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Psicothema 2008. Vol. 20, nº 4, pp. 812-817 Chronic sildenafil (Viagra) administration reduces anxiety in intact
and castrated male rats
Abdel A. Solís, José A. Bethancourt* and Gabrielle B. Britton* Universidad de Salamanca and * Instituto de Investigaciones Científicas y Servicios de Alta Tecnología Epidemiological research indicates that sildenafil (Viagra) abuse is associated with increased riskbehaviors. The present study employs the open field, a standard animal model used in the field of anxietyresearch, to examine whether chronic exposure to sildenafil affects anxiety and risk-taking behaviors ingonadally intact and castrated male Wistar rats. Sildenafil (10 mg/kg) or saline were administered threetimes a week for three weeks. Animals were tested once a week in the open field during and after drugtreatment. Sildenafil treatment increased the number of center entries and time spent in the center inintact and castrated animals during and after treatment, suggesting that repeated drug use decreasesanxiety. Sildenafil also restored the deficits in exploration and locomotion produced by castration,indicating that sildenafil effects on open field behaviors are independent of endogenous androgens. Wecaution against generalizing from this study to human behaviors, but propose that the behavioral effectsproduced by a chronic high dose of sildenafil warrant further studies into its abuse potential.
La administración crónica de sildenafil (Viagra) reduce la ansiedad en ratas machos intactas y cas-tradas. Estudios epidemiológicos indican que el abuso de sildenafil (Viagra) está asociado con com-portamientos de riesgo. En el presente estudio utilizamos el campo abierto, un modelo animal están-dar en investigaciones sobre la ansiedad, para examinar los efectos de la administración crónica desildenafil sobre la ansiedad y comportamientos de riesgo en ratas machos Wistar intactas y castradas.
Sildenafil (10 mg/kg) o suero salino fueron administrados tres veces semanalmente durante tres sema-nas. Se midió el comportamiento en el campo abierto una vez por semana durante y posteriormente altratamiento. El tratamiento con sildenafil incrementó las entradas al centro del campo y el tiempo enel centro en animales intactos y castrados, lo que sugiere que la administración crónica disminuye laansiedad. Sildenafil también restauró los déficit asociados con la castración, lo que indica que los efec-tos de sildenafil sobre comportamientos en el campo abierto son independientes de la presencia de an-drógenos endógenos. Alertamos en contra de generalizar estos resultados a los comportamientos hu-manos, pero proponemos que los efectos conductuales que produce la administración crónica de unadosis alta de sildenafil justifican el estudio del potencial de abuso de esta sustancia.
Sildenafil (Viagra), a powerful treatment for male erectile Osmond, & Catania, 2005; Swearingen & Klausner, 2005) and illicit dysfunction (Goldstein et al., 1998), has become one of the most substance abuse (Crosby & DiClemente, 2004; Paul et al., 2005).
commonly prescribed and abused drugs available (Swearingen & In addition to the peripheral effects of sildenafil, the Klausner, 2005). The drug, a selective inhibitor of localization of PDE-5 to the brain enables sildenafil to affect phosphodiesterase type 5 (PDE-5), facilitates penile erection by central nervous system (CNS) functions such as cognitive, producing an accumulation in cyclic guanosine monophosphate motivational and emotional processes (Devan et al., 2006; Kurt et (cGMP) in the corpus cavernosum, causing smooth muscle al., 2004; Prickaerts et al., 2002; Tahsili-Fahadan et al., 2006). A relaxation and increased blood flow to the penis (Langtry & recent animal behavior study provided evidence that sildenafil has Markham, 1999). Because sildenafil prolongs erection and rewarding properties, which may be related to its abuse potential ejaculation latency in men without erectile dysfunction, it is a (Tahsili-Fahadan et al., 2006). Similarly, observations that popular drug of abuse (Swearingen & Klausner, 2005).
sildenafil modifies anxiety-related behaviors (Kurt et al., 2004; Epidemiological data indicate that sildenafil abuse is associated with Volke, Wegener, & Vasar, 2003) may also be relevant to its abuse increased risk behaviors, including unprotected sex (Paul, Pollack, potential in light of the relationship between anxiety and risk-taking behavior in humans (Kashdan, Collins, & Elhai, 2006;Mitte, 2007) and animals (Laviola, Macri, Morley-Fletcher, &Adriani, 2003). To our knowledge, the effects of repeated Fecha recepción: 31-8-07 • Fecha aceptación: 25-2-08 sildenafil use on anxiety have not been explored, but may offer insight into the relationship between sildenafil abuse and risk- Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP) taking behaviors. A recent study showed that chronic sildenafil (10 mg/kg) exposure over three weeks produced an increase in CHRONIC SILDENAFIL (VIAGRA) ADMINISTRATION REDUCES ANXIETY IN INTACT AND CASTRATED MALE RATS aggressive behavior in mice following but not during drug day. Behavioral sessions were conducted in an isolated, air- administration (Hotchkiss et al., 2005), but did not report other conditioned room. Experiments were conducted in accordance behavioral data. Thus, the purpose of the present study was to with the National Institutes of Health regulations relating to the characterize the effects of repeated sildenafil use and withdrawal care and use of laboratory animals (Publication No. 85-23).
on anxiety-related and risk-taking behaviors using the rat openfield (OF) paradigm, a standard procedure employed in the field of anxiety research (for a review see Prut & Belzung, 2003). Novelopen environments such as the OF create conflict situations in Subjects were randomly assigned to castrated (n= 23) and rodents by simultaneously evoking exploration and anxiety-related intact (n= 22) groups. Animals were castrated under anesthesia behaviors. In OF testing, rodents naturally prefer the periphery with pentobarbital (40 mg/kg, i.p.). A midline scrotal incision was over the central parts due to an innate aversion towards open areas.
made, and the testes and surrounding fat tissue were tied off and Therefore, entries into the center areas and the frequency of removed. Following surgery, animals were left undisturbed in their rearing behavior can be interpreted as measures of anxiolysis and risk-taking, respectively (Prut & Belzung, 2003). Although thereare limitations to the applicability of rodent models to human behaviors, the neural and psychological processes related toanxiety have revealed remarkable consistency across human and Animals were randomly assigned to one of two drug treatment animal species (Rosen & Donley, 2006). As such, much can be conditions, and received either saline or sildenafil (10 mg/kg; gained from examining drug effects on basic animal behaviors. Pfizer) injections in a volume of 1 ml/kg (i.p.) three times weekly Our first aim was to examine how sildenafil affects anxiety and over the course of three weeks with 48 h between injections. We risk-taking behaviors in the OF, which permits the assessment of selected a dose of sildenafil that would effectively mimic drug abuse three different kinds of behavioral responses: anxiety-like patterns, but that would not impair basic OF behaviors. The dose of behaviors (central area exploration), risk assessment (investigating 10 mg/kg and pattern of administration were obtained from a report aversive areas in a stretched posture known as rearing), and that suggested possible withdrawal effects following chronic drug locomotion (a simple control for drug-induced impairment of administration (Hotchkiss et al., 2005); in contrast, acute drug locomotor capacity). Chronic dosing with sildenafil (10 mg/kg; administration with the same dose has been shown to have no effect Hotchkiss et al., 2005) was conducted over three weeks in order to on locomotion or exploration (Prickaerts et al., 2005; Tahsili- characterize the effects of repeated drug use and withdrawal on Fahadan et al., 2006; Volke et al., 2003). Sildenafil tablets (50 mg) anxiety and risk-taking behaviors. Moreover, because a number of were ground into powder, mixed with saline, and filtered through 40 pharmacological studies have established that baseline behavior in µm filter paper. The solution was refrigerated at 4° C and brought to tests such as the OF can vary widely between sessions (Prut & room temperature prior to injections. All animals were weighed on Belzung, 2003), repeated testing was conducted in order to assess injection days to ensure appropriate drug dosing and equal changes in behavior that may not emerge in a single session. handling. Treatment groups were as follows: castrated animals A second aim was to investigate sildenafil effects on OF treated with sildenafil (n= 8); intact animals treated with sildenafil behaviors in the absence of the drug’s sexually stimulating effects.
(n= 7); castrated control group (n= 15); intact control group (n= 15).
Sildenafil has been shown to facilitate sexual behavior ingonadally intact but not in castrated male rats (Ottani, Giuliani, & Ferrari, 2002). It is well known that sexual behavior is totallydisrupted by castration (Beach & Holz-Tucker, 1949), and that A circular OF (100 cm diameter and 25 cm walls) was castration significantly reduces aggression (Albert, Walsh, constructed out of aluminum and painted gray. The floor was Gorzalka, Siemens, & Louie, 1986). Thus, in order to control for divided into four equivalent quadrants using a black permanent the non-specific influence of testosterone-dependent behaviors on marker. The perimeter was marked along the 20-cm wide ring OF performance, we examined sildenafil effects in castrated as adjacent to the walls, and a 20-cm diameter circle marked the well as intact male rats. Castration has been shown to reduce center. Two 100-W lamps focused bright illumination over the locomotion, exploration, and entries into the central area of an OF arena. A video camera recorded all behavioral sessions.
(Adler, Vescovo, Robinson, & Kritzer, 1999; Edinger & Frye, OF observations were conducted once a week for four 2005, 2006). Thus, by including castrated animals in our study, we consecutive weeks. During drug treatment, OF testing occurred on examined whether sildenafil and testosterone interact to produce the third injection day, allowing 30-45 min between injection and changes in anxiety and risk-taking behaviors. placement in the OF. A fourth test was conducted one week afterthe last injection. The order in which animals were tested was randomized each week. On test days, animals were transportedindividually in clear plastic tubs, placed in the center of the OF, and allowed to explore freely for five min. At the conclusion of thetest, animals were returned to their home cages and the arena was Forty-five adult male Wistar rats (Harlan, Mexico) weighing 200-250 g at the outset of the experiment were used. Animals were The following variables were measured: entries into the center single-housed in polyurethane tubs within a colony maintained at of the arena, time spent in the perimeter and central areas, 25° C on a 12 h light/dark cycle, and were provided free access to quadrant crossings and rearing. An animal was considered within food and water throughout the experiment. Except for the one- the perimeter of the arena when all four paws were within the week period following surgery, animals were handled every other marked area and in the center when both front paws crossed into ABDEL A. SOLÍS, JOSÉ A. BETHANCOURT AND GABRIELLE B. BRITTON the center circle. These measures served as indices of anxious Table 1 summarizes the frequency of rearing across sessions.
behavior. Quadrant crossings were recorded when all four paws Three-way ANOVA revealed a significant main effect of test crossed from one quadrant into another and served as a measure of session, F(3,123)= 7.51, p<.001, and two-way interactions overall motor activity. Rearing was scored when both front paws between test session and surgical condition, F(3,123)= 4.15, left the floor in a stretching posture and grooming did not occur, p<.01, test session and drug treatment, F(3,123)= 8.19, p<.001, and served as a measure of exploration. Videotaped sessions were and surgical condition and drug treatment, F(1,41)= 7.41, p<.05.
analyzed by three independent observers unaware of the subjects’treatment conditions. Inter-rater reliability checks revealed the observer correlations to be over .94 in each case (M= .97).
Three-factor analysis of variance (ANOVA) with surgical condition and drug treatment as between-subjects factors and test session as the within-subjects factor was applied to four measures: verage Center
entries into the center, time spent in the center, frequency of quadrant crossings and rearing. Significant interactions involving Test Session
test session were analyzed with post hoc one-way ANOVAs toexamine effects on a week-by-week basis. Interactions between surgical condition and drug treatment were examined with one- way ANOVA comparing two means. Mean differences were considered statistically significant if p<.05. When significant differences involving anxiety-related measures were obtained, analysis of covariance (ANCOVA) was applied to these measures Spent in Center
with locomotor activity as a covariate. Remaining significant differences between groups indicate independence between measures of locomotor activity and anxiety-related behaviors. Figure 1. Sildenafil treatment produced anxiolytic effects in OF testing.
(A) Sildenafil treatment significantly increased the number of center en-

tries performed by intact and castrated rats on the third and fourth test ses-sions. Values are group means + standard error of the mean (SEM) (* Three-way ANOVA conducted on center entries revealed a p<.05; ** p<.01 versus control groups on corresponding weeks). (B)Sildenafil treatment also increased the time spent in the center of the field. significant main effect of drug treatment, F(1,41)= 7.41, p<.01, Values are drug treatment group averages (+ SEM) across test sessions (** where sildenafil-treated animals performed more center entries p<.01). INT= intact; CAST= castrated; SILD= sildenafil (10 mg/kg); than controls, and a test session × drug treatment interaction F(3,123)= 2.82, p<.05, indicating that behavior differed across testsessions between drug treatment groups. One-way ANOVAs revealed that sildenafil-treated rats exhibited a greater number of entries into the center than controls on the third [F(1,43)= 9.78,p<.01] and fourth [F(1,43)= 4.45, p<.05] sessions (figure 1A).
Three-way ANOVA conducted on time spent in the center revealed a main effect of drug treatment, F(1,41)= 11.54, p<.01, where sildenafil-treated animals not only entered the center area more verage Cr
often than controls, but also spent more time in the center (figure 1B). As expected, parallel results were obtained for the time spent in the periphery; sildenafil treatment reduced thigmotaxis relative Table 1 summarizes the number of grid crossings across test sessions. Three-way ANOVA revealed a significant main effect of surgical condition, F(1,41)= 4.05, p= .05, and two-way interactions between test session and surgical condition, F(3,123)= 3.82, p<.05, test session and drug treatment, F(3,123)= 3.92, p<.05, and surgical condition and drug treatment, F(1,41)= 8.34, p<.01. One-way equency of Rearing
ANOVA used to analyze the interactions involving test session confirmed that castration reduced locomotion on the first [F(1,43) = 17.89, p < .001] and third [F(1,43)= 10.84, p<.01] sessions, while verage Fr
A

sildenafil treatment restored locomotion on the second test session,F(1,43)= 4.32, p<.05. Figure 2A illustrates the interaction between Figure 2. Sildenafil treatment restored motor activity and exploration in
castrated animals in OF testing. (A) Sildenafil treatment reversed the

surgical condition and drug treatment, confirming that castrated deficits in the number of grid crossings and (B) the frequency of rearing animals that did not receive drug treatment exhibited reduced produced by castration. Values are drug treatment group averages (+ motor activity relative to all other groups (p<.01).
SEM) across test sessions (** p<.01) CHRONIC SILDENAFIL (VIAGRA) ADMINISTRATION REDUCES ANXIETY IN INTACT AND CASTRATED MALE RATS One-way ANOVAs indicated that castration reduced rearing treatment with a selective inhibitor of PDE-5 modifies OF behavior on the first [F(1,43)= 6.37, p<.05] and third [F(1,43)= behavior in a manner consistent with anxiolytic compounds (Prut 7.30, p<.05] sessions, whereas drug treatment restored rearing on & Belzung, 2003). The observation that sildenafil-treated rats the fourth test session [F(1,43)= 14.63, p<.001] after the cessation were more likely to enter the center of the arena and remain in the of drug treatment. Figure 2B illustrates the interaction between center on the third and fourth weeks of testing suggests that surgical condition and drug treatment, where castrated animals changes in cGMP breakdown produced by chronic drug treatment that did not receive drug treatment exhibited reduced exploration were inadequate to produce behavioral changes after two weeks of relative to all other groups (p<.01). treatment, but were revealed during the third week and after the Because levels of overall motor activity can affect anxiety- cessation of drug treatment. To our knowledge, the present study related measures, we applied ANCOVA to center entries and time and that of Hotchkiss et al. (2005) are the reports of the effects of spent in the center, with quadrant crossings as a covariate, to chronic sildenafil treatment on innate behaviors. Taken together, assess whether differences between drug treatment groups in these observations provide evidence that repeated sildenafil anxiety-related behaviors and motor activity were independent.
exposure produces alterations in innate behaviors that emerge after ANCOVA revealed that the increases in center entries [F(1,39)= repeated testing, which supports possible withdrawal and abuse 5.71, p<.05] and time spent in the center [F(1,39)= 9.34, p<.01] in sildenafil-treated animals remained significant, even after Whether the effects of chronic sildenafil treatment on innate accounting for the variance associated with overall levels of motor behaviors are mediated by cGMP is unclear. It is possible that the activity. Thus, sildenafil treatment decreased anxiety in OF testing.
accumulation of cGMP as a consequence of chronic drug We also tested the assumption that anxiety-related measures were treatment produces changes in the expression of various receptors related to exploration on corresponding weeks. Bivariate associated with cGMP or in the responsiveness of these receptors correlations revealed significant positive associations between in the brain. Alternatively, the inhibition of cGMP breakdown may center entries and rearing on the first [r(43)= .53, p<.001], third produce changes in nitric oxide (NO) production via negative [r(43)= .39, p<.01] and fourth [r(43)= .77, p<.001] test sessions, feedback mechanisms (Canteros et al., 1996). PDE-5 inhibitors are and a trend toward significance on the second test session [r(43)= believed to affect anxiety-related behaviors by acting on the nitric .27, p= .07]. However, rearing was not correlated with time spent oxide (NO)-cGMP signaling pathway, but this assertion is in the center on any test session. Thus, increases in exploration complicated by an abundance of contradictory results. To cite one were associated with a greater number of entries into the center example, a single injection of sildenafil at low doses has been area, but not with a tendency to remain in the center.
reported to produce both increases (Kurt et al., 2004) and noeffects (Volke et al., 2003) on anxious behaviors using the elevated plus-maze test in mice. As discrepancies among behavioral studiesindicate, further investigation into whether sildenafil treatment The purpose of the present study was to determine whether differentially affects performance according to species, drug chronic exposure to sildenafil modifies basic behaviors related to treatment, and testing protocols in animal models of anxiety is anxiety and risk-taking. Our results show that sildenafil treatment merited. Similarly, studies investigating the effects of NO levels on in castrated and intact male rats produced an increase in the anxiety-related responses have also reported contradictory results; number of center entries and time spent in the center of the OF, as both increases (Czech, Jacobson, LeSueur-Reed, & Kazel, 2003; well as a decrease in the time spent in the periphery of the OF, on Vale, Green, Montgomery, & Shafi, 1998) and decreases (Faria et the third and fourth weeks of testing. These effects were shown to al., 1997; Forestiero, Manfrim, Guimarães, & de Oliveria, 2006) in be independent of overall motor activity, and indicate that chronic anxiety have been linked to inhibition of NO by nitric oxidesynthase (NOS) inhibitors. Sildenafil and other PDE-5 inhibitorshave been shown to increase cGMP in the hippocampus in vitro (Prickaerts et al., 2002), but it remains to be determined whether Frequency or rearing and quadrant crossings recorded during four open field sessions in intact (INT) and castrated (CAST) rats treated with sildenafil the anxiolytic effects of sildenafil observed in the present study are (SILD) or not treated (CONT)a. Drug treatment ceased after the third test related to enhanced cGMP levels or to its indirect effects on NO.
One problem is the lack of information regarding the specificeffects of sildenafil on the NO-cGMP pathway and the corresponding behavioral consequences of modifying activity 29.7 ± 2.6+++ 15.8 ± 2.2++ 21.9 ± 1.6+++ 19.8 ± 2.1+++ within the pathway. Changes in NO levels may either facilitate or CAST/CONT 08.1 ± 1.2+++ 09.7 ± 1.8++ 08.0 ± 1.7+++ 06.3 ± 1.4+++ inhibit anxiety depending on the magnitude of NOS inhibition (Li,Chung, & Quock, 2004). Further, since NOS is not evenly 17.0 ± 5.6+++ 17.4 ± 7.7++ 16.7 ± 7.1+++ 17.1 ± 8.5+++ expressed throughout the brain (Singh, Pervin, Shryne, Gorski, & CAST/SILD 18.1 ± 4.4*** 22.4 ± 3.8** 14.9 ± 3.7*** 22.8 ± 5.1*** Chaudhuri, 2000), NO may be able to affect neurotransmitter 21.0 ± 1.8+++ 10.5 ± 1.7++ 17.8 ± 2.2+++ 11.3 ± 1.2+++ activity differentially across brain systems. CAST/CONT 08.0 ± 1.2+++ 10.4 ± 2.1++ 07.5 ± 2.0+++ 06.5 ± 1.7+++ The observed effects of sildenafil on the behavior of castrated animals offer further evidence regarding the relationship between 13.6 ± 4.6+++ 05.0 ± 2.0++ 15.6 ± 4.0+++ 16.4 ± 5.3+++ NO-cGMP signaling and anxious behaviors. CAST/SILD 17.9 ± 4.7*** 10.6 ± 1.7++ 14.6 ± 3.0*** 22.8 ± 4.4*** As predicted, castrated animals without treatment exhibited more time in the periphery of the field, less center entries, less * p<.05; ** p<.01 versus castrated control (CAST/CONT) group rearing and locomotion than all other groups (Adler et al., 1999; + p<.05; +++ p<.001 versus intact control (INT/CONT) group Edinger & Frye, 2005, 2006). Sildenafil administration reversed ABDEL A. SOLÍS, JOSÉ A. BETHANCOURT AND GABRIELLE B. BRITTON the decline in center entries, and restored locomotion during and Fahadan et al., 2006; Volke et al., 2003) or exploratory behavior after treatment, which suggests that drug effects were independent (Prickaerts et al., 2005), which suggests that at this dose the drug of the influence of endogenous androgens. Research has shown does not produce a generalized increase in arousal related to that castration significantly increases NOS activity in various brain changes in blood pressure. However, in castrated animals, the regions, particularly in the hypothalamus and amygdala (Singh et effects of a high dose of sildenafil on blood pressure have not been al., 2000), two areas that participate in stress and defensive examined previously, although castration alone has been shown to responses. PDE-5 expression and functional activity are also have no effect on blood pressure in at least two animal models significantly reduced by castration (Morelli et al., 2004; Traish et (Blanco-Rivero, Balfagón, & Ferrer, 2005; Traish et al., 1999).
al., 1999), which suggests that in the absence of androgens, Thus, we believe it is unlikely that sildenafil treatment in castrated changes in NOS levels might be accompanied by lower cGMP animals produced adverse effects that interfered with OF behaviors, degradation (Morelli et al., 2004). It remains unclear how PDE-5 but we cannot rule out this possibility.
inhibitors and a reduction in PDE-5 expression interact to affect In conclusion, administration of sildenafil decreased anxious anxiety-related behaviors in castrated animals. PDE-5 inhibition behavior in male rats, and restored the deficits in locomotion and may differentially activate and inhibit receptors and enzymes exploration produced by castration. These results suggest that associated with cGMP, or may produce changes in receptor repeated sildenafil use over prolonged periods modifies anxiety- sensitivity at target sites. Thus, we cannot exclude the possibility related and risk-taking behaviors in addition to producing its that other centrally- or peripherally-mediated actions influenced effects on peripheral tissues. However, it is important to note that the applicability of spontaneous behaviors of rodents in the OF to In our study, the use of a high dose of sildenafil may limit the human anxiety-related and risk-taking behaviors remains unclear.
generalizability of our results because of the possibility of drug- Moreover, additional testing using other animal models of anxiety, produced side effects. This is particularly relevant in light of the such as the elevated plus-maze and light-dark box, should be reported vasodilatory effects of sildenafil (Zusman, Morales, completed in order to gain a better understanding of how sildenafil Glasser, & Osterloh, 1999). The 10 mg/kg dose was chosen in order use modifies anxiety-related behaviors. These studies are to examine possible withdrawal effects reported in a previous study warranted to determine whether the reported effects of chronically (Hotchkiss et al., 2005), but also because fewer administrations of administered sildenafil on anxious behaviors are related to its the same dose produced no effects on locomotor activity (Tahsili- Adler, A., Vescovo, P., Robinson, J.K., & Kritzer, M.F. (1999). Gonadec- behavior in intact and DHT-replaced male rats. Hormones and tomy in adult life increases tyrosine hydroxylase immunoreactivity in the prefrontal cortex and decreases open field activity in male rats.
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