The hypothermic effect of nicotine is mediated by central nAChRs (Mansner et al.
1974) and can be prevented by elevating the ambient temperature (Haikala et al.
1986). In several studies chronic nicotine treatment was found to induce tolerance to the nicotine-induced decrease of body temperature (Mansner et al. 1974; Marks and Collins 1985). Further, in mice withdrawn for 24 h from a seven-week oral nicotine administration schedule (Pietilä et al. 1996), acute nicotine challenge induced significantly less hypothermia than in controls indicating the development of tolerance to the hypothermic effect of nicotine. Tolerance also developed to the locomotor-depressant effects of acute nicotine in these mice (Pietilä et al. 1998). In Study IV, acute nicotine doses of 1 and 2 mg/kg induced hypothermia in a dose-dependent manner which was at its maximum at 30 min after administration of the drug. In mice infused chronically with nicotine from subcutaneously implanted nicotine-releasing reservoirs for 7 days, tolerance was found to the hypothermic effect of the acute nicotine dose of 1 mg/kg but not to the dose of 2 mg/kg. Previously no tolerance was observed to the hypothermic effect of large or repeated (3 mg/kg or 1 x 4 mg/kg s.c.) acute nicotine doses after 7-day chronic nicotine infusion in mice (Leikola-Pelho et al.
1990). Thus, we found that increasing the nicotine dose overcomes the attenuation of
the hypothermic effect of nicotine. This suggests that tolerance, in the classical sense, i.e. an effect that is characterised by the fact that increasing the dose of the drug overcomes the diminution of its effect following repeated administration, develops to nicotine-hypothermia during chronic treatment. In contrast, during chronic nicotine treatment, acute nicotine did not increase the concentrations of striatal DA metabolites suggesting that desensitization is the main mechanism by which the nAChRs regulating striatal DA metabolism, are inactivated under the present experimental conditions. Thus, the nAChRs involved in these two effects differ.
7 SUMMARY AND CONCLUSIONS
In the present study both desensitization and long-lasting inactivation of the nAChRs involved in the mediation of nicotine’s central effects on cerebral dopamine metabolism and on Fos expression were demonstrated in vivo in rodent brain during chronic nicotine administration and its withdrawal.
1) In rat acute administration of nicotine induced Fos IS both in the CPU and limbic dopaminergic areas. Acutely administered nicotine also induced Fos IS in both the PVN and SON, which are stress-related brain areas, and in MT and IPN. Diazepam induced Fos IS in all stress-related areas studied (PVN, SON, ACe), but not in any of the other brain areas studied. No significant interactions were found between the acute effects of diazepam and nicotine on Fos expression and this finding suggests that these drugs activate different sets of neurons within the stress-related brain areas.
2) The results from studies performed in the rat suggest that the degree of desensitization of nAChRs in various brain areas differs. The nAChRs in the striatal areas seem to be desensitized more easily than those in the limbic areas during prolonged nicotine infusion. Thus, in the CPU area neither the elevation of DA metabolites nor the expression of Fos protein was affected by acute nicotine during chronic nicotine infusion. In contrast, acute nicotine administration caused some elevation of both limbic HVA and Fos expression in the NAcc of rats during chronic nicotine infusion. No reduction of nicotine-induced Fos expression was found in the Cg and ACe, and only a slight reduction was found in the IPN which are known to be brain areas involved in regulation of various behavioural reactions. Further, the nAChRs in the hypothalamic areas, PVN and SON, or in their input areas regulating nicotine’s effects on hormone secretion also seem to be more easily desensitized than the nAChRs in the limbic areas.
We also found evidence for a long-lasting inactivation of nAChRs mediating nicotine’s effects in vivo. Thus, at 24 h after withdrawal acute nicotine did not elevate limbic DOPAC, but striatal DOPAC and HVA as well as limbic HVA were elevated to the same degree as in control rats. Furthermore, acute nicotine did not increase the Fos
expression in the CPU or NAcc, although in ACe its effects were similar to that in controls.
After longer withdrawal (72 h) nicotine’s effects on cerebral dopamine metabolism and Fos protein expression were restored showing that these functional changes of nAChRs are reversible phenomena.
3) In mice, the responses of striatal DA metabolism and body temperature to acute nicotine were both reduced during constant nicotine infusion. However, the tolerance to nicotine’s hypothermic effect could be overcome to some degree by increasing the dose of nicotine, suggesting that tolerance, in the classical sense, develops in nAChRs involved in thermoregulation during chronic nicotine treatment. In contrast, during chronic nicotine treatment acute nicotine did not increase the concentrations of striatal DA metabolites suggesting that desensitization is the main mechanism by which nAChRs regulating striatal DA metabolism are inactivated under the present experimental conditions. Thus, the nAChRs involved in these two effects differ.
In conclusion, there seems to be variations in the functional states and/or in the subunit combinations of nAChRs mediating nicotine’s effects in brain. It has been hypothesized that smokers, seeking the most rewarding effect, adjust their way of smoking so that they reach the appropriate combination of stimulated and desensitized nAChRs. The long-lasting inactivation of nAChRs is one of the important factors in the development of tolerance to nicotine. The variations in responses to nicotine may prove to be useful when studying the protective effect of nicotine in Parkinson’s disease as well as in its reinforcing and dependence-producing properties.
ACKNOWLEDGEMENTS
This work was carried out at the Division of Pharmacology and Toxicology, Department of Pharmacy, University of Helsinki.
I express my deepest gratitude to my tutor and supervisor, Professor Liisa Ahtee, for her inspiring enthusiasm and encouragement. Her profound knowledge of neuropharmacology combined with great teaching skills have made the completion of this work possible. I will always value the hospitality shown to me by Prof. Ahtee whilst preparing papers to be published.
Docent Jouni Sirviö and docent Sampsa Vanhatalo offered constructive criticism on the manuscript and valuable suggestions which led to its improvement, and to them I extend my sincere thanks. I am furthermore grateful to Mr. Adrian Mogg (University of Bath, United Kingdom) for revising the language of the manuscript.
I am deeply grateful to the co-authors of these studies, M. Sc. Tiina Seppä, M. Sc.
Helena Gäddnäs and M. Sc. Sirpa Lahtinen, for their excellent collaboration and fruitful discussions during the study. To Ph. D. Kirsi Pietilä I want to extend my sincere thanks for first being my tutor and then for excellent collaboration in the field of nicotine research. To M. Sc. Mikaela Moed I express my appreciation for her capable assistance during the course of her pro gradu study. Further, I wish to thank Ms. Marjo Vaha for her skilful assistance in all stages of this work.
I was introduced to the world of Fos immunohistochemistry during a stay at the University of Cambridge, where I visited the Department of Anatomy, the laboratory of Dr. Joe Herbert in spring 1992. I am deeply grateful to him and his skilful staff for guidance in my first steps in the field of immunohistochemistry. Further thanks go to Prof. Pertti Panula and his staff at the Department of Anatomy, University of Helsinki at that time to help me with setting up the method. I wish to thank Ph. Lic. Juhani Tuominen for his advice concerning statistical problems.
Special thanks go to M. Sc. Ulla-Mari Parkkisenniemi for great friendship both in the work and leisure. I wish also to thank the entire staff of the Department of Pharmacology and Toxicology for creating a friendly and inspiring atmosphere in which it has been pleasant to work.
Finally, I owe my warmest gratitude to my husband Arto and to our children Laura and Riikka for their encouragement, support and never-ending love during the many years of the research. They certainly have kept my feet firmly on the ground. Also, the support, encouragement and love of my dear parents Raili and Jussi and my dear brother Timo has been essential. Further, I want to express sincere thanks to Minna Nieminen for being invaluable friend and support during all these years.
Financial support from University of Helsinki, the Finnish Cultural Foundation and the Research Council for Health of the Academy of Finland is gratefully acknowledged.
Helsinki, July 2000
Outi Salminen
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