Neuropharmacological studies of Parkinson´s disease with some emphasis on serotonin transmission

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by hypokinesia, rigidity, tremor, gait disturbances and depression. There is an accumulative of protein aggregates, Lewy bodies, which appear to begin in the brainstem and progress caudorostrally. Several symptoms are caused by loss of dopaminergic neurons in the substantia nigra pars compacta that innervate striatum. The principal treatment for PD is dopamine replacement, particularly with the dopamine precursor, 3,4 dihydroxyphenyl-L-alanine (L-DOPA). However, ultimately these treatments are insufficient and cause, via largely unknown mechanisms, severe side-effects, such as dyskinesias and hallucinations. The present studies examined non-dopaminergic adaptive changes in the 6-hydroxydopamine (6-OHDA) lesion animal model of PD with or without L-DOPA treatment. Pharmacological experiments were performed with non-dopaminergic drugs and symptomatic improvements registered. There is a considerable overlap in dopaminergic and serotonergic innervation in the brain. There is evidence that the serotonin system is less degenerated in PD and may compensate loss of dopamine. Moreover, in severe PD, a substantial amount of L-DOPA is converted into dopamine in serotonin neurons. As a proof of principle, sarizotan, a 5-HT1A receptor (5-HT1AR) agonist and D2-like partial agonist has beneficial effects in some severe Parkinsonian patients. 6-OHDA lesioning was found to have no effect on 5-HT1BRs, increased 5-HT2ARs, but decreased 5-HT2CRs and 5-HT6Rs in striatum. L-DOPA treatment caused an increase of 5-HT1BRs, a decrease of 5HT2ARs and had no effect on 5-HT2CRs. In pharmacological experiments, the 5-HT1AR agonist, sarizotan, and the 5-HT1BR agonist, CP94253, decreased the number of rotations and abnormal involuntary movements induced by L-DOPA. Sarizotan also increased cell proliferation in the subgranular zone of dentate gyrus. These data suggest that serotonergic agents may have potential to reduce L-DOPA induced side effects and non-motor symptoms in PD. Adaptive changes occur in neuropeptide levels in experimental models of PD or post-mortem material from PD patients, indicating that neuropeptides are involved in the pathophysiological process in PD. 6-OHDA lesioning tended to increase neurokinin B (NKB) and decrease substance P (SP). An acute injection of L-DOPA had no effect on NKB, but restored SP, in the 6-OHDAlesioned hemisphere. However, subchronic or chronic administration of L-DOPA increased NKB in the dopamine-depleted hemisphere. In a pharmacological experiment, the NK3R antagonist, SB222200, potentiated L-DOPA-induced contralateral rotations. These data suggest a role of NKB/NK3R signalling in patients with advanced PD that are treated with L-DOPA. A peptidomic screen showed changes in the precursors of secretogranin (Sg)-1, Sg-3, somatostatin, preproenkephalin B and cholecystokinin, in the 6-OHDA lesion animal model of PD with or without L-DOPA treatment. The levels of peptides derived from the Sg-1 were increased in the lesioned side. A peptide derived from Sg-3 was lower in the lesioned side but following L-DOPA the levels were higher. Two peptides derived from somatostatin-28 were upregulated in the lesioned side, but reduced following L-DOPA. L-DOPA treatment increases the expression of preproenkephalin B peptides. Two peptides derived from the cholecystokinin precursor were increased following L-DOPA. Recent PD research has suggested that small neuroimmunophilin or neurotrophic proteins are putative targets for the treatment of PD. Using a proteomic approach, it was found that dopamine denervation caused a significant elevation of FKBP-12. Repeated L-DOPA treatment increased BDNF expression in the dopamine-depleted subthalamic nucleus but not in striatum, indicating that BDNF may have physiological consequences on the trophic support and physiology of nigral and pallidal neurons that receive subthalamic inputs and express TrkB receptors. Taken together, these studies have provided insight into adaptive non-dopaminergic changes in PD and identified novel putative targets for pharmacological treatment of motor symptoms of PD. It is speculated that these non-dopaminergic targets could also be used against non-motor symptoms, particularly depression in PD, for which there is a need for improved medications. List of Publications 1. Zhang, X. , Andren, P.E. , Greengard, P., Svenningsson, P. (2008) Evidence for a role of the 5HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of Parkinsonism. Proc Natl Acad Sci U S A. 105:2163-2168. 2. Zhang, X. , Andren, P.E. , Svenningsson, P. (2007) Changes in 5-HT2 receptors in striatum and subthalamic nucleus in Parkinson s Disease model. Physiol Behav. 92:29-33. 3. Zhang, X. , Egeland, M. , Svenningsson, P. Sarizotan stimulates cell proliferation in neurogenic regions in experimental Parkinsonism. Submitted manuscipt. 4. Zhang, X. , Andren, P.E. , Glennon, R. , Svenningsson P. Differences in the distribution, levels, pharmacology and regulation of 5-HT6 receptors between mice, rats and marmosets with special reference to a Parkinson model. Submitted manuscipt. 5. Zhang, X. , Andren, P.E. , Chergui, K. , Svenningsson, P. (2008) Neurokinin B/NK3 receptors exert feedback inhibition on L-DOPA actions in the 6-OHDA lesion rat model of Parkinson's disease. Neuropharmacology. 54:1143-1152. 6. Nilsson, A. , Skold, K. , Sjogren, B. , Svensson, M. , Pierson, J., Zhang, X. , Caprioli, R.M. , Buijs, J., Persson, B. , Svenningsson, P., Andren, P.E. (2007) Increased Striatal mRNA and Protein Levels of the Immunophilin FKBP-12 in Experimental Parkinson’s Disease and Identification of FKBP-12-Binding Proteins. Journal of Proteome Research. 6:3952-3961. 7. Nilsson, A. , Falth, M. , Zhang, X. , Kultima, K. , Skold, K. , Svenningsson, P., Andren, P.E. Striatal alterations of secretogranin-1, somatostatin, prodynorphin and cholecystokinin peptides in an experimental mouse model of Parkinson’s disease. Submitted manuscipt. 8. Zhang, X. , Andren, P.E. , Svenningsson, P. (2006) Repeated L-DOPA treatment increases c-fos and BDNF mRNAs in the subthalamic nucleus in the 6-OHDA rat model of Parkinson's disease. Brain Res. 1095:207-210. Additional publications during PhD study 1. Svenningsson, P., Chergui, K. , Rachleff, I. , Flajolet, M. , Zhang, X. , El Yacoubi, M. , Vaugeois, J.M. , Nomikos, G.G. , Greengard, P. (2006) Alterations in 5-HT1B receptor function by p11 in depression-like states. Science. 311:77-80. 2. Kindlundh-Hogberg, A.M., Zhang, X. , Svenningsson, P. (2008) S100B overexpressing mutant mice exhibit prolonged behavioural and biochemical responses towards repeated intermittent binge treatments with MDMA. Int J Neuropsychopharmacol. Published on-line. 3. Qi, H. , Mailliet, F. , Spedding, M. , Rocher, C. , Zhang, X. , Delagrange, P., McEwen, B. , Jay, T.M. , Svenningsson, P. (2008) Antidepressants reverse the attenuation of the neurotrophic MEK/MAPK cascade in frontal cortex by elevated platform stress; reversal of effects on LTP is associated with GluA1 phosphorylation. Neuropharmacology. Published on-line.