Behavioral and neurochemical effects of the serotonin (5-HT)1A receptor ligand spiroxatrine.
The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)1A receptor, were compared with compounds believed to function as agonists at the 5-HT1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock ("conflict" procedure). Under the multiple schedule, spiroxatrine (0.3-1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01-1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [3H]8-OH-DPAT binding to pigeon cerebral membranes with IC50 values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine antagonist component.
Barrett
J E
JE
Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.
Hoffmann
S M
SM
Olmstead
S N
SN
Foust
M J
MJ
Harrod
C
C
Weissman
B A
BA
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002065:Buspirone / Q000494:pharmacology; D010856:Columbidae; D003216:Conditioning, Operant / Q000187:drug effects; D004146:Dioxanes / Q000494:pharmacology*; D004147:Dioxins / Q000494:pharmacology*; D018492:Dopamine Antagonists; D010891:Piribedil / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes
D015306:Biogenic Monoamines; D004146:Dioxanes; D004147:Dioxins; D018492:Dopamine Antagonists; D011985:Receptors, Serotonin; D013141:Spiro Compounds; D013764:Tetrahydronaphthalenes; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010891:Piribedil; C018387:spiroxatrine; D002065:Buspirone