Oral buspirone causes a shift in the dose-response curve between the elevated-plus maze and Vogel conflict tests in Long-Evans rats: relation of brain levels of buspirone and 1-PP to anxiolytic action.
Most studies concerning the effects of oral buspirone in the rat elevated plus-maze (EPM) test, spontaneous motor activity (SMA) test, and Vogel conflict (VC) test have used Sprague-Dawley or Wistar rats. Although it has been documented that the behavior of Long-Evans rats is more sensitive to detection of anxiolytics when compared to the aforementioned strains, the effects of oral buspirone have not been fully characterized in the Long-Evans strain in the EPM and VC tests. Thus, we studied the effects of orally administered buspirone (0.03-10.0 mg/kg) in the EPM, SMA, and VC (0.3-60.0 mg/kg) tests in Long-Evans rats. In a separate experiment, brain and plasma concentrations of buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP) were determined after oral administration of buspirone (0.3 and 10 mg/kg) to relate the behavioral effects of buspirone with brain and plasma concentrations of buspirone and 1-PP. Our results showed that buspirone exhibited an inverted-U-shaped dose-response curve in both the EPM and the VC tests. In the EPM, buspirone produced anxiolytic activity in a low, narrow dose-range (0.03, 0.1, 0.3 mg/kg, p.o.) with maximum efficacy at 0.3 mg/kg, whereas in the VC test, significant anxiolytic activity was observed in a high, narrow dose-range (10, 30 mg/kg, p.o.) with maximum efficacy occurring at 10 mg/kg. In the SMA test, buspirone (10 mg/kg, p.o.) significantly decreased horizontal activity and vertical movements suggestive of sedation. Also, one hour following oral doses of buspirone (0.3 and 10 mg/kg), both buspirone and 1-PP concentrations were higher in brain when compared with those in plasma. Additionally, the concentrations of 1-PP were always higher in brain and in plasma compared with the concentrations of buspirone. Of particular interest is our finding of the shift in the dose-response curve between the EPM and VC tests. This shift in the dose-response curve is discussed in relation to brain levels of buspirone and 1-PP levels and their anxiolytic action.
Vaidya
A H
AH
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, Pennsylvania 19477-0776, USA. avaidya@prdus.jnj.com
Rosenthal
D I
DI
Lang
W
W
Crooke
J J
JJ
Benjamin
D
D
Ilyin
S E
SE
Reitz
A B
AB
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D002065:Buspirone / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D003220:Conflict, Psychological; D004305:Dose-Response Relationship, Drug; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D017366:Serotonin Receptor Agonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D017366:Serotonin Receptor Agonists; C037921:1-(2-pyrimidinyl)piperazine; D002065:Buspirone