Discriminative stimulus properties of the novel serotonin (5-HT)2C receptor agonist, RO 60-0175: a pharmacological analysis

Neuropharmacology. 1999 Mar;38(3):415-23. doi: 10.1016/s0028-3908(98)00203-2.

Abstract

Employing a Fixed-Ratio 10, food-reinforced protocol, rats were trained to recognize the discriminative stimulus (DS) properties of the novel, potent, 5-HT2C agonist, Ro 60-0175 (2.5 mg/kg, i.p.). This schedule generated appropriate drug versus vehicle responding after 50 + 5 training sessions and Ro 60-0175 elicited full (100%) drug selection with an effective dose50 (ED50) of 0.6 mg/kg, i.p.. The 5-HT2C receptor agonists, mCPP and MK 212, fully generalized to Ro 60-0175 with ED50s of 0.8 and 0.4 mg/kg, s.c., respectively, whereas the preferential 5-HT2B agonist, BW 723C86 ( > 10.0 mg/kg, s.c.) and the 5-HT2A agonist, DOI ( > 2.5 mg/kg, s.c.), were ineffective. The 5-HT2A/2B/2C receptor antagonist, mianserin, dose-dependently blocked the DS properties of Ro 60-0175 with an ED50 of 0.7 mg/kg, s.c. This action was mimicked by the novel, 5-HT2B/2C antagonist, SB 206,553 (ED50 = 0.3 mg/kg, s.c.), whereas the selective 5-HT2A antagonist, MDL 100,907 ( > 0.63 mg/kg, s.c.), was ineffective. Further, the selective 5-HT2C antagonist, SB 242,084, dose-dependently and fully blocked drug selection (ED50 = 0.2 mg/kg, i.p.), whereas the selective 5-HT2B antagonist, SB 204,741, was not active ( > 0.63 mg/kg, i.p.). In conclusion, these data demonstrate that Ro 60-0175 generates a robust DS and suggest that activation of 5-HT2C receptors is the principal mechanism underlying its DS properties.

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Aminopyridines / pharmacology
  • Animals
  • Conditioning, Operant / drug effects*
  • Conditioning, Operant / physiology
  • Ethylamines / pharmacology*
  • Fluorobenzenes / pharmacology
  • Indoles / pharmacology*
  • Male
  • Mianserin / pharmacology
  • Piperazines / pharmacology
  • Piperidines / pharmacology
  • Pyrazines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin / physiology*
  • Reinforcement, Psychology
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology*
  • Thiophenes / pharmacology

Substances

  • 1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine
  • 6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline
  • Aminopyridines
  • Ethylamines
  • Fluorobenzenes
  • Indoles
  • Piperazines
  • Piperidines
  • Pyrazines
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin
  • Ro 60-0175
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Thiophenes
  • Mianserin
  • 6-chloro-2-(1-piperazinyl)pyrazine
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • volinanserin
  • 1-(3-chlorophenyl)piperazine