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Importance of and changes in brain neurotransmitters in drug effects and dependenc

Liisa Ahtee, Prof
Department of Pharmacy
Division of Pharmacology and Toxicology

The neurobiological basis of drug addiction is studied by investigating the effects of abused drugs (opioids, nicotine, alcohol, psychostimulants) on cerebral neurotransmitter release, receptor binding, second messengers and gene expression. Especially, the mechanisms involved in the development of neurochemical and behavioural sensitisation to these drugs are studied, because this phenomenon is thought to be crucial in the development of drug addiction. Using an in vivo microdialysis technique we have shown that in addition to its stimulatory effect on nigrostriatal dopamine release, morphine has an inhibitory effect on the terminals of these neurons. Tolerance develops more readily to this inhibitory effect, indicating that disappearance of the inhibitory effect might contribute to the sensitisation of dopamine release during repeated administration of morphine. At present, we are studying the roles m-opioid receptor subtypes (m1 and m2) in the development of opioid addiction. The genetic aspects involved in the susceptibility to addictive behaviour are studied by using rat lines selected for high alcohol (AA, Alko Alcohol) and low alcohol (ANA, Alko NonAlcohol) consumption. Presently we are investigating whether these rat lines are dissimilarly sensitised to neurochemical and behavioural effects of morphine and cocaine. We have also found that nicotine activates c-fos expression in different sets of neurons within striatal, limbic and stress-related brain areas of rats. Nicotinic receptor antagonists were found to vary in their effect of blocking this activation. The aim of our taurine project is to clarify the importance of this abundant amino acid in the central nervous system. The physiological role of taurine is still unknown, but taurine and its derivatives might have therapeutic pontential as antiepileptic or anticraving drugs. We have studied the significance of other neurotransmitters, particularly dopamine, as mediator of central effects of taurine using in vivo microdialysis. Our results indicate that taurine both inhibits and stimulates dopamine release in basal ganglia. The stimulatory effect of taurine on dopamine release is partially mediated by an interaction of taurine with GABAA-receptor complex. Since taurine poorly penetrates into the CNS we collaborate with several laboratories to find taurine derivatives that pass the blood brain barrier. Pharmacological effects of these derivatives are screened using receptor binding assay and behavioural tests. Furthermore, microdialysis is used to measure the concentrations of amino acids in the extracellular fluid in order to study if these derivatives work as taurine pro drug.

Personnel

Juha Airio, Pharm.Lic.; Petteri Piepponen, M.Sc. (Pharm.); Janne Mikkola, M.Sc. (Pharm.); Kirsi Pietilä, Pharm. Lic.; Outi Salminen, M.Sc. (Pharm.); Tiina Seppä, M.Sc. (Pharm.); Helena Gäddnäs, M.Sc. (Pharm.); Minna Ruotsalainen, Pharm.D.; technicians: Marjo Vaha; Anne Karhunen. Collaborations with groups at National Public Heath Institute, Karoliska Institute, University of Tartu, Latvian Institute of Organic Synthesis, University of MŸnster, Catholic University of Louvain.

Selected publications

Airio, J., Ahtee, L. Role of cerebral dopamine and noradrenaline in the morphine-induced locomotor sensitisation in mice. Pharmacol Biochem Behav 58, 379-386, 1997.

Piepponen, T.P., Kivastik, T., Katajamäki, J., Zharkovsky, A., Ahtee, L. Involvement of opioid m1-receptors in morphine-induced conditioned place preference in rats. Pharmacol Biochem Behav 58, 275-279, 1997.

Ruotsalainen, M., Ahtee, L. Intrastriatal taurine increases striatal extracellular dopamine in a tetrodotoxin-sensitive manner in rats. Neurosci Lett .212, 935-946, 1996.

Pietilä, K., Lähde, T., Attila, M., Ahtee, L., Nordberg, A. Regulation of nicotinic receptors in the brain of mice withdrawn from chronic oral nicotine treatment. Naunyn-Schmiedeberg«s Arch Phamacol 357, 176-182, 1998.

Funding

University of Helsinki, Academy of Finland, the Finnish Foundation for Alcohol Studies, the Finnish Cultural Foundation

Last update 01.07.1998 Maintained by Jari Ylänne (ylanne@csc.fi)