Multifunctional Pharmacology of Flibanserin: Possible Mechanism of Therapeutic Action in Hypoactive Sexual Desire Disorder

Journal of Sexual Medicine

Volumn 8, Issue 1, 2011, Pages 15-27

  Stahl, Stephen M ^a,b   Sommer, Bernd ^c   Allers, Kelly A ^c  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^c BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

Author keywords

Female Sexual Dysfunction; Flibanserin; Hypoactive Sexual Desire Disorder; Monoamines; Sexual Desire

Indexed keywords

4 AMINOBUTYRIC ACID; BUSPIRONE; DOPAMINE 4 RECEPTOR; FLIBANSERIN; GLUTAMIC ACID; MONOAMINE; NORADRENALIN; SEROTONIN 1A RECEPTOR; SEROTONIN 2A RECEPTOR; SEROTONIN 2B RECEPTOR; SEROTONIN 2C RECEPTOR;

AROUSAL; BINDING AFFINITY; BRAIN REGION; DRUG BINDING; DRUG MECHANISM; EXCITATION; HIPPOCAMPUS; HUMAN; HYPOACTIVE SEXUAL DESIRE DISORDER; HYPOTHALAMUS; HYPOTHESIS; MONOAMINE RELEASE; NEUROMODULATION; NONHUMAN; NUCLEUS ACCUMBENS; POSTSYNAPTIC POTENTIAL; PREFRONTAL CORTEX; PRESYNAPTIC NERVE; PRIORITY JOURNAL; PYRAMIDAL NERVE CELL; REVIEW; SEXUAL FUNCTION; TREATMENT OUTCOME;

EID: 78650791761     PISSN: 17436095     EISSN: 17436109     Source Type: Journal    
DOI: 10.1111/j.1743-6109.2010.02032.x     Document Type: Review

References (66)

1. Balon R, Segraves RT. Clinical manual of sexual disorders. Arlington, VA: American Psychiatric Publishing; 2009.
2. Stahl SM. Stahl's essential psychopharmacology. 3rd edition. New York: Cambridge University Press; 2008.
3. Stahl SM. Essential psychopharmacology: The prescriber's guide. 3rd edition. New York: Cambridge University Press; 2009.
4. Clayton A, Jayne C, Jacobs M, Kimura T, Pyke R, Lewis D'Agostino D. Efficacy of flibanserin as a potential treatment for hypoactive sexual desire disorder in North American premenopausal women: Results from the DAHLIA trial. J Sex Med 2009;6(suppl 5):408.
5. Goldfischer ER, Breaux J, Katz M, Kaufman J, Smith WB, Patel P, Mikl J, Sand M, Pyke R. Efficacy of continued flibanserin treatment in premenopausal women with hypoactive sexual desire disorder: Results from the ROSE study. J Sex Med 2009;6:114.
6. Jolly E, Clayton AH, Thorp J, Kimura T, Sand M, Pyke R. Efficacy of flibanserin 100 mg qhs as a potential treatment for hypoactive sexual desire disorder in North American premenopausal women. J Sex Med 2009;6(suppl 5):465.
7. Pyke R, Cotton D, Kennedy S, Lewis D'Agostino D. Flibanserin: A novel centrally acting agent that is not an effective antidepressant but has potential to treat decreased sexual desire in women. Proceedings of American Psychiatric Association Annual Meeting. 2008:268.
8. Kennedy S. Flibanserin: Initial evidence of efficacy on sexual dysfunction, in patients with major depressive disorder. J Sex Med 2010. E pub ahead of print. DOI: 10.1111/j.1743 6109.2010.01938.x.
9. Allers KA, Dremencov E, Ceci A, Flik G, Ferger B, Cremers T, Sommer B. Chronic flibanserin administration in female rats modulates monoamines differently across brain areas: A microdialysis study. J Sex Med 2010;7:1757-67.
10. Aubert Y, Converse A, Sommer B, Allers K, Abbott D. Comparison of flibanserin with the 5 HT1A agonist (+) 8 OH DPAT in affecting interactions between male female marmoset pairs. J Sex Med 2009;6(suppl 5):422.
11. Borsini F, Ceci A, Bietti G, Donetti A. BIMT 17, a 5 HT1A receptor agonist/5 HT2A receptor antagonist, directly activates postsynaptic 5 HT inhibitory responses in the rat cerebral cortex. Naunyn Schmiedebergs Arch Pharmacol 1995;352:283-90.
12. Borsini F, Cesana R, Kelly J, Leonard BE, McNamara M, Richards J, Seiden L. BIMT 17: A putative antidepressant with a fast onset of action? Psychopharmacology (Berl) 1997;134:378-86.
13. Borsini F, Brambilla A, Ceci A, Cesana R, Giraldo E, Ladinsky H, Monferini E, Turconi M. Flibanserin: Antidepressant, 5 HT1A receptor agonist, 5 HT2 receptor antagonist. Drugs Future 1998;23:9-16.
14. Borsini F, Brambilla A, Grippa N, Pitsikas N. Behavioral effects of flibanserin (BIMT 17). Pharmacol Biochem Behav 1999;64:137-46.
15. Borsini F, Cesana R. Further characterisation of potential antidepressant action of flibanserin. Psychopharmacology (Berl) 2001;159:64-9.
16. Borsini F, Cesana R. Mechanism of action of flibanserin in the learned helplessness paradigm in rats. Eur J Pharmacol 2001;433:81-9.
17. Borsini F, Brambilla A, Cesana R, Grippa N. Lack of interaction between flibanserin and antidepressants in inducing serotonergic syndrome in rats. Int J Neuropsychopharmacol 2001;4:9-15.
18. Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S. Pharmacology of flibanserin. CNS Drug Rev 2002;8:117-42.
19. Brambilla A, Baschirotto A, Grippa N, Borsini F. Effect of flibanserin (BIMT 17), fluoxetine, 8 OH DPAT and buspirone on serotonin synthesis in rat brain. Eur Neuropsychopharmacol 1999;10:63-7.
20. Cervo L, Ferger B, Ceci A, Allers KA, Sommer B. Involvement of 5 HT1A receptors in flibanserin discriminative stimulus in female rats. Program No. 465.20, 2009 Society for Neuroscience meeting planner, Chicago IL, Society for Neuroscience 2009, online.
21. Cesana R, Ciprandi C, Borsini F. The effect of BIMT 17, a new potential antidepressant, in the forced swimming test in mice. Behav Pharmacol 1995;6:688-94.
22. Ferger B, Shimasaki M, Ceci A, Ittrich C, Allers KA, Sommer B. Flibanserin, a drug intended for treatment of hypoactive sexual desire disorder in pre menopausal women, affects spontaneous motor activity and brain neurochemistry in female rats. Naunyn Schmiedebergs Arch Pharmacol 2010;381:573-9.
23. Invernizzi RW, Sacchetti G, Parini S, Acconcia S, Samanin R. Flibanserin, a potential antidepressant drug, lowers 5 HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: Role of 5 HT(1A) receptors. Br J Pharmacol 2003;139:1281-8.
24. Marazziti D, Palego L, Giromella A, Mazzoni MR, Borsini F, Mayer N, Naccarato AG, Lucacchini A, Cassano GB. Region dependent effects of flibanserin and buspirone on adenylyl cyclase activity in the human brain. Int J Neuropsychopharmacol 2002;5:131-40.
25. Podhorna J, Brown RE. Flibanserin has anxiolytic effects without locomotor side effects in the infant rat ultrasonic vocalization model of anxiety. Br J Pharmacol 2000;130:739-46.
26. Rueter LE, de Montigny C, Blier P. In vivo electrophysiological assessment of the agonistic properties of flibanserin at pre and postsynaptic 5 HT1A receptors in the rat brain. Synapse 1998;29:392-405.
27. Rueter LE, Blier P. Electrophysiological examination of the effects of sustained flibanserin administration on serotonin receptors in rat brain. Br J Pharmacol 1999;126:627-38.
28. Scandroglio A, Monferini E, Borsini F. Ex vivo binding of flibanserin to serotonin 5 HT1A and 5 HT2A receptors. Pharmacol Res 2001;43:179-83.
29. Pfaus JG. Pathways of sexual desire. J Sex Med 2009;6:1506-33.
30. Stahl SM. Multifunctional drugs: A novel concept for psychopharmacology. CNS Spectr 2009;14:71-3.
31. Maurel JL, Autin JM, Funes P, Newman Tancredi A, Colpaert F, High efficacy VB. 5 HT1A agonists for antidepressant treatment: A renewed opportunity. J Med Chem 2007;50:5024-33.
32. Newman Tancredi A, Heusler P, Martel JC, Ormiere AM, Leduc N, Cussac D. Agonist and antagonist properties of antipsychotics at human dopamine D4.4 receptors: G protein activation and K+ channel modulation in transfected cells. Int J Neuropsychopharmacol 2008;11:293-307.
33. Newman Tancredi A, Martel JC, Assie MB, Buritova J, Lauressergues E, Cosi C, Heusler P, Bruins SL, Colpaert FC, Vacher B, Cussac D. Signal transduction and functional selectivity of F15599, a preferential post synaptic 5 HT1A receptor agonist. Br J Pharmacol 2009;156:338-53.
34. Liu S, Bubar MJ, Lanfranco MF, Hillman GR, Cunningham KA. Serotonin2C receptor localization in GABA neurons of the rat medial prefrontal cortex: Implications for understanding the neurobiology of addiction. Neuroscience 2007;146:1677-88.
35. Heusler P, Bruins SL, Rauly Lestienne I, Palmier C, Tardif S, Tourette A, Ailhaud MC, Cussac D. Activation of G proteins and extracellular signal regulated kinase 1/2 phosphorylation via human dopamine D4.4 receptors: Differential pathway dependent potencies of receptor agonists. Naunyn Schmiedebergs Arch Pharmacol 2009;379:87-99.
36. Choi DS, Maroteaux L. Immunohistochemical localisation of the serotonin 5 HT2B receptor in mouse gut, cardiovascular system, and brain. FEBS Lett 1996;391:45-51.
37. Gelez H, Allers KA, Sommer B, Giuliano F. Chronic flibanserin treatment increases solicitations in the female rat. J Sex Med 2010;7(suppl 3):118. Ref type: Abstract.
38. Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F. Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex 2004;14:1100-9.
39. Celada P, Puig MV, Casanovas JM, Guillazo G, Artigas F. Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: Involvement of serotonin 1A, GABA(A), and glutamate receptors. J Neurosci 2001;21:9917-29.
40. Hajos M, Hajos Korcsok E, Sharp T. Role of the medial prefrontal cortex in 5 HT1A receptor induced inhibition of 5 HT neuronal activity in the rat. Br J Pharmacol 1999;126:1741-50.
41. Martin Ruiz R, Puig MV, Celada P, Shapiro DA, Roth BL, Mengod G, Artigas F. Control of serotonergic function in medial prefrontal cortex by serotonin 2A receptors through a glutamate dependent mechanism. J Neurosci 2001;21:9856-66.
42. Alex KD, Pehek EA. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 2007;113:296-320.
43. Bortolozzi A, Az Mataix L, Scorza MC, Celada P, Artigas F. The activation of 5 HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem 2005;95:1597-607.
44. Diaz Mataix L, Scorza MC, Bortolozzi A, Toth M, Celada P, Artigas F. Involvement of 5 HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: Role in atypical antipsychotic action. J Neurosci 2005;25:10831-43.
45. Fink KB, Gothert M. 5 HT receptor regulation of neurotransmitter release. Pharmacol Rev 2007;59:360-417.
46. Lee HS, Kim MA, Waterhouse BD. Retrograde double labeling study of common afferent projections to the dorsal raphe and the nuclear core of the locus coeruleus in the rat. J Comp Neurol 2005;481:179-93.
47. Aston Jones G, Zhu Y, Card JP. Numerous GABAergic afferents to locus ceruleus in the pericerulear dendritic zone: Possible interneuronal pool. J Neurosci 2004;24:2313-21.
48. Harsing LG. The pharmacology of the neurochemical transmission in the midbrain raphe nuclei of the rat. Curr Neuropharmacol 2006;4:313-39.
49. Harte M, O'Connor WT. Evidence for a differential medial prefrontal dopamine D1 and D2 receptor regulation of local and ventral tegmental glutamate and GABA release: A dual probe microdialysis study in the awake rat. Brain Res 2004;1017:120-9.
50. Jodo E, Chiang C, Ston Jones G. Potent excitatory influence of prefrontal cortex activity on noradrenergic locus coeruleus neurons. Neuroscience 1998;83:63-79.
51. Loughlin SE, Foote SL, Grzanna R. Efferent projections of nucleus locus coeruleus: Morphologic subpopulations have different efferent targets. Neuroscience 1986;18:307-19.
52. Berridge CW. Noradrenergic modulation of arousal. Brain Res Rev 2008;58:1-17.
53. Fields HL, Hjelmstad GO, Margolis EB, Nicola SM. Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement. Annu Rev Neurosci 2007;30:289-316.
54. Korotkova TM, Ponomarenko AA, Brown RE, Haas HL. Functional diversity of ventral midbrain dopamine and GABAergic neurons. Mol Neurobiol 2004;29:243-59.
55. Bubar MJ, Cunningham KA. Distribution of serotonin 5 HT2C receptors in the ventral tegmental area. Neuroscience 2007;146:286-97.
56. Dunlop J, Marquis KL, Lim HK, Leung L, Kao J, Cheesman C, Rosenzweig Lipson S. Pharmacological profile of the 5 HT(2C) receptor agonist WAY 163909; therapeutic potential in multiple indications. CNS Drug Rev 2006;12:167-77.
57. Invernizzi RW, Pierucci M, Calcagno E, Di GG, Di MV, Benigno A, Esposito E. Selective activation of 5 HT(2C) receptors stimulates GABA ergic function in the rat substantia nigra pars reticulata: A combined in vivo electrophysiological and neurochemical study. Neuroscience 2007;144:1523-35.
58. Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999;21(suppl):106S-15S.
59. Valdizan EM, Castro E, Pazos A. Agonist dependent modulation of G protein coupling and transduction of 5 HT1A receptors in rat dorsal raphe nucleus. Int J Neuropsychopharmacol 2009;9:1-9.
60. Casanovas JM, Hervas I, Artigas F. Postsynaptic 5 HT1A receptors control 5 HT release in the rat medial prefrontal cortex. Neuroreport 1999;10:1441-5.
61. Vezina P. Sensitization of midbrain dopamine neuron reactivity and the self administration of psychomotor stimulant drugs. Neurosci Biobehav Rev 2004;27:827-39.
62. Arnsten AF, Li BM. Neurobiology of executive functions: Catecholamine influences on prefrontal cortical functions. Biol Psychiatry 2005;57:1377-84.
63. Robbins TW. The 5 choice serial reaction time task: Behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl) 2002;163:362-80.
64. Arnow BA, Millheiser L, Garrett A, Lake PM, Glover GH, Hill KR, Lightbody A, Watson C, Banner L, Smart T, Buchanan T, Desmond JE. Women with hypoactive sexual desire disorder compared to normal females: A functional magnetic resonance imaging study. Neuroscience 2009;158:484-502.
65. Holstege G, Willemsen A, Beers C, Lont E, Schultz WW, Jansen M, Dierck R. Differences in brain activity in premenopausal women with hypoactive sexual desire disorder (HSDD) compared to women without sexual dysfunction. J Sex Med 2009;6(Suppl. 5):407.
66. McCall K, Meston C. Cues resulting in desire for sexual activity in women. J Sex Med 2006;3:838-52.