Elsevier

Brain Research

Volume 782, Issues 1–2, 26 January 1998, Pages 36-42
Brain Research

Research report
Increase of glucose transporter densities (Glut1 and Glut3) during chronic administration of nicotine in rat brain

https://doi.org/10.1016/S0006-8993(97)01264-XGet rights and content

Abstract

Chronic infusion of nicotine is known to result in a distinct pattern of increases in local cerebral glucose utilization (LCGU). The present study addresses the question whether this increase in LCGU is paralleled by (1) a local increase in Glut1 and/or Glut3 glucose transporter densities and (2) a local increase in capillary density in the brain. Nicotine was infused by osmotic minipumps for one week. In cryosections of rat brains local densities of Glut1 (vascular) and Glut3 (neuronal) glucose transporters were measured by immunoautoradiographic methods whereas local capillary densities were determined by an immunofluorescent method. Densities of glucose transporters Glut1 and Glut3 were increased in 12 of the 27 structures investigated. Glut1 was elevated in four additional structures and Glut3 in two more structures. Comparison of the changes in transporter densities with the changes of LCGU measured in a previous study during chronic nicotine infusion showed that LCGU was also elevated in most of these structures. In contrast, capillary density remained unchanged in all structures investigated. It is concluded that one week of nicotine infusion is sufficient to raise the densities of Glut1 and Glut3 glucose transporters predominantly in those structures in which LCGU is elevated. The unchanged capillary density under these conditions indicates an increased density of Glut1 transporters per capillary.

Introduction

Glucose transport proteins mediate the facilitated diffusion of glucose across cell membranes. To date, six functional glucose transporter isoforms (Glut1–5, Glut7) have been identified by molecular cloning techniques. In the brain, mainly two of these isoforms have been found. The glucose transporter Glut1 is localized at the blood–brain barrier endothelium and in perivascular endfeet of astrocytes 4, 11, 14whereas the glucose transporter Glut3 is found in neurons 13, 14, 18. Previous studies have shown an uneven distribution of Glut1 and Glut3 in the brain during normal control conditions 24, 25. Little is known whether local changes in the transporter densities can occur. Since chronic administration of nicotine induces increases of local cerebral glucose utilization (LCGU) in distinct brain areas 6, 12the question arose whether this increase in LCGU is paralleled by increases in the local distribution of Glut1 and/or Glut3 and of capillary density. To this end, rats received osmotic minipumps filled with a nicotine solution. After one week, the local densities of glucose transporters Glut1 and Glut3 were quantified by immunoautoradiographic methods recently developed in our laboratory 24, 25. In the same animals capillaries were made visible by indirect immunofluorescence 5, 21. The results were compared with those of a previous 2-deoxyglucose study of LCGU during chronic nicotine infusion [6].

Section snippets

Materials and methods

Glucose transporters and capillary densities were measured in 12 male Sprague–Dawley rats weighing 240 to 330 g. The animals were anesthetized by a gas mixture of halothane (1–1.5%), N2O (70–80%) and O2 (remainder). Osmotic minipumps (Alzet model 2001, Alza, Palo Alto, CA, USA), filled with l-nicotine (Free base, Sigma, Deisenhofen, Germany), were implanted subcutaneously. The pumps were filled with l-nicotine such as to result in a dosage of 12.5 μg kg−1 min−1 (n=6). Control animals received

Results

Table 1 shows hemodynamic, arterial acid–base and other relevant parameters of both rat groups investigated. In the nicotine group, blood pressure, heart rate, acid base status, hematocrit, body temperature and glucose concentration were unchanged as compared to control rats. Nicotine and cotinine levels were in the targeted range during chronic nicotine infusion. Body weight of the control rats increased continuously from 305±22 g to 349±11 g during the one-week experiment whereas it decreased

Discussion of the methods

The immunoautoradiographic methods developed by our group for the detection of the density of Glut1 and Glut3 have a local resolution of 100–200 μm which is comparable to that of the 2-deoxyglucose method [20]. Whereas the 2-deoxyglucose method allows one to detect the local functional activity of the brain by measuring its glucose utilization, the immunoautoradiographic methods applied in the present study can be used to illustrate the morphological basis of local glucose utilization by

Conclusion

In summary, chronic infusion of nicotine causes an increase in LCGU in distinct brain areas. This increase is paralleled by an upregulation of glucose transporters Glut1 and Glut3 in the same brain areas, whereas capillary density remains unchanged.

Acknowledgements

This study was supported by a grant from VERUM, Stiftung für Verhalten und Umwelt, Munich, Germany. The authors thank PD Dr. G. Scherer, Munich, for the determination of plasma concentrations of nicotine and cotinine.

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