Alterations of central serotonin and dopamine turnover in rats treated with ipsapirone and other 5-hydroxytryptamine1A agonists with potential anxiolytic properties.
Measurements of tissue levels of monoamines and their metabolites, and of the rates of 5-hydroxytryptophan and dihydroxy-phenylalanine accumulation after blockade of aromatic amino acid decarboxylase by benserazid indicated that ipsapirone (1-10 mg/kg i.p.) decreased 5-hydroxytryptamine (5-HT) turnover and accelerated dopamine (DA) turnover in various brain regions. The reduced 5-HT turnover probably resulted from the stimulation of 5-HT1A autoreceptors within the anterior raphe nuclei as in vitro tests [( 3H]-8-hydroxy-2-[di-n-propylamino]tetralin binding and adenylate cyclase assays) demonstrated that ipsapirone was a 5-HT1A agonist almost as potent as 8-OH-DPAT, and the same decrease in 5-hydroxytryptophan accumulation could be induced by the i.p. (5 mg/kg) or intraraphe (1 microgram) injection of ipsapirone. Ipsapirone-induced acceleration of DA turnover persisted after the selective degeneration of serotoninergic neurons by intraraphe 5,7-dihydroxytryptamine infusion, and could be reproduced by i.p. administration of other 5-HT1A agonists like buspirone and gepirone, but not 8-OH-DPAT. These results demonstrate that ipsapirone-induced acceleration of DA turnover did not result from the stimulation of 5-HT1A (auto)receptors, but involved additional target(s) of the drug. The possible participation of dopaminergic systems in the "anxiolytic" properties of ipsapirone should deserve further investigations.
Hamon
M
M
Institut National de la Santé et de la Recherche Médicale U. 288, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Fattaccini
C M
CM
Adrien
J
J
Gallissot
M C
MC
Martin
P
P
Gozlan
H
H
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C043077:ipsapirone; D004298:Dopamine