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Smoking is one of the leading causes of preventable death, where nicotine has been identified as the primary addictive constituent of tobacco. Consequently, there have been extensive investigations into the neuroadaptations that occur as nicotine dependence develops, where numerous neurological systems have been implicated. The focus of this review was on nicotinic acetylcholine receptor neuroadaptations that occur during the development of nicotine dependence. This focus was selected because (1) the nicotinic receptors are the primary binding sites for both nicotine and the most efficacious pharmacological smoking cessation treatments and (2) the receptors are located throughout the brain with considerable neuromodulatory ability. However, there was difficulty associated in outlining the role of nicotinic receptors in the development of nicotine dependence because it comprises a series of stages involving different neurological systems rather than a single state. To address this issue, the review adopts a novel approach and considers the role of nicotinic receptor subtypes at separate stages of the nicotine dependence cycle. This information was then used to examine the nicotinic receptor-related therapeutic mechanisms of three main pharmacological smoking cessation treatments.

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Evidence that the widely used methamphetamine analog MDMA (3,4-methylenedioxymethamphetamine, ecstasy) might damage brain serotonin neurones in humans is derived from imaging investigations showing variably decreased binding of radioligands to the serotonin transporter (SERT), a marker of serotonin neurones. However, in humans, it is not known whether low SERT binding reflects actual loss of SERT protein itself. As this question can only be answered in post-mortem brain, we measured protein levels of SERT and that of the rate-limiting serotonin-synthesizing enzyme tryptophan hydroxylase (TPH) in autopsied brain of a high-dose MDMA user. As compared with control values, SERT protein levels were markedly (-48% to -58%) reduced in striatum (caudate, putamen) and occipital cortex and less affected (-25%) in frontal and temporal cortices, whereas TPH protein was severely decreased in caudate and putamen (-68% and -95%, respectively). The magnitude of the striatal SERT protein reduction was greater than the SERT binding decrease typically reported in imaging studies. Although acknowledging limitations of a case study, these findings extend imaging data based on SERT binding and suggest that high-dose MDMA exposure could cause loss of two key protein markers of brain serotonin neurones, a finding compatible with either physical damage to serotonin neurones or downregulation of components therein.

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The novel finding of decreased activity of aconitase, a key Krebs cycle enzyme highly sensitive to oxidative damage, in cybrid cell lines using mitochondrial DNA from patients with progressive supranuclear palsy (PSP) implies an enzyme abnormality in brain. However, the authors found that postmortem brain aconitase activity is normal in PSP. This suggests that patients with PSP do not have systemic aconitase deficiency and that data derived from cybrid cell models of neurodegenerative disorders might not always predict similar changes in human brain.

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There have been no reports of changes in free radical inactivating enzymes in the anterior horn of the spinal cord in ALS despite great interest in the possibility that free radicals might be important in the aetiology of the disease. In this study we have measured copper/zinc superoxide dismutase (Cu/ZnSOD), manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GSHPX) activities in anterior horn tissue obtained from patients with ALS and from controls. Total SOD activity was no different in the anterior horn of ALS cases compared to controls, but Cu/ZnSOD activity was reduced, and that of MnSOD increased, at thoracic cord level only. No detectable activity of GSHPX or cytochrome P450 (unpublished data) was found. These latter negative findings are important because they suggest that generation of free radicals from exogenous chemicals is not important in ALS and further that the neurone (as compared to other cell types) is poorly protected against the toxicity of hydrogen peroxide.

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Studies on anterior horn dissected from MND patients have demonstrated that MnSOD activity is increased when expressed as a percentage of total SOD activity when compared to controls. Total SOD activity (mean +/- SD) in controls = 414 +/- 105 U mg-1 tissue and in MND patients = 373 +/- 115 U mg-1 tissue, whereas CuZnSOD activity was higher in controls (290 +/- 91 U mg-1 tissue) than in MND patients (197 +/- 81 U mg-1 tissue). The reduction in CuZnSOD was compensated for by a concomitant elevation of MnSOD activity (control = 123 +/- 40.5 U mg-1 tissue, MND patients = 175 +/- 47 U mg-1 tissue). These data not only show an important deficit in anterior horn cell body protection against free radical-mediated cell damage, but are also are the first measurements of SOD isoenzymes in anterior horn neurones.

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