title: The anxiolytic serotonin 5-HT1A receptor agonists buspirone, ipsapirone and gepirone are inhibitors of tyrosine hydroxylation in rat striatum.
abstract: The anxiolytics buspirone (BUS), ipsapirone (IPSAP) and gepirone (GEP) were investigated as 5-HT1A receptor-mediated inhibitors of tyrosine hydroxylation (TH) in a synaptosome-rich preparation of rat striatum. BUS, IPSAP and GEP were moderately potent inhibitors of TH with EC50 values of 48.4 microM, 50 microM and 836 microM, respectively. By comparison, 8-OH-DPAT, a 5-HT1A receptor selective agonist, has been previously shown to be more potent with an EC50 value of 7.0 microM. Each of these agents demonstrated full agonist activity at the striatal 5-HT1A receptors regulating TH. The inhibitory effects of each agent were attenuated by prior exposure to the 5-HT1A antagonist NAN-190, (10 microM) (P < 0.05), but not by the dopamine D2 antagonist (-)-sulpiride (10 microM). The potencies of 8-OH-DPAT, BUS, IPSAP and GEP were correlated with their reported affinities for the 5-HT1A receptor (P < 0.01) but not the dopamine D2 receptor. These results support the hypothesis that BUS, IPSAP and GEP inhibit TH through activation of a striatal 5-HT1A heteroreceptor on dopamine nerve terminals.
authors.affiliation: Department of Behavioral Medicine and Psychiatry, Robert C. Byrd Health Sciences Center of West Virginia University, Morgantown 26506, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Johnson
authors.forename: J L
authors.initials: JL
authors.lastname: Fox
authors.forename: A J
authors.initials: AJ
authors.lastname: Azzaro
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002065:Buspirone / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology*; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013469:Sulpiride / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors*
chemical_list: D014151:Anti-Anxiety Agents; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; C043077:ipsapirone; D013469:Sulpiride; D014446:Tyrosine 3-Monooxygenase; C039979:gepirone; D002065:Buspirone