In vivo imaging of nicotinic receptor upregulation following chronic (-)-nicotine treatment in baboon using SPECT

Kassiou, Michael; Eberl, Stefan; Meikle, Steven R.; Birrell, A.; Constable, Chris; Fulham, Michael; Wong, Dean F.; Musachio, John L.

doi:10.1016/s0969-8051(00)00206-7

Cited by 56 publications

(41 citation statements)

References 30 publications

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“…The result of the increased Vt of the 123 I-5IA was in agreement with the upregulation of the nAChRs in the brains of smokers reported in postmortem human studies (10)(11)(12) and in animal studies (6)(7)(8)(9). Staley et al have described similar findings in human brain (13).…”

Section: Discussionsupporting

confidence: 86%

“…Previous animal studies have shown that chronic nicotine treatment induces an increase in high-affinity nicotinic receptor binding (6)(7)(8)(9), and human postmortem studies have found a similar increase in 3 H-nicotine binding to high-affinity receptors in the postmortem cortex, cerebellum, and hippocampus of smokers compared with that in nonsmokers (10)(11)(12).…”

Section: Discussionmentioning

confidence: 79%

“…Previous efforts to demonstrate nAChR upregulation in the human brain have also been reported primarily in in vitro binding assays (10,11). Kassiou et al reported the upregulation of nAChRs with chronic (2)-nicotine treatment in the brain of a live baboon (12). More recently, Staley et al described the upregulation of nAChRs in human brains after early abstinence of tobacco smoking using 5-123 I-iodo-A-85380 ( 123 I-5IA) and SPECT images (13).…”

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confidence: 99%

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Temporal Change in Human Nicotinic Acetylcholine Receptor After Smoking Cessation: 5IA SPECT Study

Mamede¹,

Ishizu²,

Ueda³

et al. 2007

Journal of Nuclear Medicine

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Nicotinic acetylcholine receptors (nAChRs) are of great interest because they are implicated in various brain functions. They also are thought to play an important role in nicotine addiction of smokers. Chronic (2)-nicotine, a nAChR agonist, treatment in mice and rats elicits a dose-dependent increase in nAChRs in the brain. Upregulation of nAChRs in postmortem human brains of smokers has also been reported. However, changes in nAChRs after cigarette smoking cessation in humans are poorly understood. The aim of this study was to detect the dynamic changes of nAChRs after smoking and smoking cessation in the brains of living subjects. Methods: We performed 5-123 Iiodo-A-85380 ( 123 I-5IA) SPECT on nonsmokers and smokers (n 5 16) who had quit smoking for 4 h, 10 d, and 21 d and calculated and compared distribution volumes (Vt) of 123 I-5IA. Results: The binding potential of nAChRs (Vt of 123 I-5IA) in the brains of smokers decreased by 33.5% 6 10.5% after 4 h of smoking cessation, increased by 25.7% 6 9.2% after 10 d of smoking cessation, and decreased to the level of nonsmokers after 21 d of smoking cessation. Conclusion: Because the upregulation of the nAChRs of the smokers after chronic exposure of the nicotine was downregulated to the nonsmokers' level by around 21 d after smoking cessation, the upregulation is a temporary effect. The decrease in nicotinic receptors to nonsmoker levels may be the breaking point during the nicotine withdrawal period.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

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Temporal Change in Human Nicotinic Acetylcholine Receptor After Smoking Cessation: 5IA SPECT Study

Mamede¹,

Ishizu²,

Ueda³

et al. 2007

Journal of Nuclear Medicine

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“…Neurochemical investigations of the cholinergic system in brain tissue have established an extensive loss of the a4b2 nAChR subtype in cortical and cerebellar regions of adults with autism (Perry et al 2001;Lee et al 2002;Martin-Ruiz et al 2004). This subtype is upregulated following the administration of nicotinic agonists such as nicotine in both human (Breese et al 1997;Court et al 1998;Perry et al 1999) and animal models (Mochizuki et al 1998;Sparks and Pauly 1999;Kassiou et al 2001). Parallel neurochemical studies have identified loss of the a4b2 nAChR in the cerebellum in autism that is similar to, but less extensive than that found in the cortex, and an increase in the a7 nAChR subtype (Lee et al 2002).…”

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confidence: 99%

Placebo-Controlled Pilot Trial of Mecamylamine for Treatment of Autism Spectrum Disorders

Arnold

Aman

Hollway

et al. 2012

Journal of Child and Adolescent Psychopharmacology

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Objective: To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient a4b2 nAChRs, excess a7 nAChRs) in brains of patients with autism. Method: Mecamylamine, because of its safety record in children with other disorders, was chosen for this first exploration. Twenty children with autism spectrum disorder age 4-12 years were randomly assigned for 14 weeks to placebo (n = 8) or mecamylamine (n = 12) in ascending fixed doses: 0.5 mg/day for 6 weeks, 2.5 mg for 2 weeks, then 5 mg/day for 6 weeks. Improvement was rated by a blinded independent evaluator. Because of small sample, data analysis was descriptive. Results: Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses ‡ 0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense. Conclusion: Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific a4b2 nAChR agonist, such as varenicline.

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“…123 I]-iodo-A-85380 [17]. The performance of AFC was evaluated by comparing it to standard fuzzy clustering in terms of estimated accuracy and reliability, and computational cost.…”

Section: Introductionmentioning

confidence: 99%

Adaptive fuzzy clustering in constructing parametric images for low SNR functional imaging

Wen

Eberl

Fulham

et al. 2008

2008 IEEE 10th Workshop on Multimedia Signal Processing

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Abstract-Functional imaging can provide quantitative functional parameters to aid early diagnosis. Low signal to noise ratio (SNR) in functional imaging, especially for single photon emission computed tomography, poses a challenge in generating voxel-wise parametric images due to unreliable or physiologically meaningless parameter estimates. Our aim was to systematically investigate the performance of our recently proposed adaptive fuzzy clustering (AFC) technique, which applies standard fuzzy clustering to sub-divided data. Monte Carlo simulations were performed to generate noisy dynamic SPECT data with quantitative analysis for the fitting using the general linear least square method (GLLS) and enhanced model-aided GLLS methods. The results show that AFC substantially improves computational efficiency and obtains improved reliability as standard fuzzy clustering in estimating parametric images but is prone to slight underestimation. Normalization of tissue time activity curves may lead to severe overestimation for small structures when AFC is applied.

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In vivo imaging of nicotinic receptor upregulation following chronic (-)-nicotine treatment in baboon using SPECT

Cited by 56 publications

References 30 publications

Temporal Change in Human Nicotinic Acetylcholine Receptor After Smoking Cessation: 5IA SPECT Study

Temporal Change in Human Nicotinic Acetylcholine Receptor After Smoking Cessation: 5IA SPECT Study

Placebo-Controlled Pilot Trial of Mecamylamine for Treatment of Autism Spectrum Disorders

Adaptive fuzzy clustering in constructing parametric images for low SNR functional imaging

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