The International Journal of Neuropsychopharmacology



Region-dependent effects of flibanserin and buspirone on adenylyl cyclase activity in the human brain


Donatella  Marazziti  a1 c1, Lionella  Palego  a1, Annalisa  Giromella  a1, Maria  Rosa Mazzoni  a1, Franco  Borsini  a2, Norbert  Mayer  a2, Antonio  Giuseppe Naccarato  a3, Antonio  Lucacchini  a1 and Giovanni  Battista Cassano  a1
a1 Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologia, Università di Pisa, via Roma 67, 56100 Pisa, Italy
a2 Boehringer Ingelheim CNS Department, Ingelheim/Rhein, Germany
a3 Dipartimento di Oncologia, Università di Pisa, via Roma 67, 56100, Pisa, Italy

Abstract

The mode of action of antidepressant drugs may be related to mechanisms of receptor adaptation, involving overall the serotonin 1A (5-HT1A) receptor subtype. However, so far, the clinical effectiveness of selective compounds acting at this level has proved disappointing. This could be explained by the heterogeneity of 5-HT1A receptors within the central nervous system. In animals, two 5-HT1A agonists, flibanserin and buspirone, have shown different pharmacological properties, depending on the brain region. Since no evidence supports this observation in humans, this study sought to investigate whether these two drugs exert different effects on 5-HT1A receptor activation in three different human brain areas: the prefrontal cortex, hippocampus and raphe nuclei. 5-HT1A-mediated inhibition of forskolin-stimulated adenylyl cyclase (AC) was taken as an index of 5-HT1A receptor activation. Flibanserin significantly reduced the activity of AC post-synaptically, i.e. in the prefrontal cortex [EC50 (mean±S.E.M.), 28±10·2 nM; Emax, 18±2·3%] and in the hippocampus (EC50, 3·5±3·1 nM; Emax, 20±4·0%), but had no effect in the raphe nuclei, i.e. at pre-synaptic level. Vice versa, buspirone was only slightly but significantly effective in the raphe (EC50, 3·0±2·8 nM; Emax, 12±1·9%). Agonist effects were sensitive to the 5-HT1A antagonists WAY-100135 and pindobind 5-HT1A in the cortex and raphe nuclei, whereas buspirone antagonized flibanserin in the hippocampus. These findings suggest a region-related action of flibanserin and buspirone on forskolin-stimulated AC activity in human brain.

(Received August 5 2001)
(Reviewed October 17 2001)
(Revised November 28 2001)
(Accepted December 2 2001)


Key Words: Adenylyl cyclase activity; buspirone; flibanserin; post-mortem human brain; 5-HT1A receptors.

Correspondence:
c1 Address for correspondence: Dr D. Marazziti, Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologia, via Roma 67, 56100 Pisa, Italy. Tel.: +39-050-835412 Fax: +39-050-21581 E-mail: dmarazzi@psico.med.unipi.it