Received October 4, 2001; Revised December 4, 2001; Accepted December 5, 2001. Author to whom all correspondence and reprint requests should be addressed: Dr. Myriam R. Laconi, Cátedra de Farmacología, Facultad de Medicina, Universidad Nacional de Cuyo, C.C.33, (5500) Mendoza, Argentina. Dr. Effect of Centrally Injected Allopregnanolone on Sexual Receptivity, Luteinizing Hormone Release, Hypothalamic Dopamine Turnover, and Release in Female Rats Myriam R. Laconi and Ricardo J. Cabrera Laboratorio de Investigaciones Neuroquímicas, Comportamentales y Endócrinas (LINCE), Instituto de Medicina y Biología Experimental de Cuyo (IMBECU-CONICET), Cátedra de Farmacología, Facultad de Ciencias Médicas, Mendoza, Argentina Endocrine, vol. 17, no. 2, 77–83, March 2002 0969–711X/02/17:77–83/$11.75 © 2002 by Humana Press Inc. All rights of any nature whatsoever reserved. 77 The effect of intracerebroventricular (icv) injection of allopregnanolone (5-pregnan-3-ol-20-one) on the dopaminergic and reproductive function in ovariecto- mized rats primed with estrogen and progesterone was investigated. Thirty minutes after icv allopregnano- lone injection, the sexual receptivity, luteinizing hor- mone (LH) release, dopamine content, and release in the medial basal hypothalamus (MBH) and preoptic area (POA) were determined. After allopregnanolone injection, LH serum levels were reduced ( p < 0.001) and lordosis behavior was inhibited ( p < 0.005). Intra- cerebroventricular injection of bicuculline (a -amino- butyric acid A [GABA A ] antagonist) alone was ineffec- tive. The injection of allopregnanolone plus bicuculline blocked the effects of allopregnanolone on sexual recep- tivity and on LH serum levels. At the same time, endog- enous dopamine concentration in both the MBH and POA was augmented ( p < 0.005 and p < 0.006, respec- tively) and the turnover rate decreased in both struc- tures. Moreover, in vitro 3 H-dopamine release from MBH and POA was lower in rats injected with allopregnan- olone in comparison with vehicle-treated rats. These results suggest that allopregnanolone influences the dopaminergic mechanisms in female rats, which may, in turn, be responsible for the reduced reproductive activity. Allopregnanolone may exert its effects on sexual behavior through GABA A receptor modulation and a decrease in dopaminergic activity in the MBH and POA. These actions could explain the inhibition of LH release. Key Words: Neurosteroids; allopregnanolone; dopam- ine; luteinizing hormone; sexual receptivity. Introduction The term neurosteroids applies to those steroids that are both formed and accumulated in the nervous system inde- pendently of peripheral steroidogenic gland secretion (1). Neurosteroids that are active on the nervous system mainly include progesterone, pregnenolone, as well as the reduced metabolite of progesterone, 5-pregnan-3-ol-20-one, called allopregnanolone (2). These neurosteroids alter neuronal excitability by modulating the activity of several neurotrans- mitter receptors, and thus can influence behavior. The beha- vioral effects of progesterone are well known. They block the induction by estradiol of both sexual behavior and the preovulatory surges of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) (3). Among the central neurotransmitters involved in the control of sexual behav- ior, dopamine is certainly one of the most extensively stud- ied. Much evidence supports the idea that dopamine, through its different neuronal systems, plays important roles in the control of several aspects of sexual behavior; that is, the incerto hypothalamic system plays a major role in the con- summation of sexual behavior (4). It is well documented that the dopaminergic neurons with terminals in ventromedial hypothalamus are part of a neuronal pathway mediating the feed back effects of estradiol on GnRH secretion and the LH surge (5). Dopamine can play an inhibitory or a facilitatory role in the proestrous LH surge depending on the hormonal status of the animals and of the brain area in the study (5,6). Further evidence suggests that -aminobutyric acid (GABA) containing neurons may inhibit LH release under certain circumstances. The GABAergic system regulates LH release via modulation of catecholaminergic systems that control LHRH secretion (7,8). Given these data, it is interesting to determine whether centrally injected allopregnanolone in the brain has the same effects as progesterone. Since the central areas of action of allopregnanolone are not completely studied, the first objec- tive of the present study was to investigate whether centrally injected allopregnanolone is able to regulate the LH serum levels and sexual receptivity in ovariectomized (OVX) estro- gen and progesterone-primed rats.