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NEUROPHARMACOLOGY
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas
Received February 25, 2005; accepted April 19, 2005.
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Abstract |
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).
Once nicotine penetrates the CNS, it acts as an agonist at the 
4
2 and 32 subtypes of nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area, an action that evokes dopamine release in the nucleus accumbens (Di Chiara, 2000). Although the addictive mechanisms of nicotine are under intensive investigation, the degree to which cotinine modifies nicotine addiction is controversial (Buccafusco and Terry, 2003). In support of cotinine addiction theories, cotinine has been shown to activate the superior cervical ganglion (Schroff et al., 2000), act as an agonist (with weak affinity) at the human 7 nAChR (Briggs and McKenna, 1998), and stimulate dopamine release from rat striatal synaptosomes at doses 30 to 50 times greater than nicotine (Crooks et al., 1997). Yet other data demonstrate that cotinine lacks significant whole brain cholinergic effect (Linville et al., 1993; Radek, 1993).
The rapid blood-brain transfer of nicotine in naive animals has been well documented due to the fact that it is a known cerebral blood flow marker (Ohno et al., 1979; Suzuki et al., 1984; Todd and Weeks, 1996; Tomiyama et al., 1999). However, limited data are present in the literature regarding nicotine BBB penetration after chronic nicotine exposure. Such studies are of significant importance given long-term nicotine exposure changes both BBB function and morphology. Specifically, nicotine has been shown to increase BBB endothelium microvilli formation (Booyse et al., 1981), decrease in vitro zonula occluden-1 expression and diminish the levels and/or function of nAChRs located at the BBB (Abbruscato et al., 2002), down-regulate Na,K,2Cl cotransporters (Abbruscato et al., 2004), and down-regulate 2 Na,K-ATPase (Wang et al., 1994).
In contrast to that of nicotine, the rate of uptake for coti- nine across the BBB is poorly defined. Literature reports on the ability of cotinine to penetrate the BBB to any significant degree are conflicting (Halldin et al., 1992; Riah et al., 1998). Cotinine has been detected in brain after nicotine exposure (Crooks et al., 1997; Riah et al., 1998), but indirect data suggest that this CNS presence may be the result of central nicotine metabolism by CYP2B1, a monooxygenase enzyme which has been detected in rat brain and shown to be induced by chronic nicotine (Jacob et al., 1997; Miksys et al., 2000). The current report documents the blood to brain transfer of cotinine using the in situ brain perfusion model and compares the kinetics with that of nicotine. Furthermore, the degree and rate of cotinine (as well as nicotine) brain uptake was evaluated in naive and chronic nicotine-exposed animals using the same model.
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Materials and Methods |
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). In this study, perfusions of 15 to 60 s were used to determine tracer brain uptake rates in naive rats and those exposed to nicotine for 28 days. Integrity of the BBB was verified in all experiments using [14C]sucrose. All studies were approved by the Institutional Animal Care and Use Committee of Texas Tech University Health Sciences Center and were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Radiochemicals. High specific activity [3H]nicotine (10 Ci/mmol, >98% purity) was obtained from Tocris Cookson Inc. (Ellisville, MO), [3H]cotinine (56 Ci/mmol) from American Radiolabeled Chemicals, Inc. (St. Louis, MO), [14C]sucrose (4.75 mCi/mmol), and [3H]diazepam (86 Ci/mmol) from PerkinElmer Life and Analytical Sciences (Boston, MA). [3H]Nicotine, [3H]cotinine, and/or [3H]diazepam were dried prior to being dissolved in perfusion buffer to remove volatile tritium contaminants including [3H]H2O.
Nicotine Administration by Osmotic Minipump. Chronic nicotine administration was comparable with previous methodology that provided nicotine and cotinine blood levels similar to those found in heavy smokers (nicotine 
80–100 ng/ml; cotinine >250 ng/ml) (Hawkins et al., 2004; Lockman et al., 2005). Briefly, osmotic minipumps (Alzet 2ML4, 28-day capacity: 2000 µl) were loaded with S-(–)nicotine (42 mg; sterile; free base/dissolved in sterile saline) and released over 28 days at a rate of 2.5 µl/h. Prior to implantation, minipumps were primed in sterile saline at 37°C for 24 h according to the manufacturer's specifications. Pumps were then removed and immediately implanted interscapularly (Castagnoli et al., 2002) into male Fischer-344 rats (220–330 g; Charles River Laboratories, Kingston, NY). The surgical procedure consisted of anesthesia (sodium pentobarbital, 50 mg/kg), rectal temperature monitoring, and maintenance of core body temperature at 37°C by a heating pad feedback device (YSI Indicating Controller; YSI Inc., Yellow Springs, OH). A small thoracolumbar subcutaneous incision (4 cm) was made, and a pocket projecting rostrally, large enough to accommodate the minipump, was opened using a blunt hemostat. Manual insertion of the minipump was completed under sterile conditions and the wound closed with staples. Rats were monitored during recovery after which they were allowed ad libitum access to food and water. Nicotine levels (72 ng/ml) were verified by high-performance liquid chromatography in a subset of animals on day 28. Cotinine levels (469 ± 27 ng/ml) were also verified by enzyme immunoassay (Cozart Bioscience Ltd, Oxfordshire, UK) prior to in situ perfusion procedures to ensure adequate nicotine exposure.
Perfusion Procedure. After 28 days of nicotine exposure, animals were anesthetized with sodium pentobarbital (50 mg/kg; intraperitoneal). A PE-60 catheter filled with heparinized saline (100 units/ml) was placed into the left common carotid artery after ligation of the left external carotid, occipital, and common carotid arteries (common carotid artery ligation was accomplished caudally to the catheter implantation site). The pterygopalatine artery was left open. Rat body temperature was monitored and maintained at 37°C by a heating pad and feedback device (YSI Indicating Controller; YSI Inc.). The buffered physiologic perfusion fluid used was titrated to pH 7.4 (osmolarity 290 mOsm; verified) and contained 128 mM NaCl, 2.4 mM NaPO3, 29.0 mM NaHCO3, 4.2 mM KCl, 1.5 mM CaCl, 0.9 mM MgCl, and 9 mM D-glucose with 0.33 µCi/ml [14C]sucrose and either 0.5 µCi/ml [3H]nicotine or 1.0 µCi/ml [3H]cotinine. Immediately prior to perfusion, the fluid was filtered and warmed to 37°C and gassed with 95% air and 5% CO2.
The perfusion fluid was infused into the left carotid artery via infusion pump for 15 to 60 s at 10 ml/m (Harvard Apparatus, Holliston, MA). This level of flow maintained carotid artery pressure at 120 mm Hg. Rats were decapitated, the brain rapidly removed from the skull, and the perfused hemisphere dissected on ice after removal of the arachnoid membrane and meningeal vessels. Brain regions and perfusion fluid samples were digested overnight at 50°C in 1 ml of 1 M piperidine. Dual-labeled scintillation counting of brain and perfusate samples was then accomplished with correction for quench, background, and efficiency (LS6500 Multipurpose scintillation counter; Beckman Coulter, Fullerton, CA).
Kinetic Analysis. Concentrations of tracer in brain and perfusion fluid are expressed as disintegrations per minute per gram of brain or disintegrations per minute per milliliter of perfusion fluid, respectively. A brain/perfusate distribution volume was ascertained as described (Smith, 2003) from the following relationship:
 | (1) |
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) by eq. 2:
 | (2) |
).
Kin values for [3H]nicotine and [3H]cotinine were converted to apparent cerebrovascular permeability-surface area products (PA) using the Crone-Renkin equation (Smith, 2003):
 | (3) |
Statistical Analysis. Data presented are from total left hemispheric brain, unless otherwise specified. Brain PA and Kin were evaluated by Student's t test, and regional data were evaluated by one-way analysis of variance followed by Bonferroni's multiple comparison test. Regional differences in Kin or PA were evaluated individually by a Student's t test (two-tailed). Differences were considered statistically significant at p < 0.05. Errors are reported as standard error of mean (GraphPad Prism version 4.0 for Windows; GraphPad Software, San Diego, CA).
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Results |
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72 ng/ml) and cotinine (the presence of cotinine was from endogenously metabolized nicotine; 469 ± 27 ng/ml). Brain uptake of [3H]nicotine was evaluated with short perfusions of 15 s (Figs. 1A and 2) to prevent significant brain to blood efflux (i.e., unilateral uptake) and CNS metabolism of nicotine to cotinine. No significant difference in total brain [3H]nicotine uptake were noted between naive (3.11 ± 0.42 x 10–2 ml/s/g) and nicotineexposed (3.31 ± 1.1 x 10–2 ml/s/g) rats (Fig. 1A). To assess whether chronic nicotine exposure altered flow in our model, we evaluated brain uptake of [3H]diazepam (Lockman et al., 2003). As seen in Fig. 1B, no apparent flow alterations were noted between control (5.11 ± 0.98 x 10–2 ml/s/g) and nicotine exposure (4.61 ± 0.81 x 10–2 ml/s/g). The increased cerebral perfusion flow rate with [3H]diazepam compared with [3H]nicotine was found to be consistent with previously published perfusion flow data (Lockman et al., 2003; Smith, 2003).
Regional brain analyses confirmed the lack of significant differences in [3H]nicotine uptake into brain between naive and nicotine-exposed animals (Fig. 2). [3H]Nicotine uptake in this study showed a pattern of uptake influenced by cerebral perfusion flow commonly found in the in situ perfused brain, where flow rates are found to be highest in the cortical regions (4.02 ± 0.59 x 10–2 ml/s/g) and lower in the cerebellum (1.39 ± 0.40 x 10–2 ml/s/g) and pons medulla (0.94 ± 0.21 x 10–2 ml/s/g) (Smith, 2003).
Considering [3H]cotinine brain uptake is approximately 10-fold less than that of [3H]nicotine, evaluation of [3H]cotinine uptake required the plotting of distribution volume per time, subtraction of vascular volume, and linear regression analysis to accurately estimate uptake rate (Kin). As shown in Fig. 3, A and B, the total brain uptake of [3H]cotinine in animals subjected to chronic nicotine exposure (Kin: 2.07 ± 0.25 x 10–3 ml/s/g; PA: 2.11 ± 0.25 x 10–3 ml/s/g) was found not to be significantly altered from control in whole brain (Kin: 2.03 ± 0.17 x 10–3 ml/g; PA: 2.06 ± 0.17 x 10–3 ml/s/g) or regionally (Fig. 4). In contrast to [3H]nicotine regional data where flow differences may result in changes of uptake between cortical and subcortical regions, [3H]cotinine is permeability limited and regional alterations of [3H]cotinine brain uptake are minimized (cortex Kin: 2.13 ± 0.26 x 10–3 ml/s/g and PA: 2.17 ± 0.27 x 10–3 ml/s/g; pons medulla Kin: 1.60 ± 0.19 x 10–3 ml/s/g and PA 1.62 ± 0.19 x 10–3 ml/s/g).
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Discussion |
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) and accordingly diminishes BBB trans- fer of compounds that are flow-dependent (i.e., extraction approximately 
80%). Therefore, to determine whether nicotine has a similar effect, we evaluated the uptake of [3H]diazepam in both naive and nicotine-exposed animals. It appears from our data that cerebral perfusion flow values are not significantly altered in the presence of chronic nicotine exposure. However, our data do not preclude the influence of effects on cerebral blood flow due to in situ model limitations, including secondary loss of cerebral blood flow (such as the absence of autoregulatory factors in a pump-driven organ perfusion flow system).
Earlier work by the group of Ghosheh on the brain distribution of nicotine found increased levels (i.e., distribution) of nicotine in brain following chronic nicotine exposure. The authors suggested several rationales for the increased nicotine brain distribution including alterations in BBB transfer rates, increased nAChR binding, and sequestration of nicotine in glial cytosol through its protonation (pKa = 9.13, glial cytosol pH 6.5–7.0) (Ghosheh et al., 2001). Our data explored the first rationale proposed by Ghosheh's group. In our experiments, the BBB transfer of [3H]nicotine was found to be 70 to 80% of flow ([3H]diazepam uptake) and consequently may be influenced by flow alterations. Therefore, if chronic nicotine exposure resulted in BBB alterations that may influence blood to brain transfer of [3H]nicotine, such changes should be apparent using the in situ model. Our findings suggest there is no alteration of [3H]nicotine brain uptake after chronic nicotine exposure either in whole brain or in any measured brain region. We believe the increased CNS distribution of nicotine seen in previous studies may be from the result of either increased neuronal binding or glial sequestration.
As a major metabolic pathway in the periphery, nicotine primarily (80%) undergoes liver aldehyde oxidation via CYP2A6 to form cotinine in humans (Messina et al., 1997; Yamanaka et al., 2004) and in rats (homolog CYP2B1) (Hammond et al., 1991; Nakayama et al., 1993). There is controversy as to whether cotinine penetrates the BBB from plasma (Halldin et al., 1992; Riah et al., 1998) or whether the detection of cotinine in brain is solely the result of central nicotine metabolism. Recently, nicotine has been shown to be metabolized in rat brain (Jacob et al., 1997) via CYP2B1 (human homolog CYP2B6), and this process is up-regulated after chronic nicotine exposure (Miksys et al., 2000) (although the amount of nicotine metabolism in brain has not been elucidated). Therefore, to determine whether brain cotinine concentrations are also altered by BBB transfer in naive and nicotine-exposed animals, we evaluated the brain uptake of [3H]cotinine.
Contrary to previous reports, our data demonstrate there is significant BBB transfer of cotinine that is generally homogeneous among brain regions. Comparison of the PA and log P for [3H]cotinine suggests [3H]cotinine crosses the BBB by passive diffusion (Ghosheh et al., 2001; Smith, 2003). This rate of [3H]cotinine BBB penetration is significant, considering it is comparable with other neuroactive molecules including theophylline, adenosine, and choline (Smith, 2003).
Our evaluation of unidirectional influx of cotinine and nicotine into brain further suggests that the nicotine metabolite penetrates the BBB significantly. The average cotinine plasma levels measured in heavy smokers were found to be fairly stable and range from 250 to 350 ng/ml (Benowitz et al., 1983; Paoletti et al., 1996). Calculation of influx (influx = Cpl x PA) reveals that cotinine enters the brain at a rate of 0.5 to 0.7 ng/s/g or 43 to 61 µg/g/day. On the other hand, nicotine plasma levels vary significantly between 10 and 50 ng/ml in smokers (Russell and Feyerabend, 1978; Benowitz et al., 1982), following increment peaks of 5 to 30 ng/ml per cigarette (t1/2 2 h) (Isaac and Rand, 1972; Armitage et al., 1975). Therefore, assuming that the highest average nicotine plasma level is 40 to 50 ng/ml over a 24-h period, the BBB influx of nicotine would approximate 1.32 to 1.65 ng/s/g or 114 to 143 µg/g/day. Comparison of influx data measured for the two compounds suggests that cotinine enters brain at amounts approximately 40% than that of nicotine regardless of prior nicotine exposure. Although our studies did not include measurement of pharmacological activity, the data suggest that cotinine may penetrate the BBB to a degree that would allow central action.
Data presented in the current study also demonstrate that vascular volumes are not altered after chronic nicotine exposure. These data are consistent with our recently published work (Lockman et al., 2005) and other reports demonstrating that chronic pharmacological relevant nicotine exposure does not alter functional BBB integrity of epithelium (Minty et al., 1984) or endothelium in vivo (Booyse et al., 1981; Allen et al., 1988; Myers et al., 1988). Taken together, these data suggest that chronic nicotine-exposed animals retain an operative BBB.
In summary, our data demonstrate that both cotinine and nicotine significantly penetrate the BBB and that transfer rates are not affected by chronic heavy nicotine exposure. This current report will be expanded further by compartmental (both central and peripheral) pharmacokinetic modeling for both nicotine and cotinine. Care must be taken to elucidate the distribution sites in such modeling studies (e.g., nicotine/cotinine accumulation in plasma, endothelium, glia, neurons, and extracellular fluid as measured in the central compartment). Such future work may significantly increase our understanding of the distribution of free drug in brain and may help elucidate the complex action of nicotine and its major metabolite in a tobacco-consuming human population.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: CNS, central nervous system; BBB, blood-brain barrier; nAChR, nicotinic acetylcholine receptor; PA, cerebrovascular permeability-surface area products.
Address correspondence to: Dr. Paul R. Lockman, Department of Pharmaceutical Sciences, Texas Tech University HSC, 1300 So. Coulter Dr., Amarillo, TX 79106-1712. E-mail: paul.lockman{at}ttuhsc.edu
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References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Abbruscato TJ, Lopez SP, Mark KS, Hawkins BT, and Davis TP (2002) Nicotine and cotinine modulate cerebral microvascular permeability and protein expression of ZO-1 through nicotinic acetylcholine receptors expressed on brain endothelial cells. J Pharm Sci 91: 2525–2538.[CrossRef][Medline]
Abbruscato TJ, Lopez SP, Roder K, and Paulson JR (2004) Regulation of blood-brain barrier Na,K,2Cl-cotransporter through phosphorylation during in vitro stroke conditions and nicotine exposure. J Pharmacol Exp Ther 310: 459–468.
Allen DR, Browse NL, Rutt DL, Butler L, and Fletcher C (1988) The effect of cigarette smoke, nicotine and carbon monoxide on the permeability of the arterial wall. J Vasc Surg 7: 139–152.[CrossRef][Medline]
Armitage AK, Dollery CT, George CF, Houseman TH, Lewis PJ, and Turner DM (1975) Absorption and metabolism of nicotine from cigarettes. Br Med J 4: 313–316.
Begley DJ and Brightman MW (2003) Structural and functional aspects of the blood-brain barrier. Prog Drug Res 61: 39–78.[Medline]
Benowitz NL, Hall SM, Herning RI, Jacob P 3rd, Jones RT, and Osman AL (1983) Smokers of low-yield cigarettes do not consume less nicotine. N Engl J Med 309: 139–142.[Abstract]
Benowitz NL, Kuyt F, and Jacob P 3rd (1982) Circadian blood nicotine concentrations during cigarette smoking. Clin Pharmacol Ther 32: 758–764.[Medline]
Booyse FM, Osikowicz G, and Quarfoot AJ (1981) Effects of chronic oral consumption of nicotine on the rabbit aortic endothelium. Am J Pathol 102: 229–238.[Abstract]
Briggs CA and McKenna DG (1998) Activation and inhibition of the human alpha7 nicotinic acetylcholine receptor by agonists. Neuropharmacology 37: 1095–1102.[CrossRef][Medline]
Buccafusco JJ and Terry AV Jr (2003) The potential role of cotinine in the cognitive and neuroprotective actions of nicotine. Life Sci 72: 2931–2942.[CrossRef][Medline]
Castagnoli K, Steyn SJ, Magnin G, Van Der Schyf CJ, Fourie I, Khalil A, and Castagnoli N Jr (2002) Studies on the interactions of tobacco leaf and tobacco smoke constituents and monoamine oxidase. Neurotox Res 4: 151–160.[CrossRef][Medline]
Crooks PA, Li M, and Dwoskin LP (1997) Metabolites of nicotine in rat brain after peripheral nicotine administration. Cotinine, nornicotine and norcotinine. Drug Metab Dispos 25: 47–54.
Di Chiara G (2000) Role of dopamine in the behavioural actions of nicotine related to addiction. Eur J Pharmacol 393: 295–314.[CrossRef][Medline]
Ghosheh OA, Dwoskin LP, Miller DK, and Crooks PA (2001) Accumulation of nicotine and its metabolites in rat brain after intermittent or continuous peripheral administration of [2'-(14)C]nicotine. Drug Metab Dispos 29: 645–651.
Halldin C, Nagren K, Swahn CG, Langstrom B, and Nyback H (1992) (S)- and (R)-[11C]nicotine and the metabolite (R/S)-[11C]cotinine. Preparation, metabolite studies and in vivo distribution in the human brain using PET. Int J Rad Appl Instrum B 19: 871–880.[Medline]
Hammond DK, Bjercke RJ, Langone JJ, and Strobel HW (1991) Metabolism of nicotine by rat liver cytochromes P-450. Assessment utilizing monoclonal antibodies to nicotine and cotinine. Drug Metab Dispos 19: 804–808.[Abstract]
Hawkins BT, Abbruscato TJ, Egleton RD, Brown RC, Huber JD, Campos CR, and Davis TP (2004) Nicotine increases in vivo blood-brain barrier permeability and alters cerebral microvascular tight junction protein distribution. Brain Res 1027: 48–58.[CrossRef][Medline]
Isaac PF and Rand MJ (1972) Cigarette smoking and plasma levels of nicotine. Nature (Lond) 236: 308–310.[CrossRef][Medline]
Jacob P 3rd, Ulgen M, and Gorrod JW (1997) Metabolism of (–)-(S)-nicotine by guinea pig and rat brain: identification of cotinine. Eur J Drug Metab Pharmacokinet 22: 391–394.[Medline]
Linville DG, Williams S, Raszkiewicz JL, and Arneric SP (1993) Nicotinic agonists modulate basal forebrain control of cortical cerebral blood flow in anesthetized rats. J Pharmacol Exp Ther 267: 440–448.
Lockman PR, Koziara J, Roder KE, Paulson J, Abbruscato TJ, Mumper RJ, and Allen DD (2003) In vivo and in vitro assessment of baseline blood-brain barrier parameters in the presence of novel nanoparticles. Pharm Res (NY) 20: 705–713.
Lockman PR, Van der Schyf CJ, Abbruscato TJ, and Allen DD (2005) Chronic nicotine exposure alters blood-brain barrier permeability and diminishes brain uptake of methyllycaconitine. J Neurochem, in press.
Messina ES, Tyndale RF, and Sellers EM (1997) A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmacol Exp Ther 282: 1608–1614.
Miksys S, Hoffmann E, and Tyndale RF (2000) Regional and cellular induction of nicotine-metabolizing CYP2B1 in rat brain by chronic nicotine treatment. Biochem Pharmacol 59: 1501–1511.[CrossRef][Medline]
Minty BD, Royston D, Jones JG, and Hulands GH (1984) The effect of nicotine on pulmonary epithelial permeability in man. Chest 86: 72–74.
Myers TO, Joyner WL, and Gilmore JP (1988) Extravasation of macromolecules and vascular reactivity of microvessels in response to nicotine in the hamster. Int J Microcirc Clin Exp 7: 139–153.[Medline]
Nakayama H, Okuda H, Nakashima T, Imaoka S, and Funae Y (1993) Nicotine metabolism by rat hepatic cytochrome P450s. Biochem Pharmacol 45: 2554–2556.[CrossRef][Medline]
Ohno K, Pettigrew KD, and Rapoport SI (1979) Local cerebral blood flow in the conscious rat as measured with 14C-antipyrine, 14C-iodoantipyrine and 3H-nicotine. Stroke 10: 62–67.
Paoletti P, Fornai E, Maggiorelli F, Puntoni R, Viegi G, Carrozzi L, Corlando A, Gustavsson G, Sawe U, and Giuntini C (1996) Importance of baseline cotinine plasma values in smoking cessation: results from a double-blind study with nicotine patch. Eur Respir J 9: 643–651.[Abstract]
Radek RJ (1993) Effects of nicotine on cortical high voltage spindles in rats. Brain Res 625: 23–28.[CrossRef][Medline]
Riah O, Courriere P, Dousset JC, Todeschi N, and Labat C (1998) Nicotine is more efficient than cotinine at passing the blood-brain barrier in rats. Cell Mol Neurobiol 18: 311–318.[CrossRef][Medline]
Rogers RL, Meyer JS, Shaw TG, Mortel KF, Hardenberg JP, and Zaid RR (1983) Cigarette smoking decreases cerebral blood flow suggesting increased risk for stroke. JAMA (J Am Med Assoc) 250: 2796–2800.
Russell MA and Feyerabend C (1978) Cigarette smoking: a dependence on high-nicotine boli. Drug Metab Rev 8: 29–57.[Medline]
Schroff KC, Lovich P, Schmitz O, Aschhoff S, Richter E, and Remien J (2000) Effects of cotinine at cholinergic nicotinic receptors of the sympathetic superior cervical ganglion of the mouse. Toxicology 144: 99–105.[CrossRef][Medline]
Smith QR (2003) A review of blood-brain barrier transport techniques. Methods Mol Med 89: 193–208.[Medline]
Suzuki R, Nitsch C, Fujiwara K, and Klatzo I (1984) Regional changes in cerebral blood flow and blood-brain barrier permeability during epileptiform seizures and in acute hypertension in rabbits. J Cereb Blood Flow Metab 4: 96–102.[Medline]
Todd MM and Weeks J (1996) Comparative effects of propofol, pentobarbital and isoflurane on cerebral blood flow and blood volume. J Neurosurg Anesthesiol 8: 296–303.[Medline]
Tomiyama Y, Brian JE Jr, and Todd MM (1999) Cerebral blood flow during hemodilution and hypoxia in rats: role of ATP-sensitive potassium channels. Stroke 30: 1942–1947; discussion 1947–1948.
Wang L, McComb JG, Weiss MH, McDonough AA, and Zlokovic BV (1994) Nicotine downregulates alpha 2 isoform of Na,K-ATPase at the blood-brain barrier and brain in rats. Biochem Biophys Res Commun 199: 1422–1427.[CrossRef][Medline]
Yamanaka H, Nakajima M, Nishimura K, Yoshida R, Fukami T, Katoh M, and Yokoi T (2004) Metabolic profile of nicotine in subjects whose CYP2A6 gene is deleted. Eur J Pharm Sci 22: 419–425.[CrossRef][Medline]
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