Blockade of androgen receptor in the medial amygdala inhibits noncontact erections in male rats

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Abstract

Our previous work demonstrated that androgens in the medial amygdala (MeA) of castrated male rats maintained noncontact erections (NCEs), which occur during exposure to an inaccessible receptive female, for one week after implantation. The present experiments investigated the effects of implantation into the MeA of either flutamide (F), a blocker of androgen receptors, or of 1,4,6-androstatrien-3,17-dione (ATD), which blocks aromatization of testosterone. One day after implantation of F, fewer males displayed NCEs, and had longer latencies to the first NCE and fewer NCEs, and spent less total time in genital grooming, compared to the control group. ATD had only weak facilitative effects on some measures of NCEs. These results suggest that androgen receptors in the MeA play a major role in the regulation of NCEs and that the MeA is one of the neuronal structures that regulate male sexual arousal. Furthermore, it is sensitive to relatively fast changes in the level of androgen receptors stimulation.

Research highlights

► Flutamide in the medial amygdala inhibit noncontact erections. ► ATD in the medial amygdala do not diminish noncontact erections. ► The medial amygdala is sensitive to relatively fast changes in androgen receptors activation.

Introduction

One of the most useful parameters describing sexual arousal is the occurrence of penis erection. In male rats exposed to inaccessible estrous females the presence of penile erections can be useful model to investigate the neuronal structures involved in the regulation of sexual arousal [40]. These noncontact erections (NCEs) are analogous to human "psychogenic" erections [37] and are presumed to reflect sexual arousal [39]. Sachs [39] analyzed mechanisms involved in the regulation of erections and concluded that neuronal structures and hormonal profile depend on the context in which erection occurs.

NCEs disappear within three days after castration and are restored within a few days by subcutaneous implants of testosterone (T) or dihydrotestosterone (DHT), but not by estradiol (E) [5], [25]. NCEs were not significantly affected in aromatase knockout mice, suggesting that the role of estrogens is small, if at all, in this phenomenon [27]. This profile of hormone sensitivity is similar to that of touch-based erections in rats, which were maintained or restored by T and DHT, but not by E, whereas male rat copulatory behavior (mounting and intromissions) responds to systemic T and E, but not to DHT [17], [30]. Intromissions (erections during copulation) were visible much longer than NCEs—they usually could be detected at least one week after castration. Touch-based erections disappeared earlier in castrated rats and were restored quicker than erections during copulation [17]. The first effect of hormonal therapy on touch-based erection occurred after 24 hours (with a maximum after 48 hours) at the time when intromissions were not visible [10]. After spinal transection, touch-based erection reappeared even faster—i.e. within hours [13]. It hardly seems possible that morphological changes in the spinal neuronal structures would develop during this time. It was recently found that loss of penile reflexes did not correspond with the time course of morphological changes either in the spinal nucleus of the bulbocavernosus innervating striated muscles of the penis (first significant effect on day 28) or striated muscles of the penis itself (bulbocavernosus and levator ani, first effect on day 14) after castration [12].

The amygdala integrates sensory and hormonal inputs involved in the regulation of sexual behavior [7], [17], [26], [49]. Volatile odors from the female are necessary and sufficient to evoke NCEs in male rats [8], [38]. Informations about such odors are transmitted via the main olfactory system [21]. Lesions of the medial amygdala (MeA)—especially in the postero-dorsal part (MeApd)—eliminate or severely disrupt NCEs, and to a lesser extent, disrupt copulation [19], [20]. In contrast, medial preoptic area (MPOA) lesions eliminate copulation without significantly disrupting NCEs [22]. The MeApd of rats is sexually dimorphic [14], and the size depends on the activation of androgen [6]. However, the dorsal region of the MeA of male rats is rich not only in androgen receptors, but also estrogen receptors [11], [44], and the postcastration atrophy of neurons in MeApd is reversible by systemic DHT or E [5]. The androgens in the medial amygdala are ineffective in the restoration of copulation in long-term castrated males [48] unless they receive subthreshold levels of systemic estradiol [1]. Blocking of androgen receptors by hydroxyflutamide did not significantly disturb the restoration of copulation in castrated males during hormonal testosterone therapy [29]. Estradiol in the medial amygdala facilitates some elements of copulatory behavior—mounting and intromission frequency but not ejaculation [16].

The androgen implants into medial amygdala briefly maintain noncontact erections after castration. About half of the males implanted with T or DHT into MeA at the time of castration showed NCEs one week later. Moreover, latency to first NCE was reversibly correlated with androgen concentration in the postero-dorsal part of MeA. The role of estrogens in MeA was not clear, as NCEs were detected two weeks after E implantation. In this experiment androgens as well as estradiol had marginal effect on copulation—increased number of males displaying mounting two weeks after castration [3].

Because NCEs disappear within three days after castration [25], it suggests a relatively fast regulation of such erections by androgens when compared to erections during copulation. It should be noted that the term “fast” does not mean the same as “rapid” because “rapid” is related to the process that does not require protein synthesis. Androgen administration can be executed by influences on penis or penis innervations and/or brain structure such as the MeA. Also because many aspects of copulatory behavior correlate with aromatase of testosterone activity [17], we decided to investigate the effects of androgen receptors and testosterone aromatization block in the MeA on NCEs simultaneously in the experiment described in this article.

The aim of our study was to establish whether the relatively fast effects of androgen receptors activation on noncontact erections can be mediated by the medial amygdala. We analyzed noncontact erections in intact male rats within the first days of drug administration, after the blocking of androgen receptors in the medial amygdala. Additionally, we blocked aromatization of testosterone to investigate the effect of lower levels of estradiol in the MeA on NCEs phenomenon.

Section snippets

Methods

In general, the scheme of experiments was based on methods described in our previous experiments [3].

Histology

Only animals with cannulae successfully implanted into at least one side of the MeA (Fig. 1) were analyzed statistically. The mean sum of both cannulae tips (3 pdMeA, 2 border pd-adMeA, 1 adMeA, 0 out of MeA) in F group was 3.44 (SE = 0.58). The mean sum of cannulae tips in ATD group was 4.25 (SE = 0.62). The cannulae of 7 males were localized outside of the MeA mostly to lateral ventricle. Twelve males from control (C), nine from F and eight from ATD treated groups were qualified for statistical

Discussion

The results of this study suggest that in the MeA (i) androgen receptors play a significant role in the regulation of NCEs; (ii) blocking the androgen receptors displays fast inhibition of NCEs; (iii) blocking P-450 testosterone aromatase activity does not diminish NCEs.

Acknowledgments

This work was supported by a grant from the Medical University of Warsaw (1MA/W1/2004-6). The protocols were approved by The Animal Care and Use Committee of The Medical University of Warsaw (2003). We thank Ewa Szczepańska-Sadowska and Maciej Śmietanowski for many useful suggestions and Robert Crayton and Peter James for language correction.

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