Effects of buspirone and its metabolite, 1-(2-pyrimidinyl)piperazine, on brain monoamines and their metabolites in rats.
Buspirone, an anxiolytic drug with selective affinity for the 5-HT-1A subtype of serotonin receptors, caused a dose-related decrease in 5-hydroxyindole acetic acid (5-HIAA) concentration in rat hypothalamus after doses of 1 to 10 mg/kg s.c. The decrease in 5-HIAA concentration after a 3 mg/kg s.c. dose of buspirone persisted at 4 hr but not at 7 hr. The decrease was due apparently to a reduced turnover of serotonin; the accumulation of 5-hydroxytryptophan after decarboxylase inhibition was also suppressed by buspirone, not only in hypothalamus but also in brain stem, hippocampus and striatum. 1-(2-Pyrimidinyl)-piperazine (1-PP), a major metabolite of buspirone, did not affect hypothalamic 5-HIAA concentration at doses up to 10 mg/kg s.c. Both buspirone and 1-PP increased hypothalamic concentrations of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) sulfate, the norepinephrine metabolite, the effect being more pronounced with 1-PP but occurring after doses as low as 0.3 mg/kg s.c. with each compound. The increase in MHPG sulfate concentration persisted for at least 4 hr after a 3 mg/kg s.c. dose of each compound. The increase in MHPG sulfate produced by buspirone may have been due partly to 5-HT-1A receptor activation, inasmuch as other serotonin agonists have been found to cause a similar increase. 1-PP is reported to lack affinity for 5-HT-1A receptors so its elevation of MHPG sulfate concentration may have resulted from alpha-2 receptor blockade. The increase in MHPG sulfate concentration after buspirone injection may have been due at least partly to formation of the metabolite, 1-PP.(ABSTRACT TRUNCATED AT 250 WORDS)
Fuller
R W
RW
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Perry
K W
KW
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002065:Buspirone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D011335:Proadifen; C037921:1-(2-pyrimidinyl)piperazine; D002065:Buspirone; D004298:Dopamine; D009638:Norepinephrine