R 76713, a new specific non-steroidal aromatase inhibitor

The effects of R 76713, a new triazole derivative, on rat ovarian, testicular and adrenal steroidogenesis were investigated both in vitro and in vivo. In vitro R 76713 is a very potent inhibitor of the aromatase enzyme in rat granulosa cells, showing an IC50-value of 3.0 +/- 0.2 nM. The compound is about 1000 times more active than aminoglutethimide which shows an IC50-value of 3900 +/- 2800 nM in the same system. R 76713 is also a highly selective aromatase inhibitor. In cultures of ovarian, testicular and adrenal cells, formation of progesterone, androgens and glucocorticoids was only affected by drug concentrations higher than 1 microM. In vivo, single oral drug doses of 0.05 mg/kg lowered plasma estradiol levels of PMSG-primed female rats by more than 90%. An ED50-value of 0.005 mg/kg could be calculated. A single oral dose of 1 mg/kg suppressed plasma estradiol levels almost completely for 24 h. A dose of 0.1 mg/kg lowered plasma estradiol by more than 90% for 8 h. In vivo, R 76713 also showed a highly selective profile. In LHRH/ACTH-injected rats, plasma levels of testicular and adrenal steroids remained unchanged after administration of a drug dose of 20 mg/kg. R 76713 at drug concentrations of 10 microM, showed no interaction in vitro with estrogen-, progestin-, androgen- and glucocorticoid-receptors. Given orally at 20 mg/kg for 3 days the compound also showed no estrogen or androgen agonistic or antagonistic effects.     

Behavioral demasculinization of female quail is induced by estrogens: studies with the new aromatase inhibitor, R76713.

The injection before Day 12 of incubation of estradiol benzoate (EB) into Japanese quail eggs produces a complete behavioral demasculinization of adult males that will hatch from these eggs. These males never show copulatory behavior even after administration of high levels of exogenous testosterone (T). It is usually assumed that such a demasculinization normally takes place in female embryos under the influence of endogenous estrogens but few experimental data are available to confirm the validity of this model. A series of four experiments was performed during which R76713, a triazole derivative that specifically inhibits aromatase (estrogen synthetase) activity, was injected into quail eggs at different stages of incubation to prevent the production of endogenous estrogens. The consequences of these embryonic treatments on the T-activated sexual behavior in adults were then quantified. When injected before Day 12 of incubation, R76713 completely blocked the behavioral demasculinization of females without affecting the behavior of the males. After a treatment with T, almost all R76713-treated females showed as adults a masculine copulatory behavior that was undistinguishable from the behavior of intact males. This effect was fully reversed by the injection in egg of EB demonstrating that the effects of R76713 were specifically due to the suppression of endogenous estrogens. Injection of R76713 during the late phase of the incubation (Day 12 or Day 15) only maintained weak copulatory behavior in females which confirmed that the behavioral demasculinization in quail takes place mainly though not exclusively during the early stages of ontogeny. In a last experiment, we combined an early R76713 treatment with an injection of EB either on Day 9 or on Day 14 of incubation. This showed that the sensitivity to differentiating effects of estrogens varies with age in a sexually differentiated manner. The EB injection on Day 9 demasculinized both male and female embryos. If this injection was delayed until Day 14, it was no longer effective in males but still caused a partial demasculinization of females. This demonstrates that even if females are not yet behaviorally demasculinized on Day 9 of incubation (suppression of aromatase activity at that age will maintain the behavior), their sensitivity to estrogens is already different from that of males.     

Effects of the nonsteroidal inhibitor R76713 on testosterone-induced sexual behavior in the Japanese quail (Coturnix coturnix japonica)

A new triazole derivative, R76713 (6-[4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H- benzotriazole), was recently shown to inhibit aromatase selectively without affecting other steroid-metabolizing enzymes and without interacting with estrogen, progestin, or androgen receptors. This compound was tested for its capacity to intefere with the induction of copulatory behavior by testosterone (T) in castrated Japanese quail (Coturnix coturnix japonica). In a first experiment, R76713 inhibited (range 0.01 to 1 mg/kg) the activation of sexual behavior by T silastic implants and hypothalamic aromatase activity in castrated male quail in a dose-dependent manner. The 5 alpha- and 5 beta- reductases of T were not systematically affected. Stereotaxic implantation of R76713 in the medial preoptic area similarly blocked the behavior activated by systemic treatment with T, demonstrating that central aromatization of androgen is implicated in the activation of behavior. These inhibiting effects of R76713 on behavior were observed when implants were placed in the medial part of the nucleus preopticus medialis, confirming the implication of this brain area in the control of male copulatory behavior. Finally, the behavioral inhibition produced by R76713 could be reversed by simultaneous treatment with a dose of estradiol, which was not behaviorally effective by itself. This suggests that the behavioral deficit induced by the inhibitor was specifically due to the suppression of estrogen production. This also shows that the activation of copulatory behavior probably results from the interaction of androgens and estrogens at the brain level, as the two treatments separately providing these hormonal stimuli (T with the aromatase inhibitor on one hand and a low dose of estradiol on the other hand) had almost no behavioral effects but they synergized to activate copulation when given concurrently. These data confirm the critical role of preoptic aromatase in the activation of reproductive behavior and demonstrate that R76713 is a useful tool for the in vivo study of estrogen-dependent processes.     

Comparative effects of the aromatase inhibitor R76713 and of its enantiomers R83839 and R83842 on steroid biosynthesis in vitro and in vivo

R76713 (6-[4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole) is a selective, non-steroidal aromatase inhibitor containing an asymmetric carbon atom. In this paper, we compare the effects of R76713 (racemate) with its enantiomers R83839 (the levo-isomer) and R83842 (the dextro-isomer) on steroid biosynthesis in rat cells in vitro and in the rat in vivo.

In rat granulosa cells, aromatase activity was inhibited by 50% at concentrations of 0.93 nM of R76713, 240 nM of R83839 and 0.44 nM of R83842, revealing a 545-fold difference in activity between both enantiomers.

Up to 1 μM, none of the compounds had any effect on steroid production in primary cultures of rat testicular cells. Above this concentration all three compounds showed a similar slight inhibition of androgen synthesis with a concomitant increase in the precursor progestins, indicative for some effect on the 17-hydroxylase/17,20-lyase enzyme. In rat adrenal cells none of the compounds showed any effect on corticosterone synthesis. At concentrations above 1 μM there was an increase in the levels of 11-deoxycorticosterone pointing towards an inhibition of the 11-hydroxylase enzyme. This increase was more pronounced for R83839 than for R76713 and R83842.

In vivo, in PMSG-primed rats, R83842 reduced plasma estradiol by 50%, 2 h after oral administration of 0.0034 mg/kg, whereas 0.011 mg/kg of R76713 and 0.25 mg/kg of R83839 were needed to obtain the same result.

Oral administration of up to 20 mg/kg of the compounds did not significantly affect plasma levels of adrenal steroids in LHRH/ACTH-injected rats. Plasma testosterone was lowered at 10 and 20 mg/kg of R83842 and at the highest dose (20 mg/kg) of R76713 and R83839.

In conclusion, the present study shows that the aromatase inhibitory activity of R76713 resides almost exclusively in its dextro-isomer R83842. R83842 exhibits a specificity for aromatase as compared to other enzymes involved in steroid biosynthesis of at least a 1000-fold in vitro as well as in vivo. This confirms the extreme selectivity previously found for the racemate.     

Sexual differentiation of brain and behavior in the zebra finch: Critical periods for effects of early estrogen treatment

In order to determine the critical period(s) during which estrogen alters sexually dimorphic behavior and neuroanatomy in zebra finches (Poephila guttata), nestlings were injected daily 20 μg estradiol benzoate (EB) during posthatching week 1, week 2, week 3, or weeks 1, 2, and 3. At 7 months of age, birds were implanted with testosterone propionate and tested with female partners for singing, dancing, and copulatory mounting. Brains were subsequently processed for morphometry, and the volumes of the song system nuclei HVC, area X, and RA and the soma sizes and densities of neurons in RA were determined. Males given EB during week 1 failed to mount. Females given EB during week 1 were fully masculinized with respect to dancing and RA neuron soma size and density, and were partially masculinized with respect to song nuclei volumes and singing. Treatment beginning after week 1 was ineffective or less effective for all measures. Only for RA neuron measures was treatment for all three weeks more effective than week 1 treatment. Thus the first post-hatching week is the most influential period of those tested for effects of exogenous estrogen on sexual differentiation in this species, and is a period during which both masculinization of females and demasculinization of males is possible. 1994 John Wiley & Sons, Inc.     

The effects of an aromatization inhibitor on the reproductive behavior of male zebra finches

Recent evidence indicates that aromatizable androgens are more effective than nonaromatizable androgens in restoring normal levels of sexual behavior in castrated male zebra finches (Poephila guttata). To determine whether the efficacy of treatment with aromatizable androgens, is in part due to their conversion to estrogens, castrated male finches were treated with androstenedione (AE), an aromatizable androgen, and their sexual and aggressive behavior was compared with that of castrates treated with AE plus 1,4,6-androstatriene-3,17-dione (ATD), an aromatization inhibitor. Males treated with AE + ATD showed less courtship activity and less copulatory behavior than AE-treated males, and were unlikely to have nests. Estradiol (E), when given concurrently with AE + ATD, reversed the inhibitory effects of ATD and restored levels of courtship and copulation to those observed in AE-treated males. Only AE- and AE + ATD + E-treated males displayed aggressive behaviors, but the frequency of such behaviors was so low that there were no significant differences across groups. These data affirm the importance of estrogen in the control of reproductive activities in male zebra finches and indicate that aromatization may be an obligatory step for maintaining normal levels of sexual and aggressive behavior.     

Hormonal specificity and activation of sexual behavior in male zebra finches

Castrated zebra finches receiving one of six hormone treatments were given three weekly tests with different females and their sexual behavior was contrasted with that of two control groups consisting of intact or castrated males given implants of cholesterol. The six hormone treatments were: two aromatizable androgens, testosterone (T) and androstenedione (AE); two nonaromatizable androgens, androsterone (AN) and dihydrotestosterone (DHT); an estrogen, estradiol (E); or a combination of E + DHT. Half the males receiving DHT received the 5α-isomer, half received the 5β-isomer. Castration significantly reduced the proportion of males which courted females, total courtship displays, high-intensity courtship displays, beak wiping activity, and significantly increased the latencies to show these behaviors compared to intact males. Castrated males never attempted to mount a female. All of these measures of courtship and copulatory behavior were restored to normal levels only by treatments providing both estrogenic and α-androgenic metabolites (i.e., T, AE, E + αDHT). AE was clearly the most effective of these, raising behavior significantly above normal on several measures. AN treatment was more effective than αDHT on all measures and not significantly different from intact birds on some. Treatment with E, αDHT, βDHT, or E + βDHT was totally ineffective. Surprisingly, females only solicited males whose hormone treatments provided estrogenic metabolites. Not only did they solicit males given aromatizable androgens, which showed high rates of courtship activity, they also solicited males given E or E + βDHT, some of which never even courted. Castration and hormone treatment also affected body and syringeal weight, but in opposite directions. Castration increased body weight while decreasing syringeal weight. Hormone treatments providing α-androgenic metabolites decreased body weight and increased syrinx weight. Treatments supplying estrogen as well were slightly more effective.     

Estrogen receptors in quail brain: a functional relationship to aromatase and aggressiveness

Estradiol (E2) mediates many of the activational effects of testosterone (T) on masculine reproductive and aggressive behaviors. Using Japanese quail (Coturnix coturnix japonica) as an animal model, together with a newly devised procedure for quantifying aggressiveness, we recently showed that aggression is E2-dependent and that individual differences in behavioral intensity are correlated with aromatase in the hypothalamus/preoptic area (HPOA). In this study we characterized estrogen receptors (ER) in quail brain and tested the hypothesis that aromatase in brain regulates T-induced behavioral responsiveness by regulating the quantity of E2 available for receptor binding. Based on standard binding assays and Sephadex LH-20 chromatography, quail brain ER was shown to be estrogen-specific, of high affinity (Kd = 0.88 nM), and of limited capacity with highest concentrations in limbic brain areas (Bmax 23-27 fmoles/gm HPOA). In addition, this ER adhered to DNA-cellulose under activating conditions. The quantitative relationship between aromatization, ER, and aggressiveness was tested in reproductively inactive (nonaggressive) males by treatment with T +/- the aromatase inhibitor 4-hydroxyandrostenedione (OHA). After 5 days, T markedly stimulated aggressiveness, and elevated aromatase and nuclear (occupied) ER in HPOA. Simultaneous treatment with OHA blocked effects on aggressiveness and aromatase, and lowered nuclear ER, but increased cytosolic (empty) ER. Total ER (nuclear plus cytosolic) was higher after T treatment whether or not OHA was administered, suggesting that androgen per se induces ER in quail HPOA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy of exemestane,a new generation of aromatase inhibitor,on sex differentiation in a gonochoristic fish

We report the first use of exemestane (EM), a steroidal aromatase inhibitor (AI) commercially known as aromasin, in studies of sex differentiation in fish. The effectiveness of EM was examined in two different age groups of the gonochoristic fish, Nile tilapia (Oreochromis niloticus). Untreated control fish (all female) showed normal ovarian differentiation through 120 days after hatching (dah), whereas fish treated with EM at 1000 and 2000 µg/g of feed from 9 dah through 35 dah, the critical period for sex differentiation, exhibited complete testicular differentiation; all stages of spermatogenic germ cells were evident and well developed efferent ducts were present. Fish treated with EM at 1000 µg/g of feed from 70 dah through 100 dah significantly suppressed plasma estradiol-17β level and increased level of 11-ketotestosterone. Furthermore, untreated control fish showed strong gonadal expression of the steroidogenic enzymes P450 cholesterol-side chain-cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase (3β-HSD), and cytochrome P450 aromatase (P450arom). In contrast, EM-treated fish showed immunopositive reactions against P450scc and 3β-HSD but not against P450arom in interstitial Leydig cells. These results indicate that treatment of tilapia juveniles with EM during sex differentiation leads to the development of testes, apparently by a complete suppression of aromatase activity.     

Sexual differentiation in quail: critical period and hormonal specificity

There is a discrepancy between results showing that male quail are demasculinized by exogenous estrogens only if the treatment is given before Day 12 of egg incubation and results showing that ovariectomy of females after hatching still affects their sexual differentiation which leads to the conclusion that female demasculinization by ovarian estrogens is a continuing process extending into posthatching life. The first experiment was performed to test different models which have been proposed to reconcile these apparently contradictory results. Male and female quail were treated with 0, 5, or 25 micrograms of estradiol benzoate (EB) on either Day 9 or Day 14 of embryonic life. Birds were castrated at the age of 4 days to avoid the confounding effects of postnatal gonadal hormones and were treated as adults with testosterone (T). Whereas EB-treatment demasculizined sexual behavior and cloacal gland growth of males when administered on Day 9, it was without effect on Day 14. This result confirms the presence of a "critical period" for sexual differentiation of behavior in embryonic life. However, the time course of sexual differentiation and the sensitivity to the demasculinizing actions of estrogens were not the same for different behavioral and morphological characteristics. Some dependent variables such as plasma levels of luteinizing hormone and crowing were still affected by the EB treatment on Day 14. These results show that the whole process of demasculinization is not retricted to the "critical period" ending on Day 12 of incubation. A second experiment was performed to determine if 5 beta-dihydrotestosterone (5 beta-DHT), a metabolite of testosterone, also exerts demasculinizing effects during embryonic life. A large dose of 5 beta-DHT (2 mg/egg) had no effects on behavior and morphology in males if administered on Day 9 of egg incubation. This suggests that 5 beta-DHT, which is a steroid devoid of behavioral effects in the adult bird, is also an inactive compound as far as sexual differentiation of the quail is concerned. The high 5 beta-reductase activity which was previously identified in the hypothalamus of the embryonic quail thus probably plays a protective role. By transforming testosterone into inactive nonaromatizable androgens, it prevents male embryos from being demasculinized by their endogenous testosterone acting through aromatization.     

Sexual differentiation of behavior in the zebra finch: effect of early gonadectomy or androgen treatment

Treatment of nestling zebra finches with estradiol benzoate (EB) has been shown to masculinize singing in females and demasculinize copulatory behavior in males, suggesting that sexual differentiation of these behaviors is under hormonal control such that testicular hormones induce the capacity for song and ovarian hormones suppress the capacity for mounting. Two experiments were carried out to obtain a more complete picture of sexual differentiation in this species. In Experiment 1, nestlings were injected daily for the first 2 weeks after hatching with testosterone propionate (TP), dihydrotestosterone propionate (DHTP), or a combination of DHTP and EB. As adults, birds were gonadectomized and implanted with TP prior to testing, then tested again after implantation with EB. Singing was not increased in females by any of the treatments. The only effect of either TP or DHTP given alone was defeminization of female proceptive behavior by DHTP. Thus androgens appear to have less influence than estrogens on sexual differentiation of behavior in this species. The combination of DHTP and EB demasculinized mounting in males. In Experiment 2, nestlings were gonadectomized at 7-9 days of age and implanted with TP prior to testing in adulthood. Early gonadectomy had little effect on later behavior; early castrated males sang, danced, and copulated normally and early ovariectomized females neither sang nor mounted.     

Appearance, “state,” and behavior in male zebra finches, Taeniopygia guttata

Secondary sexual traits are often costly to produce and therefore an individual’s appearance can signal its quality. As the quality of an individual influences the payoffs associated with the actions it can perform, its appearance should also influence its behavior. Here we investigate whether male zebra finches, Taeniopygia guttata, change their behavior (and their energetic states) after artificial manipulations of their appearance, using different colored leg bands, and if such effects carry over after the end of the manipulation, as might be expected if appearance-mediated social dynamics “lock” individuals into different states. During three experimental phases, in which all males in a group wore neutral colored leg bands at the beginning (phase I), then wore attractive, unattractive, and neutral colored bands, respectively (phase II), before wearing the neutral color again (phase III), we found no evidence of an effect of the appearance manipulation on state, weight or any behavioral traits we measured. Nevertheless, we found that individuals that stored more fat were more likely to initiate and win aggressive interactions but were less likely to be recipients of aggression. This association between energetic state and aggressive behavior is discussed from both strategic body mass regulation and sexual selection perspectives.     

Developmental changes in the cellular composition of a brain nucleus involved with song learning in zebra finches

Using a double-labeling technique to characterize projection neurons and androgen target cells, we examined ontogenetic changes in the cellular composition of IMAN, a forebrain nucleus that plays an important role in song learning during a restricted period of male zebra finch development. This nucleus undergoes a massive loss of neurons during the time of song acquisition. We report that during the period of cell loss in IMAN, neither the property of projecting to an efferent target nor the ability to concentrate androgens is able to spare neurons from ontogenetic cell death. Furthermore, we report that, at the time when IMAN ceases to influence song production, a large proportion of androgen-sensitive cells that do not make an efferent projection lose the ability to accumulate androgens.     

Lesions of a telencephalic nucleus in male zebra finches: Influences on vocal behavior in juveniles and adults

Male zebra finches learn to sing during a restricted phase of juvenile development. Song learning is characterized by the progressive modification of unstable song vocalizations by juvenile birds during development, a process that leads to the production of stereotyped vocal patterns as birds reach adulthood. The medial magnocellular nucleus of the anterior neostriatum (mMAN) is a small cortical region that has been implicated in song behavior based on its neuronal projection to the High Vocal Center (HVC), a nucleus that is critical for adult vocal production and presumably also plays a role in song learning. To assess the function of mMAN in song, ibotenic acid lesions of this brain region were made in juvenile male zebra finches during the period of vocal learning (40-50 days of age) and in adult males that were producing stable song (>90 days of age). Birds lesioned as juveniles produced highly abnormal, poor quality song as adults. Although the overall song quality of birds lesioned as adults was not highly disrupted or abnormal, the postoperative song behavior of these birds was discernibly different due to slight increases in variability of vocal production, particularly at the onset of singing. These results demonstrate that mMAN plays some important role in vocal production during the sensitive period for song learning, and is also important for consistent initiation and stereotyped production of adult song behavior.     

ARIMIDEX: A new oral, once-a-day aromatase inhibitor

ARIMIDEX® is a potent and selective aromatase inhibitor undergoing evaluation as a treatment for postmenopausal women with advanced breast cancer. Studies examining the pharmacology of ARIMIDEX were conducted in both animals and humans. In animals, ARIMIDEX elicits maximal aromatase suppressive activity at a dose of approx. 0.1 mg/kg, does not alter adrenal steroid hormone biosynthesis, and at a dose of 1 mg/kg, has no other pharmacologic effects other than aromatase inhibition. In this overview, the pharmacodynamic, pharmacokinetic, and safety profiles of single and multiple daily doses of ARIMIDEX are reported in humans. Daily doses of 1–10 mg of ARIMIDEX suppressed estradiol levels to the maximum degree measurable using sensitive estrogen assays. ARIMIDEX had no clinically significant effects on the response of cortisol and aldosterone to ACTH stimulation. Absorption of ARIMIDEX was rapid, with maximum plasma concentrations occurring within 2 h after oral administration. Plasma concentrations of ARIMIDEX rose with increasing doses of the drug. The elimination half-life of ARIMIDEX in humans ranged from 30 to 60 h. Consistent with the long plasma half-life, steady state plasma concentrations were 3–4-fold higher than plasma concentrations observed after single administration of 1, 3, 5, or 10 mg doses. Long term treatment of breast cancer patients with 10 mg/day has continued in 17 patients without an escape of estradiol suppression. Previously, these patients had received on average 2.6 systemic treatments for breast cancer and had significant metastatic disease. Three of the 17 patients continued ARIMIDEX treatment for 20 months and beyond. Given the number of previous treatments and tumor burden at the start of treatment, the response to ARIMIDEX treatment is encouraging. Phase III studies are now underway to assess the efficacy and safety of ARIMIDEX in the treatment of advanced breast cancer.     

Genetic variation and differentiation in captive and wild zebra finches (Taeniopygia guttata)

The zebra finch (Taeniopygia guttata) is a small Australian grassland songbird that has been domesticated over the past two centuries. Because it is easy to breed in captivity, it has become a widely used study organism, especially in behavioural research. Most work has been conducted on domesticated populations maintained at numerous laboratories in Europe and North America. However, little is known about the extent to which, during the process of domestication, captive populations have gone through bottlenecks in population size, leading to inbred and potentially genetically differentiated study populations. This is an important issue, because (i) behavioural studies on captive populations might suffer from artefacts arising from high levels of inbreeding or lack of genetic variation in such populations, and (ii) it may hamper the comparability of research findings. To address this issue, we genotyped 1000 zebra finches from 18 captive and two wild populations at 10 highly variable microsatellite loci. We found that all captive populations have lost some of the genetic variability present in the wild, but there is no evidence that they have gone through a severe bottleneck, as the average captive population still showed a mean of 11.7 alleles per locus, compared to a mean of 19.3 alleles/locus for wild zebra finches. We found significant differentiation between the captive populations (F(ST) = 0.062). Patterns of genetic similarity closely match geographical relationships, so the most pronounced differences occur between the three continents: Australia, North America, and Europe. By providing a tree of the genetic similarity of the different captive populations, we hope to contribute to a better understanding of variation in research findings obtained by different laboratories.     

Exemestane,a new steroidal aromatase inhibitor of clinical relevance

Breast cancer is the leading cause of death among women and the contribution of circulating oestrogens to the growth of some mammary tumours has been recognized. Consequently, suppression of oestrogen action by inhibition of their biosynthesis at the androstenedione-oestrone aromatization step, by means of selective inhibitors of the enzyme aromatase, has become an effective therapeutic option for the treatment of hormone-dependent breast cancer. Exemestane (6-methylenandrosta-1,4-diene-3,17-dione) is a novel steroidal irreversible aromatase inhibitor recently approved and introduced into the global market under the name Aromasin. The design, laboratory and viable syntheses of exemestane, starting from a variety of steroidal precursors, are presented and discussed. Data from biochemical and pharmacological studies as well as the clinical impact of the compound are briefly reviewed. The drug is an orally active and well-tolerated hormonal therapy for postmenopausal patients with advanced breast cancer that has become refractory to standard current hormonal therapies.     

Speed of exploration and risk-taking behavior are linked to corticosterone titres in zebra finches

The existence of consistent individual differences in behavioral strategies ("personalities" or coping styles) has been reported in several animal species. Recent work in great tits has shown that such traits are heritable and exhibit significant genetic variation. Free-living birds respond to environmental stresses by up-regulating corticosterone production. Behavior during mild stress can occur in accordance to two types of coping styles, i.e. active and passive. Using artificially selected lines of zebra finches that vary in the amount of corticosterone produced in response to a manual restraint stressor we ran three "personality" experiments. We show that birds in the different corticosterone lines differ in their exploratory and risk-taking behaviors. There was an increase in exploratory behavior as corticosterone titre increased but only in the low corticosterone line. Birds in high corticosterone line showed greater risk-taking behavior than birds in the other lines. Thus, in general, higher levels of circulating corticosterone following a mild stress result in greater exploratory behavior and greater risk taking. This study shows that lines of animals selected for endocrine hormonal responses differ in their "coping" styles or "personalities".     

Neural correlates of singing behavior in male zebra finches (Taeniopygia guttata)

This study examined the relationship between the volumes of four song control nuclei: the high vocal center (HVC), the lateral part of the magnocellular nucleus of the anterior neostriatum (lMAN), Area X, and the robust nucleus of the archistriatum (RA), as well as syrinx mass, with several measures of song output and song complexity in male zebra finches (Taeniopygia guttata). Male zebra finches' songs were recorded in standardized recording sessions. The syrinx and brain were subsequently collected from each bird. Volumes of the song control nuclei were reconstructed by measuring the cross-sectional area of serial sections. Syrinx mass was positively correlated with RA volume. The volume of lMAN was negatively related to element repertoire size and the number of elements per phrase. We found no other correlations between brain and behavioral measures. This study, combined with others, indicates that the evidence for a general relationship among songbirds between HVC volume and song complexity is equivocal. There are clear species differences in this brain-behavior correlation. © 1998 John Wiley & Sons, Inc. J Neurobiol 36: 421–430, 1998