Serotonin-2 receptor stimulation normalizes striatal preprotachykinin messenger RNA in an animal model of Parkinson's disease

Neuroscience. 1999;93(3):831-41. doi: 10.1016/s0306-4522(99)00238-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamines / pharmacology
  • Animals
  • Corpus Striatum / metabolism*
  • Disease Models, Animal
  • Dopamine / deficiency
  • Dopamine / physiology
  • Drug Administration Schedule
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • In Situ Hybridization
  • Male
  • Neural Pathways / drug effects
  • Neural Pathways / physiopathology
  • Oxidopamine / toxicity
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / genetics
  • Parkinson Disease, Secondary / metabolism*
  • Protein Precursors / genetics*
  • RNA, Messenger / metabolism*
  • Raphe Nuclei / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / physiology*
  • Serotonin / physiology*
  • Serotonin Receptor Agonists / pharmacology*
  • Substance P / biosynthesis
  • Substantia Nigra / metabolism
  • Tachykinins / genetics*


  • Amphetamines
  • Protein Precursors
  • RNA, Messenger
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • Tachykinins
  • preprotachykinin
  • Serotonin
  • Substance P
  • 2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine
  • Oxidopamine
  • Dopamine