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CARDIOVASCULAR
Fundación para la Investigación y el Desarrollo en Andrología, Madrid, Spain (J.A., I.S.d.T.); Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain (P.C., B.C.); and Department of Pharmacology and Toxicology, Forest Research Institute, Jersey City, New Jersey (S.G.)
Received November 23, 2003; accepted March 18, 2004.
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Abstract |
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-adrenergic receptor blocker phentolamine had no effect on paroxetine-induced reduction of GVRs, partially prevented the inhibitory effects of duloxetine, and fully prevented the effects of venlafaxine (93.0 and 96.7%). Duloxetine-induced inhibition of GVRs was completely prevented by combined administration of L-arginine and phentolamine (123.5 and 103.6%). Although 5-HT or the highly selective SRI escitalopram did not inhibit GVRs, NE or inhibition of nitric oxide (NO) synthesis did. Inhibition of the NO pathway by paroxetine and duloxetine or activation of -adrenergic mechanisms by venlafaxine and duloxetine lead to antidepressant-induced inhibition of GVRs in female rabbits.
). Antidepressant-induced sexual dysfunction affects men and women and includes orgasm delay, anorgasmia, and impotence (Labbate et al., 1998), which usually disappear when the treatment is discontinued (Rothschild, 1995); however, the likelihood of producing sexual side effects varies between the different serotonin (5-HT) reuptake and mixed 5-HT and norepinephrine (NE) reuptake inhibitor antidepressants (Arias et al., 2000). Paroxetine has often been reported to induce sexual dysfunction (Zajecka et al., 1997; Kennedy et al., 2000), whereas citalopram has been shown to produce significantly fewer alterations of sexual function (Mendels et al., 1999; Hovorka et al., 2000). In fact, we have previously reported that acute as well as chronic administration of paroxetine, but not citalopram, inhibit erectile responses in male rats by inhibiting nitric oxide (NO) production (Angulo et al., 2001b). Venlafaxine (a mixed 5-HT and NE reuptake inhibitor) is also among the drugs that are associated with the highest incidence of sexual dysfunction (over 50% in some studies) (Zajecka et al., 1997; Kennedy et al., 2000).
Sexual function in women is also altered by the treatment with antidepressants, but little is known about the mechanisms involved in this effect. Increases of blood flow into the vagina and clitoris is a measurable physiological response to sexual stimulation in females and is therefore important for the study of female sexuality. Indeed, several techniques are currently used to assess female sexual function by measuring indices of genital blood flow in women (Berman et al., 1999; Sommer et al., 2001). In female animals (rabbits, rats, and dogs), the increase of female genital blood flow in response to pelvic nerve stimulation has recently been suggested as a model of female sexual response (Giuliano et al., 2001; Angulo et al., 2003; Kim et al., 2003).
Although the neurogenic control of the vascular events in female genitalia has not been thoroughly investigated, it is known that the NO/cGMP pathway plays an important role in the clitoris and vagina. This pathway mediates neurogenic relaxation of the rabbit clitoral corpus cavernosum (Cellek and Moncada, 1998) and is involved in the neurogenic relaxation of the rabbit vagina (Ziessen et al., 2002). Nitrergic innervation has also been identified in the human vagina and clitoris (Hoyle et al., 1996; Burnett et al., 1997). We have recently shown that the enhancement of the NO/cGMP pathway by the inhibition of type 5 phosphodiesterase potentiates increases in vaginal and clitoral blood flow in response to pelvic nerve electrical stimulation (PNES) in female dogs (Angulo et al., 2003). On the other hand, it has been suggested that the adrenergic system could play a functional antagonistic role to the NO pathway in female sexual responses (Giuliano et al., 2001), as occurs in males.
The aims of the present study were to investigate the basic mechanisms that regulate female genital vascular response (GVR) to PNES and to investigate the effects of acute administration of antidepressants that have selective 5-HT or mixed 5-HT and NE reuptake inhibitory activity on GVRs in female rabbits.
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Materials and Methods |
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An abdominal midline incision was made, and the pelvic nerve was dissected and surrounded by a subminiature bipolar electrode (Harvard Apparatus Inc., Holliston, MA). The clitoris was carefully exposed, and a flow needle probe was inserted into the corpus cavernosum. Another flow needle probe was placed inside the vaginal wall. The signal from the probes was processed by a laser Doppler blood flow monitor (floLAB; Moor Instruments, Devon, UK) and recorded by the PowerLab data acquisition system. PNES was applied by means of a constant current stimulator (Cibertec CS-9; Cibertec, Madrid, Spain) connected to the bipolar electrode. The stimulation parameters were based on reported studies using this model (Kim et al., 2003). The intensity of the current was 10 mA, with a pulse duration of 0.8 ms for 30 s. In pilot experiments, we evaluated the responses to 16 Hz, but these responses were, in many cases, not larger than those to 8 Hz and less consistent. Thus, the frequencies chosen were ones that induced near-to-maximal responses (8 Hz) and clearly produced submaximal responses (4 Hz).
After a stabilization period, PNES was applied at 4 and 8 Hz. The first stimulation checked for the existence of an increment of vaginal and clitoral blood flow to PNES. After 20 min, PNES was repeated, and the responses were compared with those obtained with checked PNES. If response curves were similar, the latter PNES was considered as the control PNES for comparisons. If response curves were different, another PNES was applied 20 min later. This process was repeated until two similar consecutive responses to PNES were obtained. An intravenous injection of either vehicle (20% 2-hydroxypropyl 
-cyclodextrin; HPCD) or drugs were then administered, and 60 min later another PNES was applied.
Responses between different animals were quite variable. Nevertheless, vaginal and clitoral blood flow responses to PNES were similar and reproducible in the same animal. For instance, after application of PNES at 8 Hz, the mean standard error could represent 40% of the mean value for vaginal blood flow response (n = 8; maximum was 15.9-fold the minimum value) and near 30% of the mean value for clitoral blood flow (n = 6; maximum was 6.8-fold the minimum value). When expressed as a percentage of the control response in the same animal, the mean standard error for the responses to PNES in the same group of animals was less than 7% for both vaginal and clitoral blood flow responses. These data reflect the fact that, although an appreciable variability between different animals was observed, repetition of PNES in the same animal yielded similar responses.
The adrenergic receptor agonist NE was infused at a rate of 0.2 µg/min for 15 min before and during the next PNES application to determine the effects of adrenergic stimulation on PNES-induced responses after first obtaining an adequate control PNES and waiting for an equilibration period. The infusion was then stopped, and 20 min later, PNES-induced responses were again evaluated. Similarly, the effects of 5-HT on PNES-induced responses were also determined by infusing 5-HT at a rate of 0.2 and 1 µg/min for 15 min before and during the evaluation of PNES-induced responses.
Data Analysis. Blood flow recordings were obtained in arbitrary flow units. Increases of vaginal and clitoral blood flow induced by PNES were measured as the area under the curve (AUC) of the response, taking into account amplitude and duration of the response. Data were expressed as the percentage of the control response (control PNES) before the treatment was applied. Comparison of vehicle- and drug-induced effects on vagina and clitoris blood flow increases in response to PNES was performed by a two-factor analysis of variance (ANOVA) test.
Drugs and Materials. NE (arterenol), serotonin (5-hydroxytryptamine), HPCD, NG-nitro-L-arginine methyl ester (L-NAME), and L-arginine were obtained from Sigma-Aldrich (St. Louis, MO). Phentolamine mesylate (Regitine) was obtained from Novartis (Basel, Switzerland). Paroxetine, escitalopram, venlafaxine, and duloxetine were provided by Forest Laboratories, Inc. (New York, NY). NE and 5-HT solutions (2 µg/ml) for intravenous infusions were supplemented with 0.01% ascorbic acid to prevent oxidation.
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Results |
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Effects of NO Synthesis Inhibition, Norepinephrine, or 5-HT Administration on GVRs in Female Rabbits. Application of PNES caused consistent increases of blood flow into the vagina and clitoris in anesthetized female rabbits. The amplitude and duration of responses were dependent on the frequency applied and were not affected by vehicle (20% HPCD) administration (Fig. 1). At 8 Hz, blood flow increments were more rapid and had a biphasic component in the clitoris when compared with responses in the vagina (see Fig. 1).
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Administration (i.v.) of the NO synthase inhibitor L-NAME (1 mg/kg) significantly reduced PNES-induced blood flow increases in the vagina and clitoris (Fig. 2). Intravenous infusion of NE (0.2 µg/min for 15 min) caused a significant inhibition of vaginal and clitoral blood flow increases in response to PNES. This inhibitory effect was transient, as it disappeared 20 min after stopping NE infusion (Fig. 3). In the vagina, NE infusion seemed to have a larger inhibitory effect at 4 Hz than at 8 Hz (54.0 ± 8.5% versus 78.5 ± 17.1% of control response, respectively), whereas the NE-induced inhibition in the clitoris was less frequency-dependent (66.9 ± 7.2% versus 61.5 ± 3.1% of control response at 4 and 8 Hz, respectively); however, intravenous infusion of 5-HT (0.2 and 1 µg/min for 15 min) did not inhibit vaginal or clitoral blood flow increases to PNES. In fact, the higher dose of 5-HT produced a slight but significant potentiation of vaginal blood flow responses to PNES (128.9 ± 21.6% and 122.6 ± 15.3% of control response at 4 and 8 Hz, respectively, p < 0.05), whereas this potentiation was not evident in the clitoris (Fig. 4).
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Effects of Escitalopram, Paroxetine, Venlafaxine, and Duloxetine on GVRs in Female Rabbits. The intravenous administration of the SSRI escitalopram (5 mg/kg i.v.) did not significantly alter the PNES-induced increase in blood flow in the clitoris or vagina (Fig. 5). In contrast, treatment with another SSRI, paroxetine, significantly and dose-dependently inhibited GVRs. This inhibitory effect was observed at 5 and 1 mg/kg paroxetine. At a dose of 0.5 mg/kg, paroxetine caused a significant inhibition of PNES-induced vascular responses in vaginal blood flow but not in clitoris blood flow (Fig. 6). The mixed 5-HT and NE reuptake inhibitors venlafaxine (5 mg/kg i.v.) and duloxetine (1 mg/kg i.v.) both caused significant inhibition of GVRs induced by PNES (Fig. 7).
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Effects of L-Arginine and Phentolamine on Inhibition of GVRs Induced by Paroxetine, Venlafaxine, and Duloxetine. Neither the NO synthase substrate L-arginine (10 mg/kg i.v.) nor the -adrenergic receptor blocker phentolamine (1 mg/kg i.v.) had a significant effect on PNES-induced GVRs (Fig. 8); however, the administration of L-arginine prevented paroxetine (5 mg/kg)-induced inhibition of vaginal and clitoral blood flow responses to PNES. Phentolamine failed to modify the inhibitory effect of paroxetine on GVRs (Fig. 9).
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Conversely, the inhibitory effect of venlafaxine (5 mg/kg) on clitoral and vaginal blood flow responses to PNES was not affected by L-arginine (10 mg/kg) but was fully prevented by phentolamine (1 mg/kg) (Fig. 10). Finally, both L-arginine and phentolamine partially reversed GVRs in female rabbits treated with duloxetine (1 mg/kg). Combined administration of L-arginine and phentolamine completely prevented the inhibitory effects of duloxetine on GVRs (Fig. 11).
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Discussion |
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). The role of NO in neurogenic relaxation and blood flow control in the clitoris and vagina is supported by substantial evidence (Cellek and Moncada, 1998; Ziessen et al., 2002; Angulo et al., 2003). Our study provides further support for a key role of the NO/cGMP pathway in GVRs since the inhibition of NOS greatly inhibits GVRs to PNES.
Sympathetic input to female rat genitalia has been shown to inhibit vascular sexual responses (Giuliano et al., 2001). 1- and 2-adrenoceptors have been characterized at biochemical and functional levels in rabbit vagina, where they mediate contraction (Kim et al., 2002). -adrenergic agonists also cause contraction of rabbit clitoral corpus cavernosum (Cellek and Moncada, 1998). In women with sexual arousal difficulties, positive effects on sexual responses were observed after the treatment with the -adrenoceptor blocker phentolamine (Rosen et al., 1999) and the combination of L-arginine and the 2-adrenoceptor antagonist yohimbine (Meston and Worcel, 2002). In our model, PNES-induced responses were significantly reduced by stimulation of the adrenergic system with NE. Therefore, our results support the hypothesis that the generation of NO facilitates genital blood flow responses to PNES, although these responses are antagonized by the activation of the adrenergic system. Thus, drugs interfering with the synthesis of NO or adrenergic neurotransmission could have an impact on female sexual function.
The mechanism underlying increased incidence of sexual dysfunction in patients under treatment with SSRIs is not thoroughly understood. The known mechanism of action of these drugs involves the inhibition of 5-HT reuptake by neurons, which increases the levels of this neurotransmitter at the synapse. High levels of 5-HT are generally thought to inhibit sexual behavior (Hull et al., 1999); however, opposite effects can be observed depending on the type of receptor activated by serotonin, since activation of the 5-HT2A receptor subtype is associated with increased sexual motivation in female rats (Nedergaard et al., 2004). Although all SSRIs enhance serotonin levels in the brain, not all of them produce the same effects on sexual function. Indeed, an increase of incidence of erectile dysfunction in patients treated with paroxetine has often been reported, whereas a lesser effect on sexual function is reported for citalopram (Mendels et al., 1999).
The three antidepressants paroxetine, venlafaxine, and duloxetine, which cause inhibition of GVRs in our model, share the ability to inhibit 5-HT reuptake; however, escitalopram, the active S-enantiomer of citalopram, a potent and highly selective inhibitor of 5-HT reuptake (Owens et al., 2001; Sanchez et al., 2003), does not affect GVRs in this model at a dose several times higher than those proven to be effective in rats (Mork et al., 2003) or than those effective in humans (Lepola et al., 2003). This would suggest that inhibition of 5-HT reuptake is not the mechanism underlying inhibition of GVRs to PNES by paroxetine, venlafaxine, or duloxetine. The observation that intravenous administration of 5-HT does not inhibit GVRs in female rabbits further supports this concept. In fact, the infusion of 1 µg/min (the higher dose tested) of 5-HT for 15 min caused a slight but significant potentiation of blood flow increases to PNES in the vagina. This effect could be due to interaction with some type of vascular 5-HT receptor mediating vasocongestion or with prejunctional 5-HT receptors modulating the release of another neurotransmitter that facilitates vasodilation in rabbit vagina. Thus, the inhibitory effects of paroxetine, venlafaxine, and duloxetine on GVRs must be related to the interference of these drugs with other regulatory mechanisms of GVRs.
Inhibition of NOS activity by paroxetine could explain the impairment of GVRs. In support of this hypothesis is the observation that L-arginine, a substrate for NOS in NO production, fully prevented the inhibitory effects of paroxetine on GVRs at a dose that did not modify GVRs to PNES under control conditions. Paroxetine caused erectile dysfunction associated with decreased NO production and NOS expression in male rats (Angulo et al., 2001b) and reduced NO production in hamster brain and depressed patients, where it inhibits NOS activity (Finkel et al., 1996). Paroxetine is a potent inhibitor of the activity of cytochrome P450 (P450) isozymes (Preskorn, 1993), which are structurally related to NOS, whereas citalopram and escitalopram are known to have no or negligible activity on P450 isozymes (Greenblatt et al., 1998; von Moltke et al., 2001). With respect to mixed 5-HT and NE reuptake inhibitors, no or weak inhibition of P450 activity by venlafaxine has been reported (Ereshefsky, 1996), but duloxetine has been shown to inhibit CYP2D6, a P450 isozyme also inhibited by paroxetine (Skinner et al., 2003).
Venlafaxine seems to inhibit GVRs by enhancing adrenergic input while not affecting the NO/cGMP pathway. These conclusions are based on the complete reversal of its inhibitory effects by the -adrenergic blocker phentolamine and the lack of effect of L-arginine treatment. Venlafaxine, although having relatively low affinity for the 5-HT and NE transporters (Table 1), has been shown to inhibit the reuptake of 5-HT and NE in humans (Harvey et al., 2000). In addition, prejunctional 2-adrenergic receptors inhibit nitrergic neurotransmission in various organs (Angulo et al., 2001a) and may represent an additional mechanism for the inhibition of GVRs by venlafaxine. A direct effect of venlafaxine on -adrenoceptors is not likely, since this compound shows low affinity for these receptors (Table 1).
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Duloxetine is also a mixed inhibitor of 5-HT and NE reuptake, as demonstrated in vitro and in vivo (Kasamo et al., 1996; Chalon et al., 2003), and is more potent than venlafaxine (Table 1). Duloxetine is currently being evaluated for the treatment of depression (Detke et al., 2002) and stress urinary incontinence (Norton et al., 2002), but sexual side effects of duloxetine have not yet been fully characterized (Detke et al., 2003). In our female rabbit model, duloxetine potently inhibited GVRs. Phentolamine significantly improved GVRs in the presence of duloxetine. Since, like venlafaxine, duloxetine does not have significant affinity for -adrenoceptors (Table 1), the inhibitory effects of duloxetine on GVRs could be related to the increased availability of NE subsequent to inhibition of NE transporter; however, in contrast to our observations with venlafaxine, treatment with phentolamine failed to completely reverse duloxetine-induced inhibition of GVRs, suggesting that additional mechanisms contribute to the inhibitory effects of this compound. Duloxetine may interfere with NO production, as suggested by the partial prevention of its inhibitory effects by L-arginine. The involvement of both adrenergic stimulation and interference with NO production in the inhibitory effects of duloxetine was further confirmed by the complete prevention of such effects by the coadministration of L-arginine and phentolamine.
Although the results obtained in the vagina generally paralleled those obtained in the clitoris, some subtle differences in response to treatments do exist. In this regard, norepinephrine seems to produce a greater reduction in vaginal blood flow at 4 Hz compared with its effect at 8 Hz. This frequency-dependent effect of NE was not evident in the clitoris. In addition, serotonin only significantly increased GVRs in the vagina, and the lowest dose of paroxetine only significantly reduced GVRs (also in the vagina). The interpretation of these differences based on our results could be rather speculative; however, it has been observed that the neurogenic relaxation involves different neurotransmitter profiles in the vagina and clitoris. Although neurogenic relaxation of the clitoral corpus cavernosum is largely mediated by NO release from nitrergic nerves (Cellek and Moncada, 1998), in vaginal tissue, in addition to NO, the neurogenic relaxation is also mediated by another unknown neurotransmitter (Ziessen et al., 2002). The participation of this unknown neurotransmitter in the vascular responses induced by pelvic nerve stimulation in the vagina could account for the differences observed between the vagina and clitoris. The divergences could also be related to a different expression of prejunctional or postjunctional receptors in the vagina and clitoris or in the arteries supplying each tissue. The pattern of neurotransmitter release and thus the functional response can be dependent on the frequency applied (Morris and Gibbins, 1992). This could explain the different shape of response observed at 8 Hz in the clitoris.
In conclusion, vaginal and clitoral blood flow increases in response to PNES in female rabbits are mediated, at least to a great extent, by NO and regulated by activation of the adrenergic system. Paroxetine reduces GVRs in this model by inhibiting NO synthesis, whereas the inhibitory effect of venlafaxine is related to its ability to increase NE levels. Inhibition of GVRs by duloxetine involves both—interference with the NOS pathway and activation of the adrenergic system. Administration of 5-HT or the SSRI escitalopram does not affect PNES-induced responses in female rabbits, suggesting that the increase in 5-HT availability is not responsible for inhibition of GVRs induced by SSRIs or 5-HT and NE reuptake inhibitors in female rabbits. These observations could be relevant for the development of therapeutic strategies to minimize sexual side effects in patients under treatment with antidepressants.
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Footnotes |
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ABBREVIATIONS: 5-HT, serotonin; NE, norepinephrine; NO, nitric oxide; PNES, pelvic nerve electrical stimulation; GVR, genital vascular response; HPCD, 2-hydroxy-propyl--cyclodextrin; AUC, area under the curve; ANOVA, analysis of variance; L-NAME, NG-nitro-L-arginine methyl ester; SSRI, selective serotonin reuptake inhibitor; NOS, nitric-oxide synthase; P450, cytochrome P450.
Address correspondence to: Dr. Iñigo Sáenz de Tejada, Antonio Robles, 4-9C, 28034 Madrid, Spain. E-mail: isdtejada{at}terra.es
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References |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Angulo J, Cuevas P, Cuevas B, Bischoff E, and Sáenz de Tejada I (2003) Vardenafil enhances clitoral and vaginal blood flow responses to pelvic nerve stimulation in female dogs. Int J Impot Res 15: 137-141.[CrossRef][Medline]
Angulo J, Cuevas P, Fernandez A, Gabancho S, and Sáenz de Tejada I (2001a) Combination of phentolamine and L-arginine or sildenafil synergistically improves neurogenic relaxation of rabbit corpus cavernosum smooth muscle. Urology 57: 585-589.[CrossRef][Medline]
Angulo J, Peiro C, Sanchez-Ferrer CF, Gabancho S, Cuevas P, Gupta S, and Sáenz de Tejada I (2001b) Differential effects of serotonin reuptake inhibitors on erectile responses, NO-production and neuronal NO synthase expression in rat corpus cavernosum tissue. Br J Pharmacol 134: 1190-1194.[CrossRef][Medline]
Arias F, Padin JJ, Rivas MT, and Sanchez A (2000) Sexual dysfunctions induced by serotonin reuptake inhibitors. Atención Primaria 26: 389-394.
Berman JR, Adhikari SP, and Goldstein I (2000) Anatomy and physiology of female sexual function and dysfunction. Classification, evaluation and treatment options. Eur Urol 38: 20-29.[CrossRef][Medline]
Berman JR, Berman LA, Werbin TJ, Flaherty EE, Leahy NM, and Goldstein I (1999) Clinical evaluation of female sexual function: effects of age and estrogen status on subjective and physiologic sexual responses. Int J Impot Res 11 (Suppl 1): S31-S38.
Burnett AL, Calvin DC, Silver RI, Peppas DS, and Docimo SG (1997) Immunohistochemical description of nitric oxide synthase isoforms in human clitoris. J Urol 158: 75-78.[CrossRef][Medline]
Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, and Wong DT (2001) Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes and other neuronal receptors. Neuropsychopharmacology 25: 871-880.[CrossRef][Medline]
Cellek S and Moncada S (1998) Nitrergic neurotransmission mediates the nonadrenergic responses in the clitoral corpus cavernosum of the rabbit. Br J Pharmacol 125: 1627-1629.[CrossRef][Medline]
Chalon SA, Granier LA, Vandenhende FR, Bieck PR, Bymaster FP, Joliat MJ, Hirth C, and Potter WZ (2003) Duloxetine increases serotonin and norepinephrine availability in healthy subjects: a double-blind, controlled study. Neuropsychopharmacology 28: 1685-1693.[CrossRef][Medline]
Detke MJ, Lu Y, Goldstein DJ, McNamara RK, and Demitrack MA (2002) Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression. J Psychiat Res 36: 383-390.[CrossRef][Medline]
Detke MJ, Wang F, Mallinckrodt CH, Tran PV, and Delgado PL (2003) Comparison of sexual functioning in patients receiving duloxetine or paroxetine: acute and long-term data. Poster presented at the 156th Annual Meeting of the American Psychiatric Association, 2003 May 17-22, San Francisco, CA. Abstract NR477.
Ereshefsky L (1996) Drug-drug interactions involving antidepressants: focus on venlafaxine. J Clin Psychopharmacol 16 (Suppl 2): 37S-50S.[Medline]
Finkel MS, Laghrissi-Thode F, Pollock BG, and Rong J (1996) Paroxetine is a novel nitric oxide synthase inhibitor. Psychopharmacol Bull 32: 653-658.[Medline]
Giuliano F, Allard J, Compagnie S, Alexandre L, Droupy S, and Bernabe J (2001) Vaginal physiological changes in a model of sexual arousal in anesthetized rats. Am J Physiol Regul Integr Comp Physiol 281: R140-R149.
Greenblatt DJ, von Moltke LL, Harmatz JS, and Shader RI (1998) Drug interactions with newer antidepressants: role of human cytochrome P450. J Clin Psychiatry 59 (Suppl 15): 19-27.
Harvey AT, Rudolph RL, and Preskorn SH (2000) Evidence of the dual mechanisms of action of venlafaxine. Arch Gen Psychiatry 57: 503-509.
Hovorka J, Herman E, and Nemcova II (2000) Treatment of interictal depression with citalopram in patients with epilepsy. Epilepsy Behav 1: 444-447.[CrossRef][Medline]
Hoyle CH, Stones RW, Robson T, Whitley K, and Burnstock G (1996) Innervation of vasculature and microvasculature of the human vagina by NOS and neuropeptide-containing nerves. J Anat 188: 633-664.
Hull EM, Lorrain DS, Du J, Matuszewich L, Lumley LA, Putnam SK, and Moses J (1999) Hormone-neurotransmitter interactions in the control of sexual behavior. Behav Brain Res 105: 105-116.[CrossRef][Medline]
Kasamo K, Blier P, and De Montigny C (1996) Blockade of the serotonin and norepinephrine uptake processes by duloxetine: in vitro and in vivo studies in the rat brain. J Pharmacol Exp Ther 277: 278-286.
Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, and Bagby RM (2000) Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline and venlafaxine. J Clin Psychiatry 61: 276-281.[Medline]
Kim NN, Min K, Huang YH, Goldstein I, and Traish AM (2002) Biochemical and functional characterization of alpha-adrenergic receptors in the rabbit vagina. Life Sci 71: 2909-2920.[CrossRef][Medline]
Kim SW, Jeong SJ, Munarriz R, Kim NN, Goldstein I, and Traish AM (2003) Role of the nitric oxide-cyclic GMP pathway in regulation of vaginal blood flow. Int J Impot Res 15: 355-361.[CrossRef][Medline]
Labbate LA, Grimes J, Hines A, Oleshanky MA, and Arana GW (1998) Sexual dysfunction induced by serotonin reuptake antidepressants. J Sex Marital Ther 24: 3-12.[Medline]
Lepola UM, Loft H, and Reines EH (2003) Escitalopram (10–20 mg/day) is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 18: 211-217.[CrossRef][Medline]
Mendels J, Kiev A, and Fabre LF (1999) Double-blind comparison of citalopram and placebo in depressed outpatients with melancholia. Depress Anxiety 9: 54-60.[CrossRef][Medline]
Meston CM and Worcel M (2002) The effects of yohimbine plus L-arginine glutamate on sexual arousal in postmenopausal women with sexual arousal disorder. Arch Sex Behav 31: 323-332.[CrossRef][Medline]
Mork A, Kreilgaard M, and Sanchez C (2003) The R-enantiomer of citalopram counteracts escitalopram-induced increase in extracellular 5-HT in the frontal cortex of freely moving rats. Neuropharmacology 45: 167-173.[CrossRef][Medline]
Morris JL and Gibbins IL (1992) Co-transmission and Neuromodulation, in Autonomic Neuroeffector Mechanisms (Burnstock G and Hoyle CHV eds) pp 33-120, Harwood Academic Publishers, Chur, Switzerland.
Nedergaard P, Sanchez C, and Mellerup E (2004) Different roles of 5-HT2A and 5-HT2C receptors in regulation of female rat paced mating behavior. Behav Brain Res 149: 151-157.[CrossRef][Medline]
Norton PA, Zinner NR, Yalcin I, and Bump RC for the Duloxetine Urinary Incontinence Study Group (2002) Duloxetine versus placebo in the treatment of stress urinary incontinence. Am J Obstet Gynecol 187: 40-48.[CrossRef][Medline]
Owens MJ, Knight DL, and Nemeroff CB (2001) Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry 50: 345-350.[CrossRef][Medline]
Owens MJ, Morgan WN, Plott SJ, and Nemeroff CB (1997) Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 283: 1305-1322.
Preskorn SH (1993) Recent pharmacologic advances in antidepressant therapy for the elderly. Am J Med 94: 2S-12S.
Rosen RC, Phillips NA, Gendrano NC 3rd, and Ferguson DM (1999) Oral phentolamine and female sexual arousal disorder: a pilot study. J Sex Marital Ther 25: 137-144.[CrossRef][Medline]
Rothschild AJ (1995) Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry 152: 1514-1516.
Sanchez C, Bergqvist PB, Brennum LT, Gupta S, Hogg S, Larsen A, and Wiborg O (2003) Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology 167: 353-362.[Medline]
Skinner MH, Kuan HY, Pan A, Sathirakul K, Knadler MP, Gonzales CR, Yeo KP, Reddy S, Lim M, Ayan-Oshodi M, et al. (2003) Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 73: 170-177.[CrossRef][Medline]
Sommer F, Caspers HP, Esders K, Klotz T, and Engelmann U (2001) Measurement of vaginal and minor labial oxygen tension for the evaluation of female sexual function. J Urol 165: 1181-1184.[CrossRef][Medline]
von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, and Shader RI (2001) Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects and comparison to R-citalopram. Drug Metab Dispos 29: 1102-1109.
Wang PS, Gilman SE, Guardino M, Christiana JM, Morselli PL, Michelson K, and Kessler RC (2000) Initiation of and adherence to treatment for mental disorders: examination of patient advocate group members in 11 countries. Med Care 38: 926-936.[CrossRef][Medline]
Zajecka J, Mitchell S, and Fawcett J (1997) Treatment-emergent changes in sexual function with selective serotonin reuptake inhibitors as measured with the Rush Sexual Inventory. Psychopharmacol Bull 33: 755-760.[Medline]
Ziessen T, Moncada S, and Cellek S (2002) Characterization of the non-nitrergic NANC relaxation responses in the rabbit vaginal wall. Br J Pharmacol 135: 546-554.[CrossRef][Medline]
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