Progesterone and the neural mechanisms of hamster sexual behavior.

Stimulation of both the ventral medial hypothalamus (VMH) and the ventral tegmental area (VTA) by progesterone is necessary to facilitate sexual behavior in female hamsters. Recently obtained evidence indicates that progesterone exerts its behaviorally relevant actions in the VTA by acting on cell membranes. When progesterone conjugated to bovine serum albumin, which cannot permeate the cell membrane, is applied to the VTA concurrent with free progesterone to the VMH, estrogen-primed hamsters become sexually receptive. Since the reverse treatment is ineffective, this suggests that progesterone's nongenomic effects in the VTA may require concurrent genomic activation by progesterone in the VMH. The nongenomic action of progesterone on sexual receptivity may involve the GABAA receptor complex, as progestins are known to modulate this receptor complex. VTA infusions of GABAA agonists enhance, and antagonists inhibit, progesterone's effectiveness on receptivity. Finally, the behavioral effectiveness of progesterone metabolites in the VTA, concurrent with progesterone in the VMH, is consistent with their relative biochemical efficacy at the GABAA complex. These data suggest that progesterone may exert its behavioral effects in the VTA through GABAA. However, it is not yet clear whether progesterone normally acts directly on GABAA in the VTA. Progesterone may also act at some other membrane binding site and GABAA may represent an indirect mechanism for progesterone.

Testosterone modulates the effects of ethanol on male mouse aggression.

In a series of three experiments, we evaluated the degree to which the effects of acutely administered ethanol on aggressive behavior of male CFW mice toward a male intruder interact with, and depend on, androgen levels. In the first experiment, mice were tested at 15 min after 0, 0.1, 0.3, 1.0, 1.7, or 3.0 g/kg of ethanol PO. The highest dose (3.0 g/kg) significantly suppressed aggression by the male residents. In the second experiment, aggressive behavior was suppressed from 5 to 60 min after 3.0 g/kg ethanol administration PO. The third experiment evaluated the role of testosterone in these effects in another set of male mice that were castrated and then implanted with a 7.5-mm or 2.5-mm silastic capsule of testosterone (T) or a silastic capsule containing cholesterol as a control. The castrated mice with 2.5-mm T capsules or cholesterol capsules had lower baseline levels of aggression than intact mice or castrated males with 7.5-mm T capsules, but they demonstrated an alcohol dose-response pattern similar to that of the intact males. The castrated males with 7.5-mm T capsules had a different dose-response curve than the other males. Doses of 1.0 and 1.7 g/kg ethanol PO significantly enhanced aggression; 5.6 g/kg was required to suppress aggression. Ethanol effects on aggressive behavior did not require T or changes in T level, but T levels altered behavioral sensitivity to ethanol.

Alcohol, allopregnanolone and aggression in mice.

RATIONALE: Aggressive behavior of certain individual animals can be greatly increased when under the influence of low doses of alcohol. One of alcohol's neurochemical actions that may be relevant to alcohol-heightened aggression (AHA) is its positive modulation of the GABA(A) receptor complex. OBJECTIVE: The objective of this study was to investigate whether alcohol interacts with an endogenous modulator of the GABA(A) receptor complex, the neurosteroid allopregnanolone, in stimulating/heightening aggressive behavior. METHODS AND RESULTS: The first experiment was designed to test the hypothesis that neurosteroid modulators of the GABA(A) receptor complex will increase aggression and to compare these effects with alcohol. Male CFW mice were injected with allopregnanolone, alphaxalone (3-30 mg/kg, i.p.), or alcohol (1.0 g/kg, p.o.) 15 min prior to a 5-min confrontation with an intruder. Moderate doses of alcohol and the neurosteroids increased aggression by ca. 50% above baseline; impaired locomotion was seen only at the highest doses. A second experiment compared AHA and ANA (i.e. alcohol-non-heightened aggression) mice by giving allopregnanolone (1-10 mg/kg) with a simultaneous oral injection of alcohol (0.6 or 1.0 g/kg) or water. When administered with water and the 0.6 g/kg dose of alcohol, allopregnanolone increased the aggression of AHA and ANA mice. Administration of the 1.0 g/kg dose of alcohol in ANA mice prevented allopregnanolone-heightened aggression. In AHA mice, addition of allopregnanolone to 1.0 g/kg alcohol dose-dependently reduced alcohol-heightened aggression, suggesting potentiation of alcohol's suppressive effects on aggression. CONCLUSIONS: The neuroactive steroid allopregnanolone appears to play an important role in alcohol-heightened aggression. Moreover, the upward shift of the aggression-heightening effects of alcohol and the downward shift at the maximally effective alcohol dose by allopregnanolone point to a shared mechanism for both positive modulators of the GABA(A) receptor complex.

Temporal and sequential patterns of agonistic behavior: effects of alcohol, anxiolytics and psychomotor stimulants.

Social and agonistic interactions are composed of a range of species-typical acts, postures, displays and other communicative signals that follow characteristic patterns. Descriptive and analytic methods permit an assessment of the temporal and sequential features of highly probable patterns of agonistic interactions. Analysis of the intervals that separate consecutive attacks by a resident mouse or rat toward an intruder identifies bursts or epochs of attacks. Amphetamine (1.25, 2.5 mg/kg), but not diazepam or alcohol, alters the burst pattern of attack behavior. Higher doses of alcohol, but not diazepam, in either resident male rats or in lactating rats confronting an intruder, reduce the sequences of aggressive acts and postures with high transition probabilities as identified by lag sequential analysis. These results suggest that temporal and sequential patterning mechanisms may be differentially altered by amphetamine- and alcohol-type substances. These neural for many types of behavior.

Alcohol and "bursts" of aggressive behavior: ethological analysis of individual differences in rats.

A quantitative ethological analysis of rodent aggression was performed in order to characterize the aggression-heightening effects of alcohol in certain individuals. In dyadic confrontations, a resident rat pursues, threatens and attacks an intruder, who reacts with defensive, flight and submissive behaviors. The behavioral data from five series of experiments conducted from 1984 through 1989 were subjected to a lag sequential analysis that identified highly predictable sequences of aggressive behavior, and to interval analysis that delineated a burst pattern of aggressive behavior. These analyses revealed a distinct behavioral sequence of pursuit----sideways threat----attack bite----aggressive posture that occurs in bursts with an inter-event interval of less than 6.6 s. In the total population, alcohol heightened attack behavior at low acute doses (0.1, 0.3, 1.0 g/kg) in 47% of the animals (n = 44), suppressed reliably attack behavior in another 25% (0.1-3.0 g/kg; n = 23) and had unreliable effects in the remaining 28% (n = 24). The peak enhancement of aggressive behavior was seen over more than a log cycle of alcohol doses (0.1, 0.3 or 1.0 g/kg) in different individuals. In an additional group of rats (n = 20), individuals were identified according to whether or not acute low alcohol doses enhanced or suppressed the frequency of attack bites. In the subgroup of five rats who doubled their attack frequency upon acute alcohol challenge, this aggression-heightening effect was confirmed on repeated occasions. The aggression-heightening effects of alcohol were seen during the high-rate interactions in the initial phase of the confrontation and particularly during the lower level of fighting later on. Regardless of alcohol dose and subgroup, the highly predictable sequence of pursuit----sideways threat----attack bite----aggressive posture remained intact as long as the individual was able to fight. The present analysis identifies those individuals in whom low alcohol doses increase the frequency of attack behavior, the number of aggressive elements in bursts and particularly the "time in burst". Alcohol produces these changes without altering the latency to initiate aggressive behavior, the rate of aggressive behavior within a burst or the number of bursts in an encounter. Alcohol may lengthen aggressive bursts by preventing termination of longer aggressive sequences rather than by altering the initiation of this behavior.

P-3-BSA, but not P-11-BSA, implants in the VTA rapidly facilitate receptivity in hamsters after progesterone priming to the VMH.

Recent evidence suggests that progesterone (P) may have behaviorally relevant actions on neuronal membranes in the ventral midbrain. In the present experiments, we exploited the rapid time course predicted for non-genomic actions of steroid hormones. Ovariectomized hamsters were implanted with chronic guide cannulae, one aimed above the ventromedial hypothalamus (VMH) and the other over the contralateral ventral tegmental area (VTA). The following week animals were estrogen-primed (10 micrograms estradiol benzoate) and pre-tested for sexual receptivity 2 h after a P or P conjugated to the macromolecule bovine serum albumin (P-3-BSA) containing tube was applied to the VMH. P-3-BSA binds well to neuronal membranes, but does not penetrate them because of the large size of the BSA molecule. After the pre-test, the opposite hormone-containing insert was applied to the VTA and hamsters were tested again for sexual receptivity 5 min after this implantation. The following week, the contents of the tubes were reversed. Receptivity only occurred when P was applied to the VMH and 2 h later P-3-BSA was applied to the VTA; the reverse treatment was ineffective. These data indicate that P is capable of rapidly facilitating receptivity by actions on cell membranes in the VTA if P has been applied to the hypothalamus 2 h earlier. Progesterone conjugated to BSA at carbon 11 (P-11-BSA) was ineffective compared to P-3-BSA using the same paradigm. This suggests that the mechanism which responds to P in the ventral midbrain may require the 11 region.

3 alpha-OH-DHP and 5 alpha-THDOC implants to the ventral tegmental area facilitate sexual receptivity in hamsters after progesterone priming to the ventral medial hypothalamus.

Progesterone (P) stimulation to both the ventral medial hypothalamus (VMH) and the ventral tegmental area (VTA) is necessary to facilitate sexual receptivity in female hamsters, despite the sparse population of estrogen-induced P receptors found in the VTA. Instead, P may act at neuronal membranes in the VTA. These P effects may be mediated by actions on the gamma-aminobutyric acid A-(GABAA)-benzodiazepine receptor complex (GBR). Many progestin metabolites have a greater effect in vitro on benzodiazepine binding and Cl- flux than P. If P's actions are due to metabolism to a progestin more potent at the GBR, then applying one of those progestin metabolites directly to the VTA should facilitate receptivity, if coupled with P to the VMH. To test this hypothesis three P metabolites, in decreasing order of activity at cortical synaptosome GBR, were tested: 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha-OH-DHP), 5 alpha-pregnan-3 alpha,21-diol-20-one (5 alpha-THDOC) and 5 beta-pregnan-3 alpha,21-diol-20-one (5 beta-THDOC). Ovariectomized hamsters were implanted with chronic cannulae, one aimed above the VMH and the other over the contralateral VTA. Animals were estrogen-primed and tested for sexual receptivity 4 h after a P containing insert was applied to the VMH and a metabolite containing insert was applied to the VTA. The following week the contents of the tubes were reversed; on the third week P was applied to both sites. Facilitation of receptivity occurred only when P was applied to the VMH and either P or a metabolite was applied to the VTA.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen and estrogen receptors in adult hamster brain.

Both androgen and estrogen receptors are present in the hypothalamus-preoptic area and remaining "brain' regions of gonadectomized adult male and female hamsters. No quantitative or qualitative sex differences are detectable in either receptor system. According to all biochemical criteria tested, both receptors are qualitatively similar to those present in mouse and rat brain. However, there are striking species differences in both the relative concentration and distribution of both androgen and estrogen receptors in hamster brain compared to mouse and rat brain.

Evidence for a non-genomic action of progestins on sexual receptivity in hamster ventral tegmental area but not hypothalamus.

Progestogenic stimulation of both the ventromedial nucleus of the hypothalamus (VMH) and the ventral tegmental area (VTA) is critical for normal receptivity in estrogen-primed hamsters. However, anatomical and biochemical studies have identified very few estrogen-induced progestin receptors in the rodent ventral midbrain. To determine whether progesterone might be working on the membrane of neurons in the VTA, progesterone 3-CMO BSA (P-3-BSA) was applied intracranially. The size of P-3-BSA makes it relatively impermeable to the cell membrane. Ovariectomized hamsters were implanted with 2 chronic cannulae, one aimed at the VMH and the other at the contralateral VTA. These animals were then estrogen-primed and tested for sexual receptivity after progesterone-containing tubes were inserted just dorsal to the VMH and P-3-BSA inserts were applied above the VTA. The following week, the hamsters were tested again with the contents of the inserts reversed. Animals with progestogenic stimulation to the VMH and P-3-BSA to the VTA were receptive yet those with P-3-BSA to the hypothalamus and progesterone to the VTA were not receptive. These data suggest that progesterone is capable of facilitating sexual receptivity within the VTA by actions on the cell membrane. The non-genomic effects in the VTA require concurrent genomic activation by progesterone within the hypothalamus.

Inhibition of sexual receptivity after intracranial cycloheximide infusions in female hamsters.

Female hamsters were ovariectomized and one week later stereotaxically infused with 20 micrograms cycloheximide (20 micrograms/microliter, 0.6 microliter/min) or 1 microliter saline bilaterally into one of several brain sites. Thirty min after the infusion, the animals were injected with 5 micrograms estradiol benzoate (EB) then 44 hr later with 500 micrograms progesterone and tested with a male for receptivity at hour 48. One week later the animals were retested with EB and progesterone but without any intracranial infusion to investigate the possibility of permanent lesion effects. The greatest inhibition of receptivity occurred in females which received cycloheximide in the ventromedial hypothalamus (VMH) or lateral to the VMH. Saline infusions into the VMH had no inhibitory effects. Inhibition was rarely seen after infusion into the preoptic area, anterior hypothalamus, dorsomedial hypothalamus, cortico-medial amygdala, or septal area. Moderate inhibition was found after infusion of cycloheximide into the third ventricle. The inhibition following cycloheximide infusion was not permanent or irreversible. On the retest one week later the animals were sexually receptive. These results suggest that protein synthesis within the VMH is an essential part of the initial action of estrogen for the induction of sexual receptivity in hamsters.

Ventral tegmental lesions impair sexual receptivity in female hamsters.

The ventral mesencephalon appears to be one of the sites of progesterone action in the control of sexual receptivity in female hamsters. The behavioral response to systemic progesterone was assessed in female hamsters following electrolytic lesions of portions of the ventral mesencephalon. Adult female hamsters were ovariectomized and pretested for sexual receptivity, then were given bilateral lesions aimed at the region of the ventral mesencephalon where progesterone implants have been shown to facilitate receptivity. Lesions were produced by stereotaxically lowering an electrode and applying anodal direct current of 1-2 mA for 5-20 seconds. One week later the hamsters were injected with estrogen followed 44 h later by progesterone. They were then tested for sexual receptivity. After this test, their brains were removed and histologically prepared. Lesion location was determined and lesion size was quantified with a digitizing pad. Lesions which were centered in and destroyed much of the ventral tegmental area produced the greatest lordosis impairments. Mesencephalic lesions which did not bilaterally damage the ventral tegmental area had little effect. These results support the hypothesis that the ventral mesencephalon, particularly the ventral tegmental area, is an important site for the facilitative action of progesterone on sexual receptivity in estrogen-primed female hamsters.

Site-specific inhibition of receptivity by intracranial anisomycin in hamsters.

The ventromedial nucleus of the hypothalamus (VMH) has been implicated in the mediation of the hormonal control of female rodent sexual behavior. However, in hamsters, progesterone (P) has been found to have effects on sexual receptivity in other diencephalic and mesencephalic sites as well. Progesterone is thought to exert its behavioral effects by altering protein synthesis in CNS target neurons. We tested the effects of 30 gauge implants of the protein synthesis inhibitor anisomycin in the preoptic area (POA), VMH, and ventral mesencephalon (VMES) 30 minutes before 500 micrograms P SC, on the facilitation of lordosis in ovariectomized estrogen-primed female hamsters. The same animals were tested one week later with estrogen and progesterone treatment but without anisomycin. Anisomycin reduced sexual receptivity (lordosis) when placed in the VMH or VMES, but not when delivered to the POA. The results confirm the importance of the VMH in the mediation of progesterone facilitation of female sexual behavior, but also provide evidence that ventral midbrain structures may play a role in female sexual receptivity in hamsters. These two structures may be important for different aspects of lordosis. Progesterone effects in both sites appear to be protein synthesis dependent.

Neuropharmacological characteristics of individual differences in alcohol effects on aggression in rodents and primates.

Many violent crimes have been associated with alcohol intoxication, but experimental research in laboratory animals has been largely inconclusive on alcohol effects on aggression. A focus on individual differences rather than group statistics has revealed that low doses of ethanol cause large and repeatable increases in aggressive behavior in subgroups of rodents and primates. The recent progress using in vivo neuropharmacological techniques makes it feasible to explore differences in brain mechanisms in animals that show enhanced aggression after ethanol vs those that do not. Effects of ethanol on three major neurotransmitter systems (i.e. GABA, serotonin, dopamine) are examined. Since these neurotransmitter substances are critically important in the neurobiology of various kinds of aggressive behavior in rodent and primate species, they are potential mechanisms by which ethanol alters aggressive behavior. Direct research on the relevance of the physiological interaction between ethanol and the GABA receptor suggests that at least some of the effects of alcohol on aggression involve the GABA(A)-benzodiazepine receptor complex. The role of serotonin (5-HT) will have to be newly defined in light of the findings that ethanol increases 5-HT release in several forebrain areas, in a dose range that can stimulate aggressive behavior in a subgroup of individuals. Recent in vivo studies show that acute exposure to ethanol increases dopamine release in discrete dopamine terminal areas, and that the initiation and execution of aggressive and defensive behavior are also synchronized with increased dopamine activity in these brain regions.

The relative effectiveness of progestins for facilitation and inhibition of sexual receptivity in hamsters.

In a series of experiments, we studied the biphasic actions of 4 progestins on sexual receptivity in female hamsters. Based on previous reports, we selected doses of progesterone (P), desoxycorticosterone acetate (DOCA), 5-alpha-dihydroprogesterone (DHP) and 20-alpha-hydroxyprogesterone (20-OHP) that were expected to have initial facilitative and/or subsequent inhibitory actions on sexual receptivity. Estrogen-primed ovariectomized female hamsters were given one of 4 doses of a progestin at hour 44 post EB, and were tested for facilitation (with tape over their vaginas to prevent intromissions) 4 hours later. At hour 68, all animals received 500 micrograms P and were tested for the inhibitory effects of the test progestin 4 hours later. In additional experiments, similar procedures were followed with an alternate vehicle (1% Tween-80 instead of sesame oil) and a longer initial progestin-to-facilitation test interval (8 rather than 4 hours) in attempts to improve bioavailability of the steroids. P and DOCA were clearly the most behaviorally effective progestins tested, and they were equally potent for facilitation and inhibition in an oil vehicle at the 4 hour interval. DHP given in oil caused some inhibition but no facilitation. 20-OHP had no behavioral effects at the doses tested. The results are discussed in light of previous results with these steroids in hamsters and other rodent species. Also, the differing patterns of effectiveness across conditions provide some, although qualified, support for our view that the biphasic actions of progestins may be controlled by separate mechanisms. However, an alternate explanation is also discussed.

Intravenous administration of progesterone and the onset of receptivity in female hamsters.

Progesterone-facilitated receptivity is believed to be a genomically mediated event. However, in contrast to estrogen, progesterone's effects occur rapidly. This experiment was designed to examine the temporal onset of receptivity in hamsters following intravenous (IV) administration of progesterone. Ovariectomized female hamsters were tested for their responsiveness to 10 micrograms estradiol benzoate (EB) plus 0, 50, or 200 micrograms progesterone, administered subcutaneously (SC). The hamsters were tested for sexual receptivity at 0.5, 1, 1.5, 2, 3 and 4 h. Three days later they were fitted with jugular catheters. Two days after catheter implantation they received 10 micrograms EB SC; 48 h later they were tested for receptivity and then received an IV injection of 0, 50, or 200 micrograms progesterone in 0.2 ml propylene glycol. Following the IV P injection the animals were again tested at 0.5, 1, 1.5, 2, 3 and 4 h. Progesterone administration (either SC or IV) resulted in an increase in total lordosis duration (TLD) over time. TLD had significantly increased from the pre-progesterone levels by 2 h after 50 micrograms progesterone IV. In contrast, 50 micrograms progesterone SC did not cause an increase in TLD until 3 h postinjection. Moreover, in comparison to SC administration, the effects of IV progesterone were short-lived; TLD was significantly decreased by 4 h after injection. Following 200 micrograms progesterone, the latency to respond was shorter than with 50 micrograms progesterone (1.5 vs. 2 h). There was no difference in the onset of receptivity as a function of route of administration at the 200 micrograms dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Fos expression in female hamsters after various stimuli associated with mating.

Detection of the expression of c-fos mRNA or its protein product, Fos, has been used to indicate differences in neuronal response to exogenous stimuli. Factors contributing to differences in Fos expression as a result of various stimuli associated with mating have been extensively studied in the female rat. Less is known about the factors that contribute to Fos expression in female hamsters. Female hamsters differ from female rats in several aspects of sexual behavior; therefore, it seems likely that Fos expression may also differ. The purpose of this study was to determine which factors associated with mating selectively affect Fos expression in the female hamster. Animals were ovariectomized, hormone treated, and then exposed to several behavioral conditions. Fos expression in several brain areas was then assessed via immunocytochemistry (ICC). As has been found by others, mating increases Fos immunoreactivity in a number of brain regions. Specifically, vaginal-cervical stimulation (VCS) was determined to be the salient factor contributing to Fos expression in the preoptic area (POA) and bed nucleus of the stria terminalis (BNST) of ovariectomized hormone primed female hamsters that received a mating interaction.

Facilitation of sexual receptivity by hypothalamic and midbrain implants of progesterone in female hamsters.

In the first experiment, ovariectomized female hamsters were stereotaxically implanted with bilateral guide cannulae aimed at the medial preoptic area (POA), ventromedial hypothalamus (VMH), or ventral tegmentum (VTA). The following week these females were injected SC with 10 micrograms estradiol benzoate (EB) and then had 27-gauge cannulae containing crystalline progesterone inserted through the guide tubes. Sexual receptivity was observed in 3 of 11 animals with VMH implants of progesterone, in 2 of 10 with VTA progesterone, but in none with POA implants. In the second experiment, the amount of intracranial progesterone was increased by mechanically expelling a 1.5 micrograms progesterone pellet from the tip of each cannula insert. This treatment facilitated receptivity in 10 of 20 hamsters with VTA implants and in 9 of 32 VMH-implanted animals. This induction of receptivity required approximately 2 hr. Progesterone pellets in the POA, mammillary region, and lateral mesencephalon were generally ineffective. In hamsters, progesterone into either the VMH or the VTA is sufficient to facilitate receptivity, although neither site is highly sensitive to progesterone. These results differ from those in recent studies in rats and this difference may reflect important species differences in the control of lordosis.

Sexual receptivity: brain sites of estrogen action in female hamsters.

In order to investigate the brain sites of estrogen action, ovariectomized hamsters were stereotaxically implanted with unilateral 27 gauge cannulae containing estradiol. Groups of females received implants into either the lateral septum, bed nucleus of the stria terminalis, preoptic area, anterior hypothalamus, ventromedial hypothalamus, arcuate nucleus, corticomedial amygdala or mesencephalic central gray. Another set of animals received implants containing cholesterol. One week later the animals were injected with progesterone and 4-5 hours later tested for sexual receptivity. The most receptivity and the most consistent response was seen in females with estradiol implants in the ventromedial hypothalamus. Only a few scattered animals in the other anatomical groups showed any receptivity. Only in animals with implants in the anterior hypothalamus was there any evidence of leakage of estrogen into peripheral circulation as measured by uterine weight. There was no response in females with cholesterol implants. Our results suggest that the ventromedial hypothalamus is the most sensitive brain area for the estrogenic induction of female sexual receptivity in hamsters.

Alcohol, benzodiazepine-GABAA receptor complex and aggression: ethological analysis of individual differences in rodents and primates.

Research in animals has only recently been successful in reliably mimicking the long-established link between alcohol and heightened aggressive behavior. The present review highlights the large individual differences in the effects of acute low alcohol doses on aggressive behavior in rodent and primate species, paralleling the human condition. Subpopulations of both species show reliable and repeatable enhancement of aggressive behavior when administered low, acute alcohol doses. Statistical analysis of the temporal patterns of aggressive behavior indicate that alcohol prolongs aggressive bouts or "bursts" and increases the number of aggressive behaviors within each burst. However, the latency to initiate attack and the time between aggressive bursts are relatively unaltered by alcohol. These alcohol-induced increases in aggression can be potentiated by benzodiazepine agonists and prevented by antagonists. In addition, highly aggressive animals can be differentiated from nonaggressive ones at the GABAA-benzodiazepine receptor complex. These data suggest an important link between alcohol, aggression and the GABAA-benzodiazepine receptor complex.

Muscimol facilitates sexual receptivity in hamsters when infused into the ventral tegmentum.

Progestogenic stimulation of both the ventral medial nucleus of the hypothalamus (VMH) and the ventral tegmental area (VTA) within the midbrain is critical for normal receptivity in female hamsters. However, few estrogen-induced progestin receptors have been found in the midbrain. In addition, recent evidence suggests that progestin's action in the VTA is mediated nongenomically at the membrane. The present experiment investigated the possible role of GABAA receptors in mediating the effects of progesterone in this brain region. Ovariectomized female hamsters were bilaterally implanted with chronic cannulae aimed toward the ventral mesencephalon. Five days after surgery, animals were injected with 10 micrograms estradiol benzoate SC. Forty hours later, the same animals were injected with either 25 or 100 micrograms progesterone and at hour 43.5, 50 ng muscimol was infused in 0.5 microliters. Control animals received 0.5 microliters vehicle, sterile saline, or no infusion. At hour 44, animals were tested for sexual receptivity by placing them in an observation arena with a sexually experienced male for 10 min, during which lordosis duration was recorded. The following week, the same regimen was given with the alternate dose of progesterone. Histology revealed that only those animals that were infused with muscimol into the VTA had total lordosis durations that were significantly longer than the controls. Implants that missed the ventral tegmental area were much less effective. These results indicate that GABA might play a facilitatory role in enhancing the efficacy of threshold doses of progesterone. Whether this interaction is due to a direct effect of progestins on the GABAA receptor complex awaits further study.