressed brain levels of serotonin would be advantageous. However, these have met with only limited success. Schizophrenics have been treated with nicotinic acid on the basis that their synthesis of NAD is impaired in some parts of the brain, and that the formation of hallucinogenic substances such as methylated indoles may be controlled. 

Nicotine increased DA levels both in vivo11,193 and in vitro. 94 196 Nicotine197 and its metabolites198 were found to both release and inhibit the reuptake of DA in rat brain slices, with uptake inhibition occurring at a lower concentration than that required for DA release. In addition, the (-) isomer was more potent than the (+) isomer.197 However, the effects of nicotine upon DA release and uptake were only apparent when brain slices were utilized because nicotine was unable to affect DA when a synaptosomal preparation was utilized.197 These results indicate that nicotine exerts its effects upon the DAT indirectly, most likely via nicotine acetylcholine receptors. This finding was supported by the results of Yamashita et al.199 in which the effect of nicotine on DA uptake was examined in PC 12 and COS cells transfected with rat DAT cDNA. Nicotine inhibited DA uptake in PC 12 cells that possess a nicotine acetylcholine receptor. This effect was blocked by the nicotinic antagonists hexamethonium and mecamylamine. Additionally, nicotine did not influence DA uptake in COS cells, which lack nicotinic acetylcholine receptors. 

Court, J., Lloyd, S., Thomas, N. et al. Dopamine and nicotinic receptor binding and the levels of dopamine and homovanillic acid in human brain related to tobacco use. Neuroscience. 87 63, 1998. 

Some quinolizine derivatives are employed as drugs. One of them is flumequine 280, a member of the quinolone family of antibacterial agents. Cytisine 9 is a ligand of the nicotinic acetylcholine receptor that acts primarily as a cholinomimetic at the ganglionar level, being used as a respiratory stimulant in some countries. Cytisine analogues with improved ability to cross the blood-brain barrier have also been developed <1999FA438>. 

Nicotine is responsible for the highly addictive properties of tobacco products. Addiction occurs in 30% of those who experiment with tobacco products, and more than 80% of those who attempt to quit smoking will relapse within a year. Withdrawal from nicotine produces a syndrome characterized by nicotine craving as well as dysphoria, anxiety, irritability, restlessness and increased appetite. It is treated with nicotine replacement therapies, such as nicotine gum and patches, and/or with buproprion, a drug that is classified as an antidepressant but has multiple and complex effects in brain. Buproprion reduces craving in some smokers. Nicotine addiction has been reviewed recently at cellular and systems levels [38-41]. 

Nanri M, Kasahara N, Yamamoto J, Miyake H, Watanabe H. (1998). A comparative study on the effects of nicotine and GTS-21, a new nicotinic agonist, on the locomotor activity and brain monoamine level. Jpn J Pharmacol. 78(3) 385-89. 

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