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PubMed1985

Litter deficits of socially stressed and low status hamster dams.

The effects of maternal social stress, induced by pairing pregnant females, and social status, measured by agonistic behavior within pairs, on pup development was investigated in hamsters. Using litters from untreated first pregnancies as a control, 40 dams were housed either alone or paired with another dam during their second pregnancy. Within a pair, the dam with more aggressive and fewer defensive responses than the other was considered dominant. Compared to their first unpaired litters, second litters of paired dams were smaller in number. Comparisons among second litters showed that paired dams, especially submissive dams, had fewer pups than unpaired dams. It was concluded that both maternal social stress and low status increase intrauterine mortality.

Animals↗
PubMed1986

Murine aggression induced by a boar chemosignal: a stimulus presentation dependency.

Male mice were used to assess for the presence of aggression-promoting cues in the boar chemosignal, 5 alpha-androst-16-ene-3-one. The findings of Experiment 1 indicated that this steroid has no aggression-promoting properties when mixed in water. When mixed in urine from castrated males, however, the steroid was shown to induce agonistic behavior in aggressors. Thus, the steroid was shown to possess aggression-promoting cues when associated with urine. Experiment 2 was designed to assess the chemosignal properties of the steroid when mixed in urine or juxtaposed either proximally or distally to urine. It was determined that the steroid needed to be either adjacent to or mixed in urine for chemosignal activity to be evidenced. It was concluded that (1) urine may function as an orienting stimulus for the appropriate detection of the steroid or (2) the conjoint presentation of the steroid and urine provided a qualitatively different stimulus complex than either stimulus presented alone. The findings of both experiments question the species specificity of the boar chemosignal and have methodological implications for studies attempting to isolate a chemocommunicative substance. Appropriate stimulus presentation procedures need to be considered for future research projects.

Aggression↗
PubMed1989

Social stress in guinea pigs.

Confrontation studies between eight pairs of two 7-8 months old male guinea pigs, each raised with one female from their 30th day of age, were conducted in an enclosure of 2 m2 in the presence of an unfamiliar female. The opponents were chronically kept together for up to 8 days. When they were not separated after 52 hr, one or (in 1 case) both males fell into a comatose state and died 5-8 days after the onset of the confrontation. Four hr after the onset of the confrontations both opponents showed significantly increased plasma glucocorticoid (CS) titers. At this time as well as 24 hr earlier, prospective winners (PW) and prospective losers (PL) did not yet differ in any physiological parameter measured. Forty-eight hr later, PW were characterized by a low body weight loss, low CS, high testosterone (T) and elevated plasma-catecholamine (CA) values. In contrast, PL showed a high body weight loss, very high CS titers, low T-titers and more elevated CA values than PW. Despite these highly significant differences in physiological parameters, PL and PW did not yet differ in the frequency of any agonistic behavioral element recorded. Seventy-two hr after the onset of the chronic cohabitation, losers began to behave more and more passive, they ceased feeding and drinking and were less and less involved in social interactions. The physiological differences between winners and losers intensified.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1986

Maternal social stress disrupts reproduction of hamsters drinking high-calorie fluids.

Adding maternal social stress, induced by housing in pairs, to maternal consumption of high-calorie fluids adversely affected hamster reproduction. Pregnancy outcomes of 67 dams housed either alone or in pairs, and given either water (WAT), or isocaloric solutions of either 30% ethanol (ETH), sucrose (SUC) or propylene glycol (PG), were compared. Pups of unpaired dams drinking any high-calorie fluid weighed less than those drinking water, but no other deficits were found. Among paired dams, those designated submissive on the basis of agonistic behavior and drinking either SUC, ETH, or PG, had fewer viable pups and more fetal resorptions and stillborn pups than WAT dams. Also, dominant PG dams delivered few pups and both dominant and submissive PG dams delivered malformed pups or embryos. Whether paired or unpaired, litters of SUC and ETH dams were similar. Drinking any high-calorie fluid reduced maternal food and fluid intake and weight gains below that of water, but pairing had no additional effect on dams.

Alcoholism↗
PubMed1981

Aggression control and structuring of social relations among recently admitted schizophrenics.

As part of a study using an ethological conceptual approach, three scales were constructed to reflect adaptive success in the structuring of social relations. Twenty recently admitted schizophrenics were studied longitudinally in an active therapeutic milieu, drug-free, and during neuroleptic treatment. Patients showed substantial failures in the ritualization of agonistic behavior, manifest in more overt flight and fight. Poor group integration and absence of bond formation characterized the sample and were correlated with social withdrawal and elevated resting pulse rate--a pattern highly reminiscent of that seen in monkeys after bilateral amygdalectomy. The paranoid subgroup was the least impaired. Four-month long intensive treatment, including neuroleptics and psychosocial therapies, produced significant but modest improvements. Considerable maladaptive functioning remained.

Adaptation, Psychological↗
PubMed1986

Inhibition of shock-elicited ultrasonic vocalization by opioid peptides in the rat: a psychotropic effect.

Following three series of electric footshocks (10 shocks/day), one out of three rats in most cages were brought to emit ultrasonic vocalization for several minutes after a single shock. The characteristics of shock-elicited ultrasound were pure tone pulses of a frequency between 22 and 28 kHz, with duration longer than 300 msec. The same type of ultrasound is produced by subordinate male rats during agonistic behavior. The intracerebroventricular injection of beta-endorphin, dynorphin, methionine-enkephalin or leucine-enkephalin attenuated the shock-elicited ultrasonic vocalization. Psychotropic drugs such as diazepam and chlorpromazine also attenuated the shock-elicited ultrasonic vocalization. A test utilizing ultrasonic vocalization in rodents can provide useful data for studying the psychotropic properties of neuropeptides.

Animals↗
PubMed2004

Lactams as EP4 prostanoid receptor subtype selective agonists. Part 1: 2-Pyrrolidinones-stereochemical and lower side-chain optimization.

A series of 7-[(5R)-substituted 2-oxo-1-pyrrolidinyl]-heptanoic acids were prepared, their isomeric purity determined, and pharmacologically evaluated. Lactams with affinity for the EP(4) receptor displayed agonist behavior. The lower side-chain of the lactam template could be substituted to afford ligands (e.g., 17, 24, 30, 31, and 33) of high potency and greater than 1000-fold affinity for EP(4) versus the other EP prostanoid receptors.

Lactams↗
PubMed2005

Reproductive division of labor, dominance, and ecdysteroid levels in hemolymph and ovary of the bumble bee Bombus terrestris.

To determine whether ecdysteroids are associated with reproductive division of labor in Bombus terrestris, we measured their levels in hemolymph and ovaries of queens and workers. Queens heading colonies had large active ovaries with high ecdysteroid content, whereas virgin gynes and mated queens before and after diapause had undeveloped ovaries with low ecdysteroid content. The hemolymph ecdysteroid titer was rather variable, but in a pooled analysis of mated queens before and after diapause versus colony-heading queens, ecdysteroid titers were higher in the latter group. In workers, agonistic behavior, ovarian activity, ovarian ecdysteroid content, and hemolymph ecdysteroid titers were positively correlated, and were lowest when a queen was present. In queenless workers, ecdysteroid levels were elevated in dominant workers, and were also influenced by the presence of brood and by group demography; hormone levels were higher in bees kept in larger groups. These findings are consistent with the premise that in B. terrestris the ovary is the primary site of ecdysteroid synthesis, and they show that ecdysteroids levels vary with the social environment.

Animals↗
PubMed2005

Effects of gonadal sex and incubation temperature on the ontogeny of gonadal steroid concentrations and secondary sex structures in leopard geckos, Eublepharis macularius.

Incubation temperature during embryonic development determines gonadal sex in the leopard gecko (Eublepharis macularius). Incubation temperature and gonadal sex jointly influence the display of sexual and agonistic behavior in adult leopard geckos. These differences in adult behavior are organized prior to sexual maturity, and it is plausible that post-natal hormones influence neural and behavioral differentiation. Here we assessed incubation temperature and sex effects on sex steroid levels in leopard geckos at 2, 10, and 25 weeks of age and monitored the development of male secondary sex structures. Males had significantly higher androgen concentrations at all time points, whereas females had significantly higher 17beta-estradiol (E2) concentrations only at 10 and 25 weeks. Within males, age but not incubation temperature affected steroid levels and morphological development. Male androgen levels increased modestly by 10 and dramatically by 25 weeks of age, whereas E2 levels remained unchanged over this period. Most males had signs of hemipenes at 10 weeks of age, and all males had hemipenes and open preanal pores by 25 weeks of age. In females, age and incubation temperature affected E2 and dihydrotestosterone (DHT) but not T concentrations. Controlling for age, females from 34 degrees C have higher DHT and lower E2 levels than females from 30 degrees C. Further, E2 concentrations increased significantly from 2 to 10 weeks, after which E2 levels remained steady. Together, these results indicate that sexually dimorphic levels of steroids play a major role in the development of leopard gecko behavior and morphology. Furthermore, these data suggest that the organizational effects of incubation temperature on adult female phenotype could be, in part, mediated by incubation temperature effects on steroid hormone levels during juvenile development.

Age Factors↗
PubMed2003

Conditioned defeat in male and female Syrian hamsters.

A brief exposure to social defeat in male Syrian hamsters (Mesocricetus auratus) leads to profound changes in the subsequent agonistic behavior exhibited by the defeated animals. Following defeat in the home cage of an aggressive conspecific, male hamsters will subsequently fail to defend their home territory even if the intruder is a smaller, nonaggressive male. This phenomenon has been called conditioned defeat. In Experiment 1, we examined the duration of conditioned defeat by repeatedly testing (every 3-5 days) defeated hamsters with a nonaggressive intruder. We found that conditioned defeat occurs in all defeated male hamsters and persists for a prolonged period of time (at least 33 days) in the majority of male hamsters tested despite the fact that these animals are never attacked by the nonaggressive intruders. In Experiment 2, we examined whether conditioned defeat could be induced in female Syrian hamsters. While conditioned defeat occurred in some females, they displayed only low levels of submissive/defensive behavior and, in contrast to males, the conditioned defeat response did not persist beyond the first test. These results suggest that in male hamsters conditioned defeat is a profound, persistent behavioral change characterized by a total absence of territorial aggression and by the frequent display of submissive and defensive behaviors. Conversely, social defeat in female hamsters does not appear to induce long-term behavioral changes. Finally, in Experiment 3, we determined that plasma adrenocorticotropin-like immunoreactivity increases in females following social defeat in a manner similar to that seen in males, suggesting that the disparate behavioral reactions of males and females are not due to sex differences in the release of, or response to, plasma adrenocorticotropin.

Adrenocorticotropic Hormone↗
PubMed2001

Modulation of aggression in male mice: influence of group size and cage size.

Aggression in group-housed male mice is known to be influenced by both cage size and group size. However, the interdependency of these two parameters has not been studied yet. In this study, the level of aggression in groups of three, five, or eight male BALB/c mice housed in cages with a floor size of either 80 or 125 cm(2)/animal was estimated weekly after cage cleaning for a period of 14 weeks. Furthermore, urine corticosterone levels, food and water intake, body weight, and number of wounds were measured weekly. At the end of the experiment, tyrosine hydroxylase (TH) activity, testosterone levels, and weight of spleen, thymus, testes, and seminal vesicles were determined. Results indicate a moderate increase of intermale aggression in larger cages when compared to the smaller cages. Aggression in groups of eight animals was considerably higher than in groups of three animals. The increase of agonistic behavior was observed both in dominant and subordinate animals. Physiological parameters indicate differences in stress levels between dominant and subordinate animals. It is concluded that aggressive behavior in group-housed male BALB/c mice is best prevented by housing the animals in small groups of three to five animals, while decreasing floor size per animal may be used as a temporary solution to decrease high levels of aggression in an existing social group.

Aggression↗
PubMed1988

Mice: the initiation and maintenance of pregnancy-induced aggression following thelectomy.

Two experiments were conducted in order to assess the effects of thelectomy (i.e., nipple removal) on the display of pregnancy-induced aggression in Rockland-Swiss (R-S) albino mice. Pregnant animals, thelectomized on Gestation Day (GD) 12, exhibit a high incidence and intensity of aggression toward adult R-S male intruders during tests conducted on GDs 14, 16, and 18 (i.e., during the last third of gestation in this species). Since thelectomized dams display levels of aggression (i.e., 63% incidence) equivalent to those of sham-operated and nonoperated animals (53 and 67% incidence, respectively), it would appear that nipple presence is not a critical factor for the maintenance of pregnancy-induced aggression in mice (Experiment 1). To examine the effects of nipple deprivation on the initiation of pregnancy-induced aggression, virgin animals were thelectomized prior to mating, then repeatedly tested for aggression at 2-day intervals of gestation. Unlike nipple-intact dams, pregnant mice, deprived of nipples prior to conception, rarely exhibit (less than 17% incidence) agonistic behaviors toward intruder males (Experiment 2). These findings suggest that the development and self-stimulation of nipples early in pregnancy may be important conditions for the display of heightened aggression with advancing pregnancy in mice.

Aggression↗
PubMed2000

C-nucleoside analogues of furanfurin as ligands to A1 adenosine receptors.

Furanfurin (2-beta-D-ribofuranosylfuran-4-carboxamide) derivatives and analogues were synthesized and their affinity for adenosine receptors was determined. The agonistic behavior of furanfurin against A1 receptors is preserved only when the furan ring is substituted with isosteric pentatomic ring systems such as oxazole, thiazole or thiophene, and the carboxamide group is unsubstituted. Replacement of the hydrogen atoms of the carboxamide group with alkyl, cycloalkyl or arylalkyl groups generates compounds endowed with moderate antagonistic activity.

Adenylyl Cyclase Inhibitors↗
PubMed2006

The all-trans-15-syn-retinal chromophore of metarhodopsin III is a partial agonist and not an inverse agonist.

Meta III is formed during the decay of rhodopsin's active receptor state at neutral to alkaline pH by thermal isomerization of the retinal Schiff base C15=N bond, converting the ligand from all-trans 15-anti to all-trans 15-syn. The thereby induced change of ligand geometry switches the receptor to an inactive conformation, such that the decay pathway to Meta III contributes to the deactivation of the signaling state at higher pH values. We have examined the conformation of Meta III over a wider pH range and found that Meta III exists in a pH-dependent conformational equilibrium between this inactive conformation at neutral to alkaline pH and an active conformation similar to that of Meta II, which, however, is assumed at very acidic pH only. The apparent pKa of this transition is around 5.1 and thus several units lower than that of the Meta I/Meta II photoproduct equilibrium with its all-trans 15-anti ligand, but still about 1 unit higher than that of the opsin conformational equilibrium in the absence of ligand. The all-trans-15-syn-retinal chromophore is therefore not an inverse agonist like 11-cis- or 9-cis-retinal, which lock the receptor in an inactive conformation, but a classical partial agonist, which is capable of activating the receptor, yet with an efficiency considerably lower than the full agonist all-trans 15-anti. As the Meta III chromophore differs structurally from this full agonist only in the isomeric state of the C15=N bond, this ligand represents an excellent model system to study principal mechanisms of partial agonism which are helpful to understand the partial agonist behavior of other ligands.

Amino Acid Substitution↗
PubMed2005

Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands.

We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.

Animals↗
PubMed1976

Influence of female's sexual cycle on aggressiveness in male rats.

Two experiments examined the relationship between the female's stage of estrus and agonistic behavior among males. Socially subordinate male albino rats were exposed to an inaccessible female and then given equal numbers of free-choice and forced-choice trials to a more aggressive "target" male or to an empty compartment. The submissive males were more aggressive following exposure to an estrous female than following exposure to a diestrous female. Furthermore, the probability of approaching the more aggressive male increased. This heightened level of aggressiveness was accompanied by a comparable increase in hostile behaviors by the dominant target males of Experiment 1. However, in the second experiment the increase in submissive-male aggressiveness was sufficient to reduce the social distance between the submissive subjects and their moderately aggressive target males.

Aggression↗
PubMed2000

Social enhancement of fitness in yellow-bellied marmots.

The yellow-bellied marmot (Marmota flaviventris) is a social, ground-dwelling squirrel that lives either individually or in kin groups of from two to five adult females. Philopatry and daughter recruitment lead to the formation and persistence of matrilines at habitat sites. By using 37 years of demographic data for 12 habitat sites, we could determine long-term trends in the effects of group size on two measures of fitness, survivorship and net reproductive rate, which otherwise are obscured by annual fluctuations in these measures. Both size and number of matrilines varied among sites and survivorship and net reproductive rate varied among sites and among matriline sizes. The role of social organization was explored further by examining the effect of matriline size, averaged over all years and sites, on fitness. For both survivorship and net reproductive rate the relationship with matriline size was curvilinear. Fitness increased with the increase in matriline size and then decreased in the largest groups. Decreased fitness in matrilines of four or five was associated with agonistic behavior, a large number of 2-year-old females in the social group, and reproductive suppression. There is no evidence that females acted to increase their fitness by increasing indirect fitness; i.e., by assisting relatives, but attempted to increase direct fitness. Direct fitness increased when mortality and fission of large matrilines reduced group size and the surviving females increased reproduction.

Animals↗
PubMed1997

Mutation of Asn111 in the third transmembrane domain of the AT1A angiotensin II receptor induces its constitutive activation.

A preliminary model of the rat AT1A angiotensin II (AII) receptor (Joseph, M. P., Maigret, B., Bonnafous J.-C., Marie, J., and Scheraga, H. A. (1995) J. Protein Chem. 14, 381-398) has predicted an interaction between Asn111 located in transmembrane domain (TM) III and Tyr292 (TM VII) in the nonactivated receptor; a disruption of this interaction upon AII activation would allow Tyr292 to interact with the conserved Asp74 (TM II). The previous verification that Tyr292 is essential for receptor coupling to phospholipase C (Marie, J., Maigret, B., Joseph, M. P., Larguier, R., Nouet, S., Lombard, C., and Bonnafous, J.-C. (1994) J. Biol. Chem. 269, 20815-20818) prompted us to check the possible alterations in receptor properties upon Asn111 --> Ala mutation. The mutated receptor (N111A) displayed: (i) strong constitutive activity, with amplification of the maximal phospholipase C response to AII; (ii) agonist behavior of the AT2-specific ligand CGP 42112A, [Sar1, Ile8]AII, and [Sar1,Ala8]AII, antagonists of the wild-type receptor; (iii) inverse agonism behavior of the non-peptide ligands DuP 753, LF 7-0156, and LF 8-0129. The results are discussed in the light of the allosteric ternary complex models and other described examples of constitutive activation of G protein-coupled receptors.

Alanine↗