Discriminative stimulus effects of serotonin agonists, neutral antagonists, and inverse agonists in pigeons: perspectives on intrinsic efficacy measurements in vivo.
BACKGROUND
The extended ternary complex theory of receptor function states a ligand can be classified as an inverse agonist, agonist, or neutral antagonist based on its ability to preferentially stabilize the inactive conformation, the active conformation, or to have no preference for conformational state, respectively.


OBJECTIVE
While serotonin(2C) (5-HT(2C)) receptor ligands are classified accordingly in vitro, whether the phenomenon of inverse agonism manifests itself and/or is physiologically relevant in vivo is unknown.


METHODS
Therefore, we tested a range of proposed agonists, neutral antagonists, and inverse agonists with activity at 5-HT(2C) receptors in three groups of pigeons trained to discriminate saline from: 1.0 mg/kg MK212, an agonist; 0.1 mg/kg methysergide, a proposed neutral antagonist; or, 10 mg/kg mianserin, a proposed inverse agonist.


RESULTS
Based on the patterns of substitution, the discriminative stimulus effects of MK212 appear to be mediated through agonist actions and the stimulus effects of methysergide and mianserin appear to be mediated through antagonist actions. Selective 5-HT(2B/2C) inverse agonist SB206,553 (1 mg/kg) blocked the MK212 discriminative stimulus cue and substituted (0.32-10 mg/kg) in both methysergide- and mianserin-trained pigeons, confirming a 5-HT(2C) receptor role in mediating these discriminative stimuli. Inverse agonists and neutral antagonists fully substituted for methysergide. In addition to SB206,553, methysergide (0.032-1.0 mg/kg) and 5-HT(1A) agonist 8-OH-DPAT (0.32-1.0 mg/kg) substituted completely for mianserin suggesting a complex discriminative stimulus profile for this proposed inverse agonist.


CONCLUSIONS
These data and the subsequent analyses suggest that the discriminative cues of MK212, methysergide, and mianserin are different and that the drug discrimination paradigm is a useful functional assay to examine intrinsic efficacy in vivo.
Farrell
Martilias
M
Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, 3307 North Broad Street, Philadelphia, PA 19140, USA.
Rosenzweig-Lipson
Sharon
S
Walker
Ellen
E
D000818:Animals; D010856:Columbidae; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D008297:Male; D008784:Methysergide / Q000008:administration & dosage / Q000494:pharmacology; D008803:Mianserin / Q000008:administration & dosage / Q000494:pharmacology; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
D011719:Pyrazines; D044405:Receptor, Serotonin, 5-HT2C; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D008803:Mianserin; C014896:6-chloro-2-(1-piperazinyl)pyrazine; D008784:Methysergide