Heightened aggression after chronic flunitrazepam in male rats: potential links to cortical and caudate–putamen-binding sites

Almeida, Rosa M. M. de; Benini, Quelin; Betat, Juliana; Hipólide, Débora Cristina; Miczek, Klaus A.; Svensson, Anders

doi:10.1007/s00213-007-1031-5

Cited by 13 publications

(10 citation statements)

References 61 publications

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“…This social encounter was videotaped, and was subsequently scored (Observer 5.0.20, Noldus Information Technologies, The Netherlands) by a blinded observer for aggressive behaviors: sniffing, boxing, and biting; defensive behavior: freezing; and other behaviors: rearing, running, and eating/drinking in resident and intruder rats. This resident-intruder paradigm has been validated by numerous laboratories as a reliable tool for the characterization of aggression in rodents (Bannai et al, 2007; de Almeida et al, 2008; de Boer and Koolhaas, 2005; van Erp and Miczek, 2007). …”

Section: Methodsmentioning

confidence: 99%

High novelty-seeking predicts aggression and gene expression differences within defined serotonergic cell groups

et al. 2011

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Aggression frequently coincides with specific dimensions of emotionality, such as impulsivity, risk-taking, and drug abuse. Serotonergic (5-HTergic) neurotransmission contributes to the regulation of numerous neurobiological functions, and is thought to play a key role in modulating aggressive responses. The current study uses selectively-bred High (bHR) and Low (bLR) Responder rats that exhibit differences in emotionality and behavioral control, with bHRs exhibiting heightened novelty-induced exploration, impulsivity, and increased sensitivity to drugs of abuse, and with bLRs characterized by exaggerated depressive- and anxiety-like behaviors. Based on this behavioral profile we hypothesized that bHR rats exhibit increased aggression along with changes in testosterone and corticosterone secretion characteristic of aggression, and that these changes are accompanied by alterations in the expression of key genes that regulate 5-HTergic neurotransmission (Tph2 and Sert) as well as in the activation of 5-HTergic cell groups following aggressive encounter. Our data demonstrate that when compared to bLR rats, bHRs express increased baseline Tph2 and Sert in select brainstem nuclei, and when tested on the resident-intruder test they exhibited: 1) increased aggressive behavior; 2) potentiated corticosterone and testosterone secretion; and 3) diminished intrusion-induced c-fos expression in select 5-HTergic brainstem cell groups. The most prominent gene expression differences occurred in the B9 cell group, pontomesencephalic reticular formation, median raphe, and the gigantocellular nucleus pars α. These data are consistent with the notion that altered 5-HT neurotransmission contributes to bHRs’ heightened aggression. Furthermore, they indicate that a specific subset of brainstem 5-HTergic cell groups contributes to the regulation of intrusion-elicited behavioral responses.

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Section: Methodsmentioning

confidence: 99%

High novelty-seeking predicts aggression and gene expression differences within defined serotonergic cell groups

et al. 2011

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“…These studies are limited by their observational nature; in particular, it is hard to rule out the possibility that participants who received benzodiazepines had different signs and symptoms of psychopathology than those who did not (confounding by indication). In male rats, midazolam, triazolam and flunitrazepam have been found to increase aggressive behaviour [32,33]. …”

Section: Introductionmentioning

confidence: 99%

Effects of 25 mg oxazepam on emotional mimicry and empathy for pain: a randomized controlled experiment

et al. 2017

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Emotional mimicry and empathy are mechanisms underlying social interaction. Benzodiazepines have been proposed to inhibit empathy and promote antisocial behaviour. First, we aimed to investigate the effects of oxazepam on emotional mimicry and empathy for pain, and second, we aimed to investigate the association of personality traits to emotional mimicry and empathy. Participants (n=76) were randomized to 25 mg oxazepam or placebo. Emotional mimicry was examined using video clips with emotional expressions. Empathy was investigated by pain stimulating the participant and a confederate. We recorded self-rated experience, activity in major zygomatic and superciliary corrugator muscles, skin conductance, and heart rate. In the mimicry experiment, oxazepam inhibited corrugator activity. In the empathy experiment, oxazepam caused increased self-rated unpleasantness and skin conductance. However, oxazepam specifically inhibited neither emotional mimicry nor empathy for pain. Responses in both experiments were associated with self-rated empathic, psychopathic and alexithymic traits. The present results do not support a specific effect of 25 mg oxazepam on emotional mimicry or empathy.

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“…In pre-clinical studies, low doses of BZDs show so-called paradoxical effects like insomnia, agitation and heightened aggression (Miczek 1974; Ben-Porath and Taylor 2002; Gourley et al 2005; de Almeida et al 2008) and alcohol can increase aggression in a significant minority of individuals (Miczek et al 1992, 1998; Van Erp and Miczek 1997, de Almeida et al 2004, Grant et al 2005, van Erp and Miczek 2007; Fish et al 2008). …”

Section: Discussionmentioning

confidence: 99%

“…We hypothesize that flunitrazepam plus alcohol may impair the neural circuit that includes in part BZD binding sites in the prefrontal cortex and which in turn leads to inhibitory dysregulation in this specific brain area (de Almeida et al 2008). Further studies with measurements of GABA and glutamate and their receptors in the prefrontal cortex would provide a direct test of this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…In rats, the measure of total aggression was calculated as the sum of the frequency counts for bites + sideways threats + pin + nip. This approach reduced the impact of large individual differences in the display of these four elements of aggressive behavior (de Almeida et al 2008). The behaviors were analyzed blind with regard to the treatment condition.…”

Section: Methodsmentioning

confidence: 99%

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Flunitrazepam in combination with alcohol engenders high levels of aggression in mice and rats

Almeida¹,

Saft²,

Rosa³

et al. 2010

Pharmacology Biochemistry and Behavior

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Rationale Higher doses of benzodiazepines and alcohol induce sedation and sleep; however, in low to moderate doses these drugs can increase aggressive behavior. Objectives To assess firstly the effects of ethanol, secondly the effects of flunitrazepam, a so-called club drug, and thirdly the effects of flunitrazepam plus alcohol on aggression in mice and rats. Methods Exhaustive behavioral records of confrontations between a male resident and a male intruder were obtained twice a week, using CF-1 mice and Wistar rats. The salient aggressive and non-aggressive elements in the resident´s reperetoire were analyzed. Initially, the effects of ethanol (1.0 g/kg), and secondly flunitrazepam (0; 0.01; 0.1; and 0.3 mg/kg) were determined in all mice and rats; subsequently, flunitrazepam or vehicle, given intraperitoneally (0; 0.01; 0.1; and 0.3 mg/kg) was administered plus ethanol 1.0 g/kg or vehicle via gavage. Results The most significant finding is the escalation of aggression after a moderate dose of ethanol, and a low dose of flunitrazepam. The largest increase in aggressive behaviour occurred after combined flunitrazepam plus ethanol treatment in mice and rats. Conclusions Ethanol can heighten aggressive behavior and flunitrazepam further increases this effect in male mice and rats.

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Heightened aggression after chronic flunitrazepam in male rats: potential links to cortical and caudate–putamen-binding sites

Abstract: Chronic flunitrazepam produces changes in receptor binding in discrete areas of the cingulate cortex and caudate-putamen that are proposed to be part of the mechanisms for increased expression of aggressive behavior.

Cited by 13 publications

References 61 publications

High novelty-seeking predicts aggression and gene expression differences within defined serotonergic cell groups

High novelty-seeking predicts aggression and gene expression differences within defined serotonergic cell groups

Effects of 25 mg oxazepam on emotional mimicry and empathy for pain: a randomized controlled experiment

Flunitrazepam in combination with alcohol engenders high levels of aggression in mice and rats

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