title: Effects of serotonin (5-HT)1A and 5-HT2A receptor agonists on schedule-controlled responding in rats: drug combination studies.
abstract: BACKGROUND
  Indirect-acting serotonin (5-HT) receptor agonists (e.g., selective 5-HT reuptake inhibitors [SSRI]) stimulate multiple 5-HT receptors, although the role of particular receptors as well as interaction(s) among different receptors in the therapeutic effects of SSRIs is not fully understood.
  
  
  OBJECTIVE
  Relatively few studies have systematically examined direct-acting agonists in combination. This study examined the 5-HT(1A) receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (8-OH-DPAT; 0.01-10.0 mg/kg) and 3-chloro-4-fluorophenyl-4-fluoro-4-([(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl)-piperidin-1-yl-methanone (F13714; 0.01-1.0 mg/kg) and the 5-HT(2A) receptor agonists 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 0.32-10.0 mg/kg) and dipropyltryptamine (DPT; 1.0-32.0 mg/kg), alone and in combination, in rats responding under a fixed ratio schedule of food presentation.
  
  
  RESULTS
  When administered alone, each drug decreased the rate of responding in a dose-related manner with the potency order being F13714 > 8-OH-DPAT > DOM > DPT. WAY100635 (5-HT(1A) receptor antagonist; 0.01-0.1 mg/kg) attenuated the rate-decreasing effects of 8-OH-DPAT and F13714 while MDL100907 (5-HT(2A) receptor antagonist; 0.01-0.1 mg/kg) attenuated the rate-decreasing effects of DOM and DPT. Dose addition analysis showed that the interaction between 8-OH-DPAT and F13714, as well as the interaction between DOM and DPT, was additive. In contrast, the interaction between 8-OH-DPAT and DOM, as well as the interaction between F13714 and DOM, was infra-additive.
  
  
  CONCLUSIONS
  This study shows that for some dose combinations, agonist actions at one 5-HT receptor subtype attenuate agonist actions at another 5-HT receptor subtype; thus, the combined neuropharmacological actions and therapeutic effects of indirect-acting agonists are not likely to be adequately characterized by examining in isolation activity at particular 5-HT receptor subtypes.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
authors.forename: Jun-Xu
authors.initials: JX
authors.lastname: Li
authors.forename: Caroline
authors.initials: C
authors.lastname: Crocker
authors.forename: Wouter
authors.initials: W
authors.lastname: Koek
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Charles P
authors.initials: CP
authors.lastname: France
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D058825:Serotonin 5-HT1 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists