University of Helsinki, Helsinki 2006
GDNF/RET signalling in regulation of brain dopaminergic systems: significance for drug addiction
Doctoral dissertation, November 2006.
Glial cell line-derived neurotrophic factor (GDNF) has been shown to be a potent neurotrophic factor for the brain dopaminergic systems. GDNF has been shown to protect and promote recovery of brain dopaminergic neurons in animal models of Parkinson's disease. As brain dopaminergic pathways are important for perceiving drug reward, and as they undergo plastic changes during chronic drug use, interactions between GDNF and responses to abused drugs are of interest. This study investigated the role of endogenous GDNF in the regulation of nigrostriatal and mesolimbic dopaminergic neurotransmission. The effects of acutely and repeatedly administered cocaine and morphine on striatal dopamine release, on behavioural sensitization and on drug reward were studied in heterozygous GDNF knockout mice. In addition, this study explored the effects of constitutive RET tyrosine kinase receptor activity on brain dopaminergic systems and on the locomotor enhancing effects of cocaine in mice. Unexpectedly, it was found that extracellular dopamine concentrations were increased in striatal brain areas in heterozygous GDNF knockout mice. This was further supported by a clear increase in the number of FosB/deltaFosB positive nuclei in the caudate/putamen and nucleus accumbens in these mice. Thus, the present results indicate that dopaminergic transmission is increased in mice with reduced GDNF levels. In addition, heterozygous GDNF+/- mice were more sensitive to morphine's dopamine releasing effect, and reduced GDNF levels were associated with a shift in the bell-shaped dose-response curve of morphine to the left. Interestingly, it was found that after repeated morphine and cocaine treatment, the extracellular dopamine concentrations in the GDNF+/- mice were decreased to a level similar to their wild-type littermates. In addition, it was found that reduced GDNF levels are involved in a more rapid development of tolerance to locomotor enhancing effects of daily 30 mg/kg morphine injections, and in increased sensitivity to locomotor sensitization by a 5 mg/kg morphine challenge dose. Furthermore, the present results show that constitutive RET activity, caused by a single point mutation Met919Thr, robustly increased dopamine concentrations in the brain, whereas noradrenaline or serotonin concentrations were not affected. Increased dopamine concentrations were associated with increased tyrosine hydroxylase protein levels, indicating that dopamine synthesis is increased in these mice. An important finding was that increased RET activity increased the number of nigrostriatal dopamine neurons in the adult mice. All in all, the present findings emphasize the important role of GDNF/RET-signalling in the regulation of brain dopaminergic systems.
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Last updated 24.10.2006