Orinoquia

Orinoquia, Volumen 9, Número 2, p. 22-27, 2005. ISSN electrónico 2011-2629. ISSN impreso 0121-3709.

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Artículo Original

Effects of picrotoxin administration on sexual behavior of male rats

Efectos de la administración de picrotoxin sobre el comportamiento sexual en ratas machos

SILVA, M. R. P.1; CRUZ-CASALLAS, P. E.2; FELÍCIO, L. F.1; BERNARDI, M. M.1 *

1-Department of Pathology, Faculty of Veterinary Medicine and Zootechny, University of São Paulo, São Paulo, SP, Brazil

2-School of Veterinary Medicine and Zootechny, University of the Llanos, Villavicencio, Meta, Colombia.

*Author to whom correspondence should be addressed: Dra. Maria Martha Bernardi.

Av. Prof. Dr. Orlando Marques de Paiva, 87 São Paulo, SP, CEP: 05508-900. Brasil.

Recibido en septiembre 5, 2005 – Aprobado en noviembre 1º, 2005

ABSTRACT

The effects of several doses of picrotoxin on sexual behaviour of inexperienced male rats were examined. The lowest doses tested (0.5 and 0.75mg kg1) did not alter the sexual behavioural parameters, whereas the higher doses (1.5 and 2.0mg kg-1) increased latencies for the first mount and intromission and reduced the number of mounts and intromissions and the total number of mounts. None of the picrotoxin doses significantly modified the mount frequency or the copulatory efficiency. The sexual activity index decreased after administration of 1.5 and 2.0mg kg1 picrotoxin. The inhibitory effects of the larger doses of picrotoxin on male sexual behaviour may be a consequence of both a drug interference with motor function and a dose-dependent picrotoxin-induced stress influence.

Key words: GABA, male sexual behavior, picrotoxin, sexual stimulation, sexual inhibition.

RESUMEN

Fueron evaluados los efectos de varias dosis de picrotoxina sobre el comportamiento sexual de ratas macho. La dosis más baja (0.5mg kg-1) no alteró, la dosis intermedia (0.75mg kg-1) facilitó algunas de las variables del comportamiento sexual (disminuyó las latencias para la primera monta, primera intromisión y eyaculación), mientras que las dosis más altas (1.5and 2.0mg kg-1) aumentaron las latencias para la primera monta e intromisión y redujeron el número total de montas e intromisiones. Ninguna de las dosis de picrotoxina estudiadas modificó significativamente la frecuencia de monta o la eficiencia copulatoria. El índice de actividad sexual disminuyó después de la administración de 1.5 o 2.0mg kg-1 de picrotoxina. Los efectos inhibitorios de las dosis más altas de picrotoxina sobre el comportamiento sexual de los machos pueden ser consecuencia, tanto de la interferencia con la función motora como de la influencia del estrés inducido por la picrotoxina.

Palabras Clave: GABA, comportamiento sexual masculino, picrotoxina, estimulación sexual, inhibición sexual.

INTRODUCTION

Male sexual behaviour is one of the many types of behaviour modified by GABA (Paredes and Agmo,1992). This neurotransmitter is believed to inhibit receptors in the middle preoptic area (MPOA) decreases the number of animals showing mounts, intromissions, and ejaculations, while the blockade of male copulatory behaviour and the whole erectile A GABA receptors dramatically decreases the response in particular. Stimulation of GABA A post ejaculatory interval (Fernández-Guasti et al.1990) and facilitates reinstatement of copulation with testosterone treatment after castration. Stimulation of GABAB sites in the lumbosacral spinal cord inhibited ex copula penile erection (Bitran and Hull,1987).

MPOA injection of drugs that induce elevation in GABA ergic function such as the potent GABA agonist, muscimol, or of an inhibitor of GABA degradation, inhibits male sexual behavior, while similar treatment with GABA antagonists such as picrotoxin or (+) bicuculline methiodide, or with 3-MPA, a GABA synthesis inhibitor, facilitates the expression of this behaviour (Fernández-Guasti et al.,1986a,1986b). In contrast, Agmo and Paredes (1985) and Agmo and Fernandez(1991) reported that picrotoxin at subconvulsive doses inhibits male sexual behaviour, whereas no effect was obtained with bicuculline. These contradictory results might be caused by differences in dose or in the experimental design. The present study was designed to examine the dose-response effects of picrotoxin administration on sexual behaviour of male rats.

METHODS

Inexperienced male and female Wistar rats from our own colony, weighing 250-270g and about 100days of age were used. The animals were housed in polypropylene cages (32x40x18cm) under controlled temperature (22-24oC), with free access to food and water. Animals were maintained on a 12 hour inverted light-dark cycle, lights on 10p.m., for at least 21 days before the experiments. The animals used in this study were maintained in accordance to the guidelines of the Committee on Care and Use of Laboratory Animal Resources, National Research Council; U.S.A. Sixty one animals were divided into 6 groups of 9-12 animals each. The groups received a single injection of saline or 0.5, 0.75, 1.0, 1.5 or 2.0mg kg-1, picrotoxin s.c., 40min before the behavioural test. All sexual behaviour tests were held for 4 to 8 hours after the beginning of the dark period. The sexual behaviour was observed as described previously (Felicio et al.,1989;Chiavegatto et al.1989). Male rats were allowed to mount ovariectomized females rendered sexually receptive with exogenous estradiol (50µg kg-1, sc, 54h before the tests) and progesterone (2mg kg-1, sc, 6h before tests). Rats were observed for the presence of mounts during the first 5minutes and the presence of ejaculation within 15minutes. The frequency and latencies for mounts, intromissions and ejaculation were observed. Also, copulatory efficiency (quotient=number of intromissions until first ejaculation/total number of mounts until first ejaculation times 100), sexual activity index (SAI), i.e. log (mount latency-1x15)+log (intromission latency-1x15)+ log (ejaculation latency-1x15)+(number of mounts+number of intromissions)1/2+(4 if the animal ejaculated within 15min. of observation or 0 if the animal did not ejaculate), intromission frequency/min (IF, i.e. number of intromissions/latency for first ejaculation) and mount frequency/min (MF, i.e. number of mounts/latency for first ejaculation) were calculated. Data were analyzed by ANOVA followed by the Dunnet test, with the level of significance set at p<0.05.

RESULTS

The two highest doses (1.5 and 2.0mg kg-1) induced significant increases in latency parameters (Figure 1). Significant variations in the latencies for the first mount and first intromission were observed. Post-hoc tests comparing picrotoxin data with the control group indicated that the groups injected with the 1.5 and 2.0mg kg-1 doses were different from the control group. No significant differences were observed between the control and experimental groups for ejaculatory or postejaculatory mount latencies.

A significant effect of picrotoxin on the number of unsuccessful mounts, number of intromissions and on the total mounts (Table 1) was observed. The post- hoc test comparing picrotoxin data with control data showed that the 1.5 and 2.0mg kg-1 doses reduced the number of uncessful mounts while only the 2.0mg kg-1 dose reduced both number of intromissions and of total mounts. No significant differences were observed between groups for the percentage of ejaculations.

No significant differences were observed in mount frequency, intromission frequency or copulatory efficiency between the control and picrotoxin-treated animals (Table 2). A numerical decrease in the percentage of animals which ejaculated was observed after dosing with 1.5 and 2.0mg kg-1 although statistical analysis did not show significant differences. Moreover, were observed a significant variation in the sexual activity index and the post-hoc test indicated that 2.0mg kg-1 picrotoxin reduced this index (Table 2).

Figure 1

Table 1

Table 2

DISCUSSION

The present results show that gabaergic inhibition by picrotoxin modifies sexual behaviour of male rats in a dose-dependent manner. The 1.5 and 2.0mg kg-1 doses increased the mount and intromission latencies and decreased the number of both mounts and intromissions while the dose range of 0.5 to 1.0mg kg-1 picrotoxin did not alter any of the sexual behaviour parameters evaluated. These results are in accordance with other reports showing an inhibitory effect of picrotoxin at subconvulsive doses on male sexual behaviour, whereas no effect was obtained with bicuculline (Agmo and Fernandez,1989; 1991).

The decrease in sexual activity index caused by 1.5 and 2.0mg kg -1 doses might be a result of a decreased intensity of sexual behaviour and/or motor function. This index represents the appetitive and consumatory aspects of sexual behaviour and a decrease reflects interference with the libido and/or with the performance. Previous reports have suggested that some gabaergic drugs affect sexual behaviour only indirectly, via an impairment of motor execution (Agmo et al.,1987; Paredes and Agmo,1989) Recently, Paredes et al.(1997) also suggested that changes in gabaergic neurotransmission reduced the sensitivity to environmental stimuli, thereby inhibiting sexual and drinking behaviour in a nonspecific way.

The present findings do not support the hypothesis that a decrease in motor function is the only factor responsible for the reduction of male sexual behaviour. In fact, no differences were observed in intromission frequencies, previously reported as a neuromotor coefficient (Soulairac,1963), after administration of all picrotoxin doses. The higher doses of picrotoxin (1.5 and 2.0mg kg-1) decreased the first mount and intromission latencies, suggesting an effect on sexual motivation drives (Paredes et al.,1993).

Stressful situations elicit adaptive responses in organisms in an attempt to reestablish homeostasis. The adaptive response to stress seems to depend on the type (physical or emotional), intensity and duration (acute or chronic) of the stimulus, as well as on the characteristics and physiological state of the organism (De Wied,1980). Physical or emotional stress is a profound disruptive factor for reproductive function (Johnson et al.,1992). The endocrine response to stress activates the hypothalamic-pituitary-adrenocortical system but also the hypothalamic- pituitary-gonadal system and other neuroendocrine axes. Some evidence from empirical and clinical data suggests that certain levels of anxiety may result in premature ejaculation, while high anxiety levels result in complete inhibition of this behaviour. Conversely, the administration of diazepam may result in an inhibition of rat sexual behaviour (Fernández-Guasti et al.,1990).

Several reports indicate that subconvulsive doses of central stimulating drugs have anxiogenic effects on adult animals and humans. File and Lister(1984) showed that subconvulsive doses of picrotoxin induce several behavioural signs of anxiety correlated with increased corticosterone levels. Moreover, injections similar to that of female control rats. These data suggest that perinatal exposure to picrotoxin may interfere with normal male masculinization, rather than increasing anxiety in male rats.

The present results showing that gabaergic inhibition modifies sexual behaviour of male rats could be a consequence of stress induced by picrotoxin. In addition, the slight facilitatory effect of picrotoxin might be similar to the effects induced by stress on copulatory behaviour which involves dopaminergic mesolimbic activation (Herman et al.,1982), mainly in the motivational component (Pfaus et al.,1990; Hull et al.,1995; Moses et al.,1995). On the other hand, the reduction of the sexual behaviour observed after the highest picrotoxin doses may be related to the actions of the drug elicited by several hormones secreted during stressful situations, such as corticotropin-releasing factor, beta-endorphin and glucocorticoids, on hypothalamic-pituitary-gonadal axis function (Doerr and Pirke,1976; Rivier et al.,of GABA A receptor antagonists such as picrotoxin and 1986; McLusky et al.,1988). The infusion of bicuculline into the dorsomedial hypothalamus of rats elicit a wide range of physiological responses, i.e., an increase in heart rate and in plasma catecholamine levels, in locomotion activity and anxiogenic behavioural like effects, as well as in conflict, in the elevated plus maze and social interaction tests (File and Lister,1984).

In a recent article we reported that perinatal exposure to a subconvulsive dose of picrotoxin interferes with the sexually dimorphic behaviours of male rats, measured in open-field and social interaction tests (Silva et al., 1997). The offspring of female rats exposed to a subconvulsive dose of picrotoxin (0.75mg kg) on day 18 of pregnancy, immediately after Corticotrophin-releasing Factor (CRF) into the third ventricle of sexually experienced male rats elicited a suppression of sexual performance (Sirinathsinghji,1987). However, in the present study we observed that low doses of picrotoxin only produced a mild facilitatory effect, a result quite different from that reported by Fernández-Guasti et al. (1986a,1986b). This fact might be the consequence of the different routes of administration employed.

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