|Year : 2011 | Volume
| Issue : 6 | Page : 707-709
Subchronic treatment with fluoxetine attenuates the proerectile effect of Aspidosperma ulei Markgr (Apocyanaceae)
Adriana Rolim Campos1, Daniel Esdras de Andrade Uch˘a2, Edilberto Silveira Rocha2, JosÚ Galberto Martins da Costa3, Vietla Satyanarayana Rao4
1 Northeast Network on Biotechnology, Vice-Rectory of Research and Post-Graduation, University of Fortaleza, Brazil
2 Departments of Organic and Inorganic Chemistry, Federal University of Cearß, Fortaleza, Brazil
3 Departments of Physiology and Pharmacology, Federal University of Cearß, Fortaleza, Brazil
4 Department of Chemical Biology, Regional University of Cariri, Crato, CE, Brazil
|Date of Submission||01-Dec-2010|
|Date of Decision||20-Apr-2011|
|Date of Acceptance||31-Aug-2011|
|Date of Web Publication||14-Nov-2011|
JosÚ Galberto Martins da Costa
Departments of Physiology and Pharmacology, Federal University of Cearß, Fortaleza
Source of Support: None, Conflict of Interest: None
Objective : To evaluate the ability of acute or chronic treatment with fluoxetine to alter the proerectile effect of Aspidosperma ulei alkaloid-rich fraction (F3-5).
Materials and Methods : In the first series of experiments, three groups of mice received either a single intraperitoneal injection of vehicle, F3-5 (25 mg/kg) or fluoxetine (10 mg/kg) + F3-5. Three behavioral responses were counted over a period of 30 min: erection, erection-like response and genital grooming. In a second series of experiments, animals treated for 13 days with fluoxetine or fluoxetine + F3-5 were assessed.
Results : A. ulei has been suggested to have proerectile effect in mice. Subchronic (13-d) treatment with fluoxetine resulted in a reduction in the number erections in F3-5-treated mice.
Conclusion : Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapy. Acute administration of fluoxetine resulted in a near total reversal of the proerectile effect of F3-5.
Keywords: Aspidosperma ulei , fluoxetine, proerectile
|How to cite this article:|
Campos AR, Uch˘a DE, Rocha ES, Martins da Costa JG, Rao VS. Subchronic treatment with fluoxetine attenuates the proerectile effect of Aspidosperma ulei Markgr (Apocyanaceae). Indian J Pharmacol 2011;43:707-9
|How to cite this URL:|
Campos AR, Uch˘a DE, Rocha ES, Martins da Costa JG, Rao VS. Subchronic treatment with fluoxetine attenuates the proerectile effect of Aspidosperma ulei Markgr (Apocyanaceae). Indian J Pharmacol [serial online] 2011 [cited 2021 Jul 31];43:707-9. Available from: https://www.ijp-online.com/text.asp?2011/43/6/707/89831
| ╗ Introduction|| |
Aspidosperma ulei is a plant that largely grows in the Amazon region of Brazil and in many other parts of South America that is found to be rich in indole alkaloids. An in vitro relaxant property of the alkaloid-containing extract of A. ulei has been described on vascular and nonvascular smooth muscle in rats, guinea-pigs and rabbits.  We have recently demonstrated a proerectile activity of an alkaloid-rich fraction (F3-5) from A. ulei root bark that might have resulted from both central and peripheral sites of action involving α-adrenergic, dopaminergic and nitrergic receptor mechanisms.  Another study has demonstrated that the fraction F3-5 from A. ulei exerts a relaxant effect on rabbit corpus cavernosum smooth muscle in vitro by a mechanism probably related to the calcium antagonism.  These reports suggest that F3-5 may have a clinical perspective in patients with erectile dysfunction (ED).
Currently available agents for ED share the same mechanism of action, pharmacologic properties and the limitations including a principal focus on erection as an end-organ process. One of the relatively unexplored areas of research has been the potential for centrally acting agents to improve male sexual response. A variety of neurohormones and neurotransmitter systems are involved in the male sexual response, including testosterone, dopamine, serotonin and the melanocortin systems.  The aim of this work was to evaluate the effect of acute and chronic treatment with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on erectile responses in male mice treated with A. ulei.
| ╗ Materials and Methods|| |
Male Swiss mice (25-30 g) obtained from the central animal house of Federal University of Cearα were used. They were housed in polypropylene cages at 232C before experimentation under standard environmental conditions (12-light/12-h dark cycle; 55-60% relative humidity) and had free access to pellet diet (Purina chow) and tap water. The Institutional Committee on the Care and Use of Animals for Experimentation approved the experimental protocols.
Plant Material, Extraction and Fractionation
A. ulei Markgr. was collected from the Garapa area of Acarape, Ceara, Brazil, after its identification, and a voucher specimen was deposited in Herbarium Prisco Bezerra (N o . 30823) of Federal University of Ceara, Fortaleza. The fraction, F3-5 was obtained from the ethanolic extract of A. ulei root bark according to a previously described procedure  1H NMR analysis of this fraction (F3-5) revealed the presence of three major indole-type alkaloids, which have been identified as uleine, nor-uleine and tetrahydro- 3, 14, 4,21-elipticine based on spectral details and in comparison with literature data. 
Penile Erection-Related Behaviors
The method described by Rampin et al  was followed. Mice were habituated to the testing room for at least a 2 h period and to the test chamber (a glass aquarium, 25 ×20 ×20 cm) for 5 min, before the start of experiment. In the first series of experiments, three groups of mice (n = 8 per group) received either a single intraperitoneal injection of vehicle (3% dimethylsulfoxide, 10 mL/kg), F3-5 (25 mg/kg) or fluoxetine 10 mg/kg s.c. + F3-5. The dose selection of F3-5 was based on our previous observations.  Personnel blind to the treatment conducted the behavioral evaluation. Observations were commenced 30 min after the plant extract injection by placing each male in the test chamber. Three behavioral responses were counted over a period of 30 min:erection (when the male stood on its hind limbs, bent its body forward, bent its head down to reach the genital area, licked its penis and displayed hip movements); erection-like response (the male stood on its hind limbs, bent its body forward, bent its head down, licked the abdomen but not the penis and displayed hip movements; the penis was not erect); and genital grooming (the male sat on its hindquarters, bent his head down and performed grooming of the genital area). In a second series of experiments, animals treated for 13 days with fluoxetine or fluoxetine + F3-5 were assessed.
Comparisons between groups were performed using one-way analysis of variance (ANOVA) followed by Student-Newman-Keul΄s test. Differences were considered statistically significant when P < 0.05.
| ╗ Results|| |
Our results show that acute administration of fluoxetine reduced the proerectile effect (no. of erections) of F3-5 by 50%. A similar effect was also seen on erection-like and genital grooming reponses (data not shown). The proerectile effect of F3-5 remained equally altered in mice receiving fluoxetine for 13 days [Table 1].
|Table 1: Effect of acute and subchronic treatment with fl uoxetine on proerectile action of F3-5 in mice|
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| ╗ Discussion|| |
Impairment of sexual activity is one of the most frequent side effects of antidepressant drugs and the increase in the synaptic concentrations of serotonin seems to be mainly responsible.  Furthermore, the activation of some serotonin (5-HT) receptor subtypes, is known to inhibit (5-HT 1A ), but others stimulate (5-HT 2C ) and penile erection. 
In previous work, we have demonstrated that the fraction F3-5 from A. ulei root bark elicits penile erection-related behaviors in male mice. Presence of indole alkaloids closely related to yohimbine in this fraction and previous studies that show the clinical efficacy of an yohimbine rich extract from the bark of Aspidosperma quebracho blanco  prompted us to undertake this study. Indole alkaloids can exert potent central and peripheral pharmacological effects by influencing various neurotransmitter systems. F3-5-induced erections in mice were abolished by clonidine, an α2-adrenoceptor agonist, suggesting that it may function as an α2-adrenoceptor blocker.
Systemic administration of α2-antagonists has been shown to enhance serotonergic neurotransmission via direct inhibition of the α2-heteroceptors located on the serotonergic nerve terminals and indirect stimulation of α1-receptors via inhibition of α2-autoreceptors.  The coadministration of an SSRI and mirtazapine (an agent with α2-antagonist activity) shortens the delay in enhancing the tonic activation of the postsynaptic 5-HT 1A receptor. 
In spite of its selective effect on 5-HT transport system, it has been reported that fluoxetine could inhibit noradrenaline uptake in brain.  It was observed by Busch et al  that long-term treatment with fluoxetine-modified isolated rat vas deferens contractility, and suggested an alteration of vas deferens contractile response to adrenergic neurotransmission. It seems then possible that some of the untoward effects associated with fluoxetine therapy could be due to an alteration of the adrenergic neurotransmission at a peripheral level.
Inhibitory effects of an acute treatment with fluoxetine on sexual behavior are consistent with prior reports.  Fluoxetine rapidly increases extracellular 5-HT in a variety of brain areas including the hypothalamus, thus, acute effects of fluoxetine are consistent with 5-HT's ability to inhibit the sexual behavior.  Since 5-HT's inhibiting effect resides, in part, from the neurotransmitter's activation of 5-HT 1A receptors,  it is tempting to speculate that fluoxetine acutely reduces the proeretile effect of F3-5 via enhanced activation of 5-HT 1A receptors.
The reduced effectiveness of the acute treatment with F3-5 in mice subchronically treated with fluoxetine is consistent with prior findings that 7-10 days of fluoxetine treatment reduced the effect of a 5-HT 1A receptor agonist on activation of the hypothalamic-pituitary-adrenal axis.  The current findings lead to the suggestion that subchronic treatment with fluoxetine reduces negative effects of fluoxetine on mouse sexual behavior. Serum concentrations of fluoxetine were not measured in the subjects. Therefore, we cannot rule out the possibility that F3-5 is having a pharmacokinetic effect that results in altered metabolism of fluoxetine.
| ╗ References|| |
|1.||Banerjee JN, Lewis JJ. Pharmacological studies in the Apocynaceous genus Aspidosperma Mart Zucc., Aspidosperma ulei MGF. J Pharm Pharmacol 1955;7:42-5. |
|2.||Campos AR, Lima RC Jr, Uchoa DE, Silveira ER, Santos FA, Rao VS. (Pro-erectile effects of an alkaloidal rich fraction from Aspidosperma ulei root bark in mice. J Ethnopharmacol 2006;104:240-4. |
|3.||Campos AR, Cunha KM, Santos FA, Silveira ER, Uchoa DE, Nascimento NR, et al. Relaxant effects of an alkaloid-rich fraction from Aspidosperma ulei root bark on isolated rabbit corpus cavernosum. Int J Impot Res 2008;20:255-63. |
|4.||Hellstrom WJ. Clinical applications of centrally acting agents in male sexual dysfunction. Int J Impot Res 2008;20(Suppl 1):S17-23. |
|5.||Staerk D, Norrby PO, Jaroszewski JW. Conformational analysis of indole alkaloids corynantheine and dihydrocorynantheine by dynamic 1H NMR spectroscopy and computational methods: Steric effects of ethyl vs vinyl group. J Org Chem 2001;66:2217-21. |
|6.||Rampin O, Jerome N, Suaudeau C. Proerectile effects of apomorphine in mice. Life Sci 2003;72:2329-36. |
|7.||Benelli A, Frigeri C, Bertolini A, Genedani S. Influence of mirtazapine on the sexual behavior of male rats. Psychopharmacology (Berl) 2004;171:250-8. |
|8.||Sanacora G, Berman RM, Capiello A, Oren DA, Kugaya A, Liu N, et al. Addition of the á2-antagonist yohimbine to fluoxetine: Effects on rate of antidepressant response. Neuropsychopharmacology 2004;29:1166-71. |
|9.||Sperling H, Lorenz A, Krege S, Arndt R, Michel MC. An extract from the bark of Aspidosperma quebracho blanco binds to human penile alpha-adrenoceptors. J Urol 2002;168:160-3. |
|10.||Millan MJ, Peglion JL, Lavielle G, Perrin-Monneyron S. 5-HT2C receptors mediate penile erections in rats: actions of novel and selective agonists and antagonists. Eur J Pharmacol 1997;325:9-12. |
|11.||Besson A, Haddjeri N, Blier P, de Montigny C. Effects of the co-administration of mirtazapine and paroxetine on serotonergic neurotransmission in the rat brain. Eur Neuropsychopharmacol 2000;10:177-88. |
|12.||Busch L, Wald M, Borda E. Long-term treatment with fluoxetine associates with peripheral effects on rat vas deferens contractility. Life Sci 1999;64:PL117-23. |
|13.||Frye CA, Petralia SM, Rhodes ME, Stein B. Fluoxetine may influence lordosis of rats through effects on midbrain 3 alpha, 5alpha-THP concentrations. Ann N Y Acad Sci 2003;1007:37-41. |
|14.||Mendelson SD. A review and reevaluation of the role of serotonin in the modulation of lordosis behavior in the female rat. Neurosci Biobehav Rev 1992;16:309-50. |
|15.||Uphouse L, Caldarola-Pastuszka M, Montanez S. Intracerebral actions of the 5-HT1A agonists, 8-OH-DPAT and buspirone and of the 5-HT1A partial agonist/antagonist, NAN-190, on female sexual behavior. Neuropharmacology 1992;31:969-81. |
|16.||Van de Kar LD, Raap DK, Battaglia G, Muma NA, Garcia F, DonCarlos LL. Treatment of cycling female rats with fluoxetine induces desensitization of hypothalamic 5-HT(1A) receptors with no change in 5-HT(2A) receptors. Neuropharmacology 2002;43:45-54. |