title: Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats.
abstract: BACKGROUND
  There is substantial evidence that lisuride can produce effects linked to 5-HT(1A) receptor occupancy. Nevertheless, this action has generally been ignored in the mechanism of action of lisuride, in favor of an exclusive role for dopamine receptors in considering its antiparkinsonian effects, or an exclusive role of 5-HT(2A/2C) receptor activation in hallucinogenesis. These conclusions are surprising when one considers that the potent interaction of lisuride with 5-HT(1A) receptors has been demonstrated in several different laboratories and that activation of 5-HT(1A) and 5-HT(1B) receptors can modulate dopaminergically mediated responses.
  
  
  OBJECTIVE
  The lack of full substitution of lisuride for lysergic acid diethylamide (LSD) in drug discrimination experiments and induction of a pronounced 5-HT syndrome by this compound at relatively low doses convinced us to execute two series of experiments that might explain the primary mechanism responsible for lisuride-mediated biological effects and its paradoxical classification as a dopamine agonist in the literature.
  
  
  RESULTS
  In drug discrimination studies, lisuride fully mimicked the 5-HT(1A) agonist LY 293284, only partially substituted for LSD and DOI, and failed to substitute for (+)-amphetamine. Lisuride produced a significant dose-related increase in flat body posture, forepaw treading, and lower-lip retraction which reflect a modulation of behavior by action at central 5-HT(1A) receptors. Only pMPPI [4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride], a selective 5-HT(1A) antagonist, was effective in inhibiting all 5-HT syndrome behaviors produced by lisuride, whereas pMPPI was without effect on any behavior induced by LSD. Lisuride dose dependently decreased body temperature in rats with a potency similar to that of the selective 5-HT(1A) agonist LY 293284. The hypothermic effect of lisuride was prevented by pre-injection of pMPPI, but not by ketanserin or haloperidol.
  
  
  CONCLUSIONS
  We have demonstrated that the behavioral effects of low doses of lisuride are clearly mediated by stimulation of 5-HT(1A) receptors.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Danuta
authors.initials: D
authors.lastname: Marona-Lewicka
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Kurrasch-Orbaugh
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Selken
authors.forename: Medhane G
authors.initials: MG
authors.lastname: Cumbay
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Lisnicchia
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects* / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D004192:Discrimination, Psychological / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008090:Lisuride / Q000378:metabolism / Q000494:pharmacology*; D008238:Lysergic Acid Diethylamide / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology
chemical_list: D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D008238:Lysergic Acid Diethylamide; D008090:Lisuride