Behavioral profile of L‐655,708, a selective ligand for the benzodiazepine site of GABA‐A receptors which contain the α5 subunit,in social encounters between male mice

GABA‐A receptor is a transmembrane hetero‐oligomeric protein which consists of five subunits, the combination of which confers unique pharmacological properties to the receptor. It is well‐known that the GABAergic system is involved in the modulation of aggression. However, the role of α5/GABA‐A receptors has not been explored. In this study, we examined the effect of L‐655,708 (0.625‐5 mg/kg), a selective ligand for the benzodiazepine site of GABA‐A receptors which contain the α5 subunit, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to an anosmic “standard opponent” 30 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. L‐655,708 (5 mg/kg) exhibited an ethopharmacological profile characterized by a marked reduction of the time spent in offensive behavior (threat and attack) without affecting immobility, accompanied by a significant increase of avoidance/flee and nonsocial exploration behaviors, suggesting that the antiaggressive effect of the drug is unselective. Overall, this behavioral profile might indicate the existence of an anxiogenic‐like activity of L‐655,708 in mice. Aggr. Behav. 30:319–325, 2004. © 2004 Wiley‐Liss, Inc.     

丙酸睾丸酮对MCF－7荷瘤裸鼠肿瘤生长的影响及临床意义

观察不同剂量丙酸睾丸酮对MCF-7荷瘤裸鼠肿瘤生长的影响,并探讨其可能机制和临床意义。构建MCF-7荷瘤裸鼠,再用不同浓度的丙酸睾丸酮（50mg／kg,400mg／kg）及化疗药物（表阿霉素）进行干预,比较各组实验鼠肿瘤的生长情况,并用微粒子发光法检测裸鼠血清睾丸酮的含量,用流式细胞技术检测肿瘤中雄激素受体的表达。发现...     

Towards mouse models of perseveration: a heritable component in extinction of operant behavior in fourteen standard and recombinant inbred mouse lines

Extinction of instrumental responses is an essential skill for adaptive behavior such as foraging. So far, only few studies have focused on extinction following appetitive conditioning in mice. We studied extinction of appetitive operant lever-press behavior in six standard inbred mouse strains (A/J, C3H/HeJ, C57BL/6J, DBA/2J, BALB/cByJ and NOD/Ltj) and eight recombinant inbred mouse lines. From the response rates at the end of operant and extinction training we computed an extinction index, with higher values indicating better capability to omit behavioral responding in absence of reward. This index varied highly across the mouse lines tested, and the variability was partially due to a significant heritable component of 12.6%.To further characterize the relationship between operant learning and extinction, we calculated the slope of the time course of extinction across sessions. While many strains showed a considerable capacity to omit responding when lever pressing was no longer rewarded, we found a few lines showing an abnormally high perseveration in lever press behavior, showing no decay in response scores over extinction sessions.No correlation was found between operant and extinction response scores, suggesting that appetitive operant learning and extinction learning are dissociable, a finding in line with previous studies indicating that these forms of learning are dependent on different brain areas. These data shed light on the heritable basis of extinction learning and may help develop animal models of addictive habits and other perseverative disorders, such as compulsive food seeking and eating.     

Rigidity in social and emotional memory in the R6/2 mouse model of Huntington's disease

Four experiments were conducted to examine social and emotional memory in the R6/2 transgenic mouse model of Huntington’s disease. First, R6/2 mice were tested in a social transmission of food preference task where they had to acquire a preference for a flavoured food (acquisition) and subsequently to learn a preference for a different flavour (shifted reinforcement). R6/2 mice performed well in the acquisition trial. However, they were impaired in the shifted reinforcement trial and perseverated on the first preference learned. Second, mice were trained in an inhibitory avoidance paradigm, with either one or two footshocks delivered during the training. WT mice given one footshock showed retention levels lower than those of mice trained with two footshocks. By contrast, there was no difference in retention levels of R6/2 mice given either one or two footshocks. Third, mice were tested in an active avoidance task that paired a mild footshock with a warning light. R6/2 mice had a strong age-dependent deficit in this task. Finally, mice were tested in a conditioned taste aversion task that paired a saccharine solution with a nausea-inducing agent (LiCl). R6/2 mice displayed normal aversion, however this was not extinguished following repeated exposure to saccharine solution alone. Our data show that while R6/2 mice have functional hippocampus-based memory, they have deficits in striatum-based memory skills. Further, social and emotional memories appear to be encoded in a rigid way that is not influenced by subsequent learning or by arousal levels.     

Effects of differing response-force requirements on food-maintained responding in CD-1 mice

The effect of force requirements on response effort was examined using outbred (CD-1) mice trained to press a disk with their snout. Lateral peak forces greater than 2 g were defined as threshold responses (i.e., all measured responses). Different force requirements were used to define criterion responses (a subclass of threshold responses) that exceeded the requirement. The reinforcer was sweetened, condensed milk, and it was delivered upon response termination. All mice were exposed to two ascending series of criterion force requirements (2, 4, 8, 16, and 32 g). Increasing the force requirement decreased criterion response rates, but increased threshold response rates. The time-integral of force (area under the force-time curve for individual responses, which is proportional to energy expenditure for each response) increased with the increase in the force requirement. These results conflict with the hypothesis that higher force requirements have aversive qualities and suggest that increased force requirements are more analogous to intermittent schedules of reinforcement. These data suggest that estimations of effort or energy expenditure should be measured independently of the force requirement. Individual differences in responding were found for the CD-1 outbred stock.     

Prenatal testosterone treatment potentiates the aggression‐inhibiting effect of the neurosteroid dehydroepiandrosterone in female mice

The neurosteroid dehydroepiandrosterone (DHEA) is a powerful inhibitor of aggression in murine models when given for 15 days and potentially may be useful in the management of inappropriate human aggression. Although the biosynthesis and metabolism of DHEA have been described, little is known about the potential effect of the steroidal environment during sexual differentiation on the subsequent response to DHEA. Whether prenatal androgen exposure influences the subsequent response to DHEA was assessed by comparing the effect of DHEA (80 μg/d) on aggression in female offspring where dams were treated with 1, 10, or 100 μg of testosterone (T) on days 15 to 18 of gestation (Experiment I) or that developed in different uterine positions (Experiment II). The results showed that DHEA decreased attack behavior in general and that the 100‐μg prenatal T treatments enhanced the antiaggressive effect of this neurosteroid. Neither the lower doses of exogenously administered T nor the uterine position led to an enhanced response to DHEA. In addition, whether DHEA produced changes in social and nonsocial activities was examined. In the 100‐μg T females, DHEA increased the duration of the former and decreased the frequency and duration of the latter, indicating that it was not a general decrement in behavioral expression that mediated the enhanced response to the antiaggressive effect of DHEA. In the second experiment, DHEA treatment led to increased frequencies of social nonaggressive and nonsocial activities. However, the uterine positions × treatment interactions were not significant, demonstrating that contiguity to male fetuses did not differentially affect the response to DHEA. Aggr. Behav. 27:130–138, 2001. © 2001 Wiley‐Liss, Inc.     

The functions of freezing in the social interactions of juvenile high‐ and low‐aggressive mice

Selectively bred low‐aggressive mice are frequently observed to freeze on social contact, despite the fact that this behavior was never a direct target of selection. To elucidate this finding, the present research aimed to identify the possible functions freezing may serve in social interactions. It was hypothesized that freezing may modify social interactions through self‐regulatory mechanisms and/or via its modulating effects on the actions of social partners. These hypotheses were evaluated with respect to the sequential changes observed over the course of a 10‐min dyadic test in freezing, social reactivity, and approaches among juvenile (24–30‐day‐old) mice from the NC900 and NC100 high‐ and low‐aggressive lines. Analyses of the patterns of social interactions between subjects and partners revealed two primary results. First, freezing was more than an expression of fear; it also functioned as a regulator of emotional arousal, as suggested by the substantial reduction of reactive behaviors seen in animals that showed high levels of freezing. Second, freezing functioned to facilitate high levels of affiliative social interaction with social partners. The implications of these results for understanding how the differentiation of the NC900 and NC100 occurred within microevolution and development are discussed. Aggr. Behav. 27:463–475, 2001. © 2001 Wiley‐Liss, Inc.     

On the assessment of genetic technology: Reaching ethical judgments in the light of modern technology

The “Model for Reaching Ethical Judgments in the context of Modern Technologies — the Case of Genetic Technology”, which is presented here, has arisen from the project “Ethical Criteria bearing upon Decisions taken in the field of Biotechnology”. This project has been pursued since 1991 in the Zentrum für interdisziplinäre Technikforschung (ZIT) of the Technical University of Darmstadt, with the purpose of examining decision-making in selected activities involving the production of transgenic plants that have a useful application. The model is the basis of an outline for interviews to investigate how far decisions concerning the development of such plants with genetic techniques take ethical criteria into account. It was necessary to design this new model because other models for reaching judgments of this kind were not conceptually suited for concrete application. This model represents a problem related approach and combines methodological with substantive typology. In this it differs from comparable models for reaching ethical judgments.     

Agonistic behavior and social reactivity of LG/J mice in both an arena and a seminatural setting

In order to determine the relatively long-term effects of having been primed for agonistic behaviors in an arena setting, 28 male LG/J mice were observed for these behaviors in a seminatural environment for a period of 5 days following a 20 min arena test. The mice were first placed in an arena in which they were allowed either immediate physical contact with another strain (control condition) or were briefly separated from another strain by a transparent partition before being allowed physical access to them (priming condition). Subjects, recorded as either having fought or not fought in the arena, were then placed in a 101 cm square seminatural setting. Seven trials, using 8 LGs each (4 arenaexperienced males and 4 naive females), were made, and agonistic behaviors were recorded for the priming and control condition subjects. The results showed that the control condition fighters (CF) like the priming condition fighters (PF) fought in the arena situation, but different agonistic patterns in the seminatural setting were noted. While in the seminatural environment, both CF and PF mice were attacked frequently and submitted frequently, but PF mice attacked opponents more frequently than did CF subjects (p < 0.025) and elicited significantly more submissions from opponent mice than did CF mice (p < 0.025). It is concluded that: (1) there are more and different agonistic behavior patterns available in the more natural environment than in the arena setting, and more specifically (2) there is a greater effect on agonistic behaviors in a seminatural environment for mice that fought when exposed to the arena priming procedure as compared with mice having fought in the arena control condition.     

Hormonal regulation of aggression: Evidence for a relationship among genotype,receptor binding,and behavioral sensitivity to androgen and estrogen

Gonadectomized male mice from the CF-1, CFW, and CD-1 strains were exposed to different androgens (testosterone, dihydrotestosterone, methyltrienolone) or estrogens (estradiol, diethylstilbestrol) and tested for aggressive behavior. Genetic differences in sensitivity to the aggression-promoting property of the various treatments were found. CF-1 mice responded to either androgenic or estrogenic stimulation, CFW males were most sensitive to the estrogen treatments, while CD-1 males responded to androgen but were relatively insensitive to the aggression-promoting property of estrogens. These data suggest that there may be multiple aggression-activating systems and that the functional pathway varies with genotype. Additional experiments examined whether receptor binding in the hypothalamic-preoptic-septal region was related to the genetic differences in behavioral responsiveness. The binding data suggested that sensitivity to the aggression-promoting property of estrogens was related to either a higher concentration of binding sites or to higher affinity binding between estrogen and its receptor. A systematic relationship between dihydrotestosterone binding and behavioral responsiveness to androgen was not found.