رفتار جنسی رنگپذیری گیرنده آندروژن هیپوتالاموس را کاهش می دهد

Male sexual behavior is regulated by limbic areas like the medial preoptic nucleus (MPN), the bed nucleus of the stria terminalis (BST), the nucleus accumbens (nAcc) and the ventromedial hypothalamic nucleus (VMN). Neurons in these brain areas are rich in androgen receptors (AR) and express FOS-immunoreactivity in response to mating. In many species sexual satiation, a state of sexual behavior inhibition, is attained after multiple ejaculations. The mechanisms underlying sexual satiation are largely unknown. In this study we show that sexual activity reduces androgen receptor immunoreactivity (AR-ir) in some of the brain areas associated with the control of male sexual behavior, but not in others. Thus, one ejaculation reduced the AR-ir in the MPN and nAcc, but not in the BST and VMN. Copulation to satiation, on the other hand, reduced AR-ir in the MPN, nAcc and VMN, and not in the BST. The AR-ir reduction observed in the MPN of sexually satiated rats was drastic when compared to that of animals ejaculating once. Serum androgen levels did not vary after one ejaculation or copulation to exhaustion. These data reveal that sexual activity reduces AR in specific brain areas and suggest the possibility that such a reduction underlies the sexual inhibition that characterizes sexual satiety.

Steroid hormones play an important role in the regulation of male sexual behavior. Thus, in general, castration decreases while exogenous androgen administration restores copulation (Meisel and Sachs, 1994). Interestingly, several factors such as previous experience, photoperiod, age, and others also influence copulatory behavior without necessarily modifying the endocrine milieu (Chubb and Desjardins, 1984, Clemens et al., 1988, Miernicki et al., 1990, Phoenix and Chambers, 1986 and Wallen, 2001). It is clear that steroids act on the brain to induce sexual behavior. Within the rat brain the hypothalamus has been proposed to play a dual role in the control of this behavior. On one side, several hypothalamic nuclei are directly involved in its neural control and, on the other, hypothalamic neurons that contain gonadotropin hormone realising factors (GnRH) participate in its neuroendocrine modulation. Regarding the latter function, lesions in certain hypothalamic areas produce gonadal atrophy and thereby suppress sexual behavior (Heimer and Larsson, 1966/1967) by three possible mechanisms: (a) direct lesions of the GnRH neurons continuum primarily located in the telencephalon-diencephalon limit; (b) lesions that damage the majority of the GnRH nerve fibers traversing to the median eminence; or (c) isolation of hypothalamic areas (like the mediobasal hypothalamus) that contribute to the functional integrity of the neuroendocrine network (Silverman, 1994). In contrast, extensive bilateral electrolytic lesions encompassing the medial preoptic region and the anterior part of the hypothalamus suppress male rat sexual behavior without causing gonadal atrophy. Attempts to arouse the lesioned rats by handling or by changing the stimulus female are ineffective in inducing sexual behavior; chronic testosterone treatment is similarly ineffective, further indicating that the effects of mPOA lesions are not an indirect result of an altered gonadal regulation (Paredes et al., 1993). The androgen sensitive neurons in the mPOA participate in the regulation of copulation, since implantation of testosterone into this brain area of castrated male rats restores sexual behavior, while selective blockade of androgen receptors (ARs) in this region inhibits mating (McGinnis et al., 1996). In the mPOA the sexual dimorphic nucleus or medial preoptic nucleus (MPN), particularly rich in ARs (Handa et al., 1996), specifically participates in the control of masculine sexual behavior (De Jonge et al., 1989). Besides, the mPOA, other limbic regions like the bed nucleus of the stria terminalis (BST) and the nucleus accumbens (nAcc), play an important role in the control of male sexual behavior. In general, it is considered that the BST participates in the transmission of the olfactory information necessary for copulation (Emery and Sachs, 1976). The nAcc has also been implicated in the control of copulatory behavior (Mitchell and Gratton, 1994) particularly sexual motivation (van Furth et al., 1995). Thus, elevations in dopamine release within this area coincide with preparatory sexual activity and copulation (Pfaus et al., 1990, Damsma et al., 1992 and Mas et al., 1990). Mating in male rats, as many other behavioral processes, importantly increases FOS expression (the protein product of the c-fos proto-oncogene) in the MPN, the BST and to a much lesser extent in the VMN ( Coolen et al., 1996). Significantly increased neuronal FOS responses have also been reported to occur in the nAcc of males that displayed non-contact penile erections or had two ejaculations ( Kelliher et al., 1999). Immunohistochemical and in situ hybridization analyses have shown that the distribution of the AR protein and the AR mRNA within the brain follows an identical pattern and reaches peak density in the MPN and the principal nucleus of the BST ( Handa et al., 1996). Additionally, using a radiolabeled ligand it was established that the highest concentration of nuclear androgen receptors is found in the VMN ( Roselli et al., 1989). Interestingly, Beatrice Gréco and co-workers recently demonstrated that mating-induced FOS expression occurs almost exclusively in AR-containing neurons ( Gréco et al., 1996 and Gréco et al., 1998) suggesting a primary role of sex-steroid sensitive neurons in male rat copulation. The male rat may ejaculate several times before reaching a state of sexual inactivity that lasts for various days. This state, named sexual satiation, is common to many species, but differs in its duration and in the amount of sexual activity necessary to be reached (Larsson, 1956 and Meisel and Sachs, 1994). Little is known on the control of this phenomenon. Recently, we have established a sexual satiation procedure in which male rats are allowed to copulate ad libitum during a 4 h period. Twenty-four hours later a major population shows a complete inhibition of sexual activity. In the control of sexual satiety, we have reported the involvement of several neurotransmitter systems ( Rodríguez-Manzo and Fernández-Guasti, 1994 and Rodríguez-Manzo and Fernández-Guasti, 1995), possibly coupled to a dopamine-mediated motivational change ( Rodríguez-Manzo, 1999). In support of this idea, an increase in dopamine release has been found in the nucleus accumbens during the anticipatory phases of sexual behavior ( Fiorino et al., 1997). In the present study we analyze whether sexual activity alters AR-ir in the MPN, BST, nAcc and VMN. These brain areas were selected because of their involvement in the neural and/or neuroendocrine control of sexual behavior. A putative participation of neuroendocrine factors in the process of sexual satiation is almost unexplored. Since the AR-ir has been found to depend on the circulating levels of androgens (Handa et al., 1996, Kruijver et al., 2001 and Wood and Newman, 1999), we also measured the serum levels of androgens in all experimental groups. We hypothesized that changes in the AR could mediate the long-term alterations in sexual behavior produced by copulation. The AR-ir in these brain areas was compared among sexually sated rats, animals that had one ejaculation and sexually experienced subjects that did not copulate.