Neuroendocrinological and neurochemical effects of sigma ligands.
The potential antipsychotic agents BMY 14802, remoxipride, tiospirone and gevotriline (WY 47,384) have a relatively high affinity for sigma binding sites in brain tissue. In the present study, the effects of these sigma ligands on concentrations of prolactin and corticosterone in serum in the rat were investigated. In addition, the effects of these agents on the synthesis and/or release of dopamine from tuberoinfundibular and nigrostriatal neurons were determined. Concentrations of prolactin and corticosterone in serum were increased dose-dependently by BMY 14802, tiospirone, remoxipride and gevotriline. The activity of tyrosine hydroxylase within the terminals of tuberoinfundibular dopamine neurons in vivo also was increased by BMY 14802, tiospirone and gevotriline, but not by remoxipride. The extracellular concentrations of dopamine and dihydroxyphenylacetic acid in the striatum, as determined by in vivo microdialysis, were increased by BMY 14802 (5-20 mg/kg, s.c.) and remoxipride (3 mg/kg, s.c.). These data suggest the involvement of sigma receptors in the regulation of secretion of prolactin and corticosterone, as well as the activity of tuberoinfundibular and nigrostriatal dopamine neurons. Moreover, the pattern of neurochemical and neuroendocrinological responses to these sigma ligands resembled those which have been determined previously for atypical antipsychotics and support the contention that these sigma ligands may be antipsychotic agents with an atypical profile of action.
Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106.
G A
GA
Gudelsky
J F
JF
Nash
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002243:Carbolines / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008473:Median Eminence / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011388:Prolactin / Q000097:blood*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017480:Receptors, sigma; D017330:Remoxipride; D013141:Spiro Compounds / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001549:Benzamides; D002243:Carbolines; D011725:Pyridines; D011743:Pyrimidines; D011957:Receptors, Opioid; D017480:Receptors, sigma; D013141:Spiro Compounds; D017330:Remoxipride; D015102:3,4-Dihydroxyphenylacetic Acid; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; C042709:tiospirone; C069280:gevotroline; D011388:Prolactin; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D003345:Corticosterone