title: Serotonin-2 receptor stimulation normalizes striatal preprotachykinin messenger RNA in an animal model of Parkinson's disease.
abstract: Dopamine and serotonin neurotransmission regulate striatal preprotachykinin messenger RNA levels. In the present study, we investigated serotonin 2A/2C receptor-mediated regulation of preprotachykinin messenger RNA expression in the rat striatum after adult dopamine depletion produced with 6-hydroxydopamine. Significant reductions (46-61% of control values) in preprotachykinin messenger RNA levels were detected by in situ hybridization in rostral, central and caudal regions of the striatum after >85% dopamine depletion. Repeated administration of the specific serotonin2A/2C receptor agonist, (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide, to dopamine-depleted rats completely reversed the reduction in preprotachykinin messenger RNA levels in rostral, central and dorsal-caudal striatal regions. In unlesioned (vehicle-injected) control animals, repeated administration of (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide did not affect preprotachykinin messenger RNA expression in rostral, central and ventral-caudal striatal regions, but decreased preprotachykinin messenger RNA levels in the dorsal-caudal striatal subregion. In addition, serotonin turnover in the dopamine-depleted rostral striatum was significantly increased by 35-45% which is consistent with serotonin hyperinnervation after 6-hydroxydopamine lesions. These data show that the decrease in striatal preprotachykinin messenger RNA after dopamine depletion can be normalized with repeated serotonin2A/2C receptor stimulation. We hypothesize that this serotonin2A/2C receptor regulation of preprotachykinin messenger RNA expression after 6-hydroxydopamine is a consequence of serotonin hyperinnervation, which may include increased striatal serotonin2A/2C receptors, induced by dopamine depletion. We also propose that the serotonin system could be pharmacologically targeted to restore the direct striatal tachykinin pathway in Parkinson's disease.
authors.affiliation: Cellular and Clinical Neurobiology Program, Department of Psychiatry and Behavioral Neurosciences, Wayne State University, School of Medicine, Detroit, MI 48201, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Gresch
authors.forename: P D
authors.initials: PD
authors.lastname: Walker
mesh_terms: D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency / Q000502:physiology; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017403:In Situ Hybridization; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D011903:Raphe Nuclei / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013373:Substance P / Q000096:biosynthesis; D013378:Substantia Nigra / Q000378:metabolism; D015320:Tachykinins / Q000235:genetics*
chemical_list: D000662:Amphetamines; D011498:Protein Precursors; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D015320:Tachykinins; C044206:preprotachykinin; D012701:Serotonin; D013373:Substance P; C079285:2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine; D016627:Oxidopamine; D004298:Dopamine