Onset of the effects of the 5-HT1A antagonist, WAY-100635, alone, and in combination with paroxetine, on olfactory bulbectomy and 8-OH-DPAT-induced changes in the rat.
5-HT1A receptor antagonists have recently been shown to accelerate the effects of some antidepressant drugs in clinical trials. In this study we investigate the effects of combining a full antagonist at the 5-HT1A receptor, WAY 100635 (0.2 mg/kg, SC) with the selective serotonin reuptake inhibitor (SSRI) paroxetine (5 mg/kg. SC) in the olfactory bulbectomized (OB) rat, an animal model of chronic (but not acute) antidepressant activity. Ambulation scores were measured in the open-field apparatus, following 3, 7, and 14 days of treatment. Further to the OB study, we simultaneously studied adaptive changes in 5-HT1A receptor function, utilizing alterations in the hypothermic response to the 5-HT1A receptor agonist 8-OH-DPAT. Paroxetine, in combination with WAY 100635, attenuated the hypothermic effects of 8-OH-DPAT as early as 3 days, with a full reversal evident following 7 days, whereas paroxetine, although attenuating the hypothermic effects in OB group by day 7, only reversed it fully after 14 days. Paroxetine alone and in combination with the antagonist reversed the olfactory bulbectomy-induced hyperactivity in the open field following 14 days of treatment only, this being the normal time of an "antidepressant" response in this model. However, there was no significant attenuation at any of the earlier time points. This further demonstrates that the reversal of this aspect of the olfactory bulbectomy-induced behavioral syndrome is insensitive to the potential faster onset of antidepressant action induced by 5-HT1A receptor antagonists. Nonetheless, WAY 100635, unlike previous studies with pindolol, did not interfere with the effects of the antidepressant in the model. The ability of the combination group to attenuate the hypothermic effects of 8-OH-DPAT faster than paroxetine alone, further emphasizes the role of the 5-HT1A receptor in the mechanism of action of antidepressants, and as a target for the development of faster acting antidepressants.
Cryan
J F
JF
Department of Psychiatry, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.
McGrath
C
C
Leonard
B E
BE
Norman
T R
TR
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage*; D003863:Depression / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004357:Drug Synergism; D005106:Exploratory Behavior / Q000187:drug effects; D007035:Hypothermia / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009830:Olfactory Bulb / Q000502:physiology; D017374:Paroxetine / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000008:administration & dosage* / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D018687:Antidepressive Agents, Second-Generation; D017374:Paroxetine; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide