Biomedical subjects

P L Gendreau

Publications and source records attributed to P L Gendreau.

9 recordsLinked to original sources

PubMed2000

D(3) and D(2) dopamine receptor agonists differentially modulate isolation-induced social-emotional reactivity in mice.

Following isolation housing, mice typically exhibit heightened emotional reactivity to mild social stimulation. Aggression, social avoidance and a variety of defensive behaviors that differ in terms of motor activation (e.g. freezing, escape) can be observed depending on strain. Previous studies suggested that D(2)-like dopamine (DA) receptors play an important, albeit strain specific, role in the mediation of particular forms of defensive behavior. D(3) receptors are subtypes of D(2)-like receptors that are highly expressed in limbic areas of the brain and, therefore, they have been hypothesized to mediate emotional behavior. This study examined the effects of the putative D(3) receptor agonists 7-OH-DPAT and PD128907 on social-emotional behavior in isolated C57BL/6J and A/J mice. These effects were compared with those of the selective D(2) receptor agonist PNU91356A. All three DA agonists increased non-locomotor forms of defensive behavior (e.g. freezing, upright defensive posture). These effects were observed at low doses in C57BL/6J and at higher doses in A/J mice. Only the D(3) receptor agonists were effective in increasing locomotor forms of defensive behavior (i.e. escape, jump) at higher doses. These effects were more pronounced in C57BL/6J mice than A/J mice. The increases in stationary and locomotor defensive behavior were accompanied by marked reduction in social investigation in both the strains. Aggressive behavior was also abolished in the aggressive C57BL/6J strain. These results support previous findings and suggest that DA agonists potentiate defensive behavior and/or social fearfulness. They also suggest that D(3) and D(2) DA receptors differentially modulate the expression of social-emotional reactivity and indicate the importance of strain in examining the effects of DA ligands on emotional behavior.

Aggression↗

PubMed1999

Impaired learning and memory and altered hippocampal neurodevelopment resulting from interleukin-2 gene deletion.

Interleukin-2 (IL-2), the protypical T cell growth factor and immunoregulatory cytokine produced by lymphocytes, has been implicated as a brain neurotrophic factor and neuromodulator. The consequences of the absence of endogenous IL-2 on brain development and function were unknown. Brain IL-2 receptors are enriched in the hippocampal formation, an area critical for the acquisition and consolidation of spatial learning and memory. Thus, we tested the hypothesis that mice lacking IL-2 would exhibit alterations in hippocampal-dependent learning and neurodevelopment. Compared with C57BL/6-IL-2+/+ wild-type mice, we observed that C57BL/6-IL-2-/- gene knockout mice had markedly impaired spatial learning and memory in the Morris water maze. No significant deficits in parameters of learning and memory performance were found in severe combined immunodeficient (SCID) mice (C57BL/6scid), however, suggesting that the impaired spatial learning and memory exhibited by IL-2 knockout mice is not attributable to generalized immunodeficiency resulting from the absence of endogenous IL-2. Examination of other domains of behavioral performance showed that the IL-2 knockout and wildtype mice did not differ in measures of fearfulness or locomotor activity in an elevated plus maze, or in reflexive startle responses to auditory stimuli--although prepulse inhibition of acoustic startle (PPI) was increased significantly in IL-2 knockout mice. The spatial learning and memory impairment in IL-2 knockout mice was accompanied by reductions in hippocampal infrapyramidal mossy neuronal fiber length, a factor shown previously to correlate positively with spatial learning ability. These findings indicate that, in addition to being a pivotal cytokine in immune regulation, IL-2 may play a role in the development and regulation of brain neurons involved in spatial learning and memory.

Acoustic Stimulation↗

PubMed1999

Differences in NK cell function in mice bred for high and low aggression: genetic linkage between complex behavioral and immunological traits?

In previous studies, we found differences in cellular immune responsiveness in Institute for Cancer Research (ICR) mice selectively bred for high and low levels of aggression. Compared to the high aggressive line, the low aggressive line had low levels of natural killer (NK) and T cell activity and increased susceptibility to tumor development. To dissect further this novel association, experiments were designed to test two competing hypotheses. The first hypothesis was that the phenotypic expression of the line differences in NK cell activity are dependent on and regulated by the expression of high and low levels aggressive behavior in the lines. The alternative hypothesis was that the differences in immune status are independent of the expression of aggression by the lines, suggesting linkage between a subset of genes involved in determining these complex behavioral and immunological traits or pleiotropic gene effects on both traits. In Experiment 1, three conditions of postweaning social experience (mice singly housed, group housed within line, or group housed between lines) were tested in males to determine whether experiential conditions which modify the expression of aggression would in turn modify the line differences in NK cell activity. This experiment revealed that the difference in NK cell activity between high aggressive and low aggressive male mice was attributable to line only. The different postweaning social conditions examined had no effect on modifying the differences in NK activity, and social dominance hierarchy did not correlate with levels of NK cell activity. Whereas males of the high and low lines exhibit differences in aggressive behaviors across most contexts, females do not exhibit such differences except in response to an intruder during the postpartum period. Therefore, in Experiment 2 we compared the NK cell activity of nulliparous females of the high and low aggressive lines. Under these conditions, females of the low aggressive line had low levels of NK activity compared to high aggressive females (differences comparable to those seen between males of the high and low lines). Taken together, these experiments lend support to the hypothesis that this association may be due to a genetic linkage between subsets of genes involved in determining these complex behavioral and immunological traits, or may possibly represent a fortuitous association which occurred during the selective breeding.

Aggression↗

PubMed1998

D1 dopamine receptors and the reversal of isolation-induced behaviors in mice.

In a previous study, it was demonstrated that the high rates of social reactivity exhibited by isolated male mice in a dyadic encounter were mediated, at least in part, by an increased sensitivity of the D1 dopamine receptors. The present research was guided by the hypothesis that the behavioral effects of isolation are reversible, and that changes in dopaminergic function support this reversibility. To this end, mice selectively bred for high and low levels of aggression were reared in isolation from weaning (21 days) to puberty (45 days), at which point they were either assigned to groups or left in isolation until day 69. By comparison to the continuous isolation condition, mice that eventually formed groups exhibited significantly less reactivity in a dyadic test conducted on day 69, showed a reduced response to dihydrexidine (DHX), and a decreased density of D1 dopamine receptors. This experiment provided evidence for the plasticity of the neurobiological system supporting reactive responses, and confirmed the view that its functional organization is open to experientially-induced changes.

Animals↗

PubMed1998

D2-like dopamine receptor mediation of social-emotional reactivity in a mouse model of anxiety: strain and experience effects.

We examined the effects of the D2-like dopamine receptor agonist quinpirole on social-emotional reactivity in two inbred mouse strains. An important objective of this study was to determine whether these effects could be modulated by differential housing conditions (i.e., isolation versus group housing). Moreover, as motor activity is an important control for the assessment of drug effects on emotional behavior, the effects of quinpirole were tested in two inbred mouse strains (A/J and C57BL/6J) low and high in motor activity, respectively. Levels of emotional reactivity were assessed in response to mild social stimulation provided by a nonaggressive conspecific. Quinpirole increased stationary forms of reactivity (i.e., startle, kicking, defensive posture, vocalization) in both isolated and group-housed A/J mice. This effect was more pronounced and observed at lower doses in isolated than in group-housed A/J mice. Quinpirole also induced jump behavior in isolated but not group-housed A/J mice. The shift to the left in the dose-response curve of quinpirole in isolated A/J mice indicated that D2-like dopamine receptor functions can be altered by social experience. Quinpirole only marginally increased stationary and locomotor reactivity (i.e., jump) in isolated C57BL/6J mice, whereas it markedly reduced motor activity in group-housed mice of this strain. The investigation of emotional reactivity within a social context and using strains that differ in motor activity permitted the effects of drugs on emotional reactivity to be dissociated from the effects on motor activity. Given that social-emotional reactivity was elicited by what typically should have been mild and nonthreatening stimuli, this model may be highly relevant to understanding the neurobiology of anxiety. Finally, these data support an important role for dopamine in the mediation of social-emotional reactivity.

Animals↗

PubMed1998

Reactive and proactive aggression differentially predict later conduct problems.

This study tested whether proactive and reactive aggression were differently predictive of later externalizing problems such as delinquency and DSM-related disruptive behaviors (i.e. oppositional defiant and conduct disorders). It also tested whether these two subtypes of aggressive behaviors interacted in predicting externalizing problems. A community sample of low SES boys participated in the study. Proactive and reactive aggression were rated by teachers when boys were 12 years old. Delinquency, oppositional disorders, and conduct disorders were assessed during mid-adolescence. Proactive but not reactive aggression predicted delinquency and disruptive behaviors. Moreover, high levels of reactive aggression weakened the link between proactive aggression and delinquency. Reactive aggression, however, did not moderate the link between proactive aggression and disruptive behaviors. We conclude that reactive and proactive aggression are two types of aggressive behaviors with different predictive abilities. We also offer tentative explanations to account for the present findings.

Adolescent↗

PubMed1997

Effects of the putative dopamine D3 receptor antagonist PNU 99194A on motor behavior and emotional reactivity in C57BL/6J mice.

Due to the regional expression of D3 dopamine receptors in limbic areas of the brain, there has been considerable interest in the potential role of this receptor subtype in mediating emotional behavior. Previous studies in habituated rats have shown that the putative dopamine D3 receptor antagonist 5,6-dimethoxy-2-(di-n-propylamino)indan (PNU 99194A) increased locomotor behavior. The present study examined the effects PNU 99194A on motor and emotional behaviors in C57BL/6J mice. Motor behavior was assessed in both habituated and nonhabituated mice. Emotional behavior was assessed using the elevated plus-maze and a social context involving an isolated C57BL/6J mouse and a nonaggressive conspecific. In mice habituated to the activity chamber prior to drug administration, PNU 99194A increased locomotion and rearing at lower doses (5, 10 mg/kg) whereas higher doses (20, 30 mg/kg) reduced these behaviors early in the test session. Thigmotaxis was increased independently of the effects on motor behavior. In mice exposed to the activity chamber for the first time, PNU 99194A produced a weak motor activation at lower doses and an initial decrease in motor behavior at higher doses that was followed by an increase in locomotion later in the test session. PNU 99194A had no systematic effects on activity in the elevated plus-maze, but dose-dependently increased flight reactivity in the social reactivity paradigm. These and previous findings raise questions about the role of dopamine D3 receptors in mediating motor behavior and emotional reactivity as well as the pharmacology of this putative dopamine D3 receptor antagonist.

Animals↗

PubMed1997

D1 dopamine receptor mediation of social and nonsocial emotional reactivity in mice: effects of housing and strain difference in motor activity.

The study examined the effects of isolation housing and the role of D1 dopamine receptors on isolation-induced social and nonsocial (acoustic startle) reactivity in mice high (C57BL/6) and low (A) in motor activity. Isolation housing had no effect on acoustic startle but increased strain-specific forms of social reactivity. The D1 agonist dihydrexidine (DHX) increased acoustic startle in isolated mice of both strains, but this effect was more pronounced in C57BL/6 mice. In this strain, DHX and the D1 agonist SKF-81297 increased locomotor forms of social reactivity (e.g., escape, jump), whereas the D1 antagonist SCH-23390 increased stationary reactivity (e.g., freezing). In A mice, DHX and SKF-81297 increased and decreased stationary reactivity, respectively, whereas SCH-23390 had no effect on these behaviors. Administration of SKF-81297 after pretreatment with SCH-23390 or the D2 antagonist sulpiride confirmed the importance of D1 receptors in mediating specific forms of social reactivity in C57BL/6 mice. These results suggest an important relationship between social reactivity and motor activity and an important, albeit strain-dependent, role for D1 receptors in mediating specific emotional behaviors.

Animals↗

PubMed1995

Rearing conditions alter social reactivity and D1 dopamine receptors in high- and low-aggressive mice.

As a result of selective breeding, NC900 mice exhibit isolation-induced attacks in a social interaction test, whereas NC100 mice do not attack but freeze instead. Administration of the D1 receptor agonist dihydrexidine was previously shown to reduce aggression in NC900 mice and nonagonistic approaches in NC100 mice. This resulted from induction of a marked social reactivity in both selected lines. Because isolation rearing also induces social reactivity, the present experiment was designed to test the hypothesis that D1 dopamine receptors mediate isolation-induced social reactivity. Isolation was expected to potentiate the effects of a D1 agonist and to increase D1 dopamine receptor density. Thus, isolated and group-reared mice were administered dihydrexidine, and their social behavior was compared to vehicle-injected controls. Dihydrexidine induced higher levels of reactivity among isolated than among group-reared animals, especially in NC900 mice. In independent experiments, increased densities of D1 dopamine receptors in the striatum of isolated animals were found, with no change in affinity. These studies suggest an important role for the D1 dopamine receptor as a mediator of isolation-induced social reactivity.

Aggression↗