title: Role of 5-HT₂C receptors in effects of monoamine releasers on intracranial self-stimulation in rats.
abstract: BACKGROUND
  Many monoamine releasers are abused by humans and produce abuse-related facilitation of intracranial self-stimulation (ICSS) in rats. Facilitation of ICSS in rats can be limited by monoamine releaser-induced serotonin (5-HT) release, but receptors that mediate 5-HT effects of monoamine releasers are unknown.
  
  
  OBJECTIVE
  The aim of this study is to investigate whether 5-HT2C receptor activation is necessary for rate-decreasing effects produced in an ICSS procedure in rats by the 5-HT-selective monoamine releaser fenfluramine and the non-selective releasers napthylisopropylamine (PAL-287) and (+)-3,4-methylenedioxymethamphetamine ((+)-MDMA).
  
  
  METHODS
  Adult male Sprague-Dawley rats with electrodes implanted in the medial forebrain bundle were trained to lever press for brain stimulation under a "frequency-rate" ICSS procedure. Effectiveness of the 5-HT2C antagonist SB 242,084 was evaluated to block rate-decreasing effects produced by (1) the 5-HT2C agonist Ro 60-0175, (2) the 5-HT-selective releaser fenfluramine, and (3) the mixed-action dopamine (DA)/norepinephrine (NE)/5-HT releasers PAL-287 (1.0-5.6 mg/kg) and (+)-MDMA (1.0-3.2 mg/kg). For comparison, effectiveness of SB 242,084 to alter rate-decreasing effects of the kappa-opioid receptor agonist U69,593 and rate-increasing effects of the DA>5-HT releaser amphetamine was also examined.
  
  
  RESULTS
  SB 242,084 pretreatment blocked rate-decreasing effects of Ro 60-0175 and fenfluramine, but not the rate-decreasing effects of U69,593 or the rate-increasing effects of amphetamine. SB 242,084 blunted the rate-decreasing effects and enhanced expression of rate-increasing effects of PAL-287 and (+)-MDMA.
  
  
  CONCLUSIONS
  These data suggest that 5-HT2C receptor activation contributes to rate-decreasing effects that are produced by selective and mixed-action 5-HT releasers in rats and that may oppose and limit the expression of abuse-related ICSS facilitation by these compounds.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th St., PO Box 980613, Richmond, VA, 23298, USA.
authors.forename: Clayton T
authors.initials: CT
authors.lastname: Bauer
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects; D004567:Electrodes, Implanted; D005277:Fenfluramine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D017473:Receptors, Opioid, kappa / Q000819:agonists; D012653:Self Stimulation / Q000187:drug effects*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000631:Aminopyridines; D044482:Benzeneacetamides; D015306:Biogenic Monoamines; D005277:Fenfluramine; D007211:Indoles; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D011759:Pyrrolidines; D044405:Receptor, Serotonin, 5-HT2C; D017473:Receptors, Opioid, kappa; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; C045444:U 69593