Anti-aggressive Effects Research Articles

GABAA/alpha1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice.

The positive modulation of gamma-aminobutyric acid type-A (GABAA) receptors is a putative mechanism via which alcohol escalates aggressive behavior. Broad-spectrum benzodiazepine antagonists block alcohol-heightened aggression in rats and monkeys. However, the degree to which GABAA subunit composition plays a role in heightened aggressive behavior induced by self-administration of a moderate alcohol dose remains unresolved. Beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) and zolpidem act preferentially at GABAA receptors containing the alpha1 subunit as antagonist and agonist, respectively, and serve as useful tools to evaluate the role of GABAA receptor subtypes in self-administered alcohol on aggression. Male resident mice, housed in breeding pairs, were conditioned to nose-poke in a removable panel in their home cage, with each fifth poke being reinforced by the delivery of 0.05 ml of 6% ethanol (EtOH). After consuming EtOH, the resident mice were given the antagonists beta-CCt and flumazenil or agonists zolpidem and triazolam, and then confronted an intruder male in their home cage for a 5-min period. Following self-administration of EtOH (1.0 g/kg, 1.7 g/kg), 14 of 37 resident mice displayed unusually large increases in the frequency of attack bites and sideways threats. Flumazenil or beta-CCt decreased alcohol-heightened and non-heightened aggression in a dose-dependent manner. Administration of 3 mg/kg beta-CCt lowered the aggression-heightening effects of 1 g/kg and 1.7 g/kg EtOH, but did not antagonize the sedative effects of 3.0 g/kg EtOH. Triazolam and zolpidem decreased alcohol-heightened and non-heightened aggressive behavior, and these antiaggressive effects were accompanied by reduced motor activity, indicating sedation. Benzodiazepine antagonists, particularly those acting preferentially at GABAA/alpha1 subunit-containing receptors, decrease alcohol-heightened and species-typical aggressive behavior, but are ineffective in attenuating the sedative effects of alcohol.

Impulsive Aggressive Behavior

Results from open-label and placebo-controlled trials suggest that the selective serotonin reuptake inhibitors reduce impulsive aggressive behavior. The objective of this open-label study was to investigate whether citalopram treatment has anti-aggressive effect on impulsive aggressive subjects meeting DSM-IV criteria for a cluster B personality disorder or intermittent explosive disorder. In this 8-week trial, subjects were initiated on 20 mg/day of citalopram and titrated up to 60 mg/day by the fourth week, if tolerated. The primary outcome measure was the Overt Aggression Scale-Modified (OAS-M), a scale used to quantify verbal and physical aggression, subjective irritability, and overt irritability. Secondary outcome measures included the Barratt Impulsiveness Scale and Buss-Durkee Hostility Inventory. Of 25 subjects enrolled, 20 completed the study. The mean daily dose was 45.5 mg, and citalopram was generally well tolerated. Statistically significant decreases were found in the OAS-M aggression scores (32.82 +/- 19.76 to 4.73 +/- 7.57, p =.000), subjective irritability scores (3.50 +/- 0.60 to 1.45 +/- 1.18, p =.000), and overt irritability scores (3.23 +/- 0.81 to 0.91 +/- 1.02, p =.000). These results suggest that citalopram is an effective treatment for reducing impulsive aggressive behavior.

Allopurinol for the treatment of aggressive behaviour in patients with dementia

Aggressive behaviour is commonly observed in patients with dementia, and current pharmacological treatments are still deficient in terms of efficacy and tolerability. Allopurinol is an inhibitor of the enzyme xanthine oxidase, with previously suggested anti-aggressive effects. After successful treatment of aggression in two patients, we performed a case-series study with allopurinol 300 mg a day orally for 6 weeks (increasing 300 mg every 2 weeks if the response was less than 50%) in six patients with dementia associated with prominent aggressive behaviour who failed to respond to two previous treatment strategies. Five patients were considerably responsive to allopurinol (four with 300 mg within 2 weeks and one with 600 mg), apparently without side-effects, which is in accordance with its well-established safety and tolerability profile. The observed therapeutic effect of allopurinol might be due to the inhibition of the enzyme xanthine oxidase, possibly decreasing production of oxigen-free radicals or promoting the accumulation of purines. Controlled studies are warranted to confirm these preliminary observations.

Antiaggressive Effects of Zolpidem and Zopiclone in Agonistic Encounters Between Male Mice

AbstractThe effects of benzodiazepines on various types of aggression have been extensively studied. These substances produce their pharmacological effects by allosterically modulating the action of GABA via specific recognition sites on the GABAA receptor called omega 1 and omega 2. The antiaggressive profile of non‐benzodiazepine compounds that also act at omega sites, such as zopiclone (a non‐selective omega 1 and 2 ligand) and zolpidem (a selective omega 1 ligand) has been scarcely explored. In this study, we examined the action of zolpidem (0.75‐3 mg/kg, intraperitoneally) and zopiclone (1.5‐6 mg/kg), administered acutely or subchronically for 10 days, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic “standard opponents” 30 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. Acute treatment with zopiclone produced a marked antiaggressive effect, reducing offensive behaviors (threat and attack) at all doses used (1.5, 3, and 6 mg/kg) without affecting immobility. Likewise, the intermediate dose of zolpidem (1.5 mg/kg) significantly decreased aggression in a specific manner, without altering immobility, whereas the highest dose (3 mg/kg) provoked a reduction of aggression accompanied by a weak (but significant) increase of immobility. With repeated treatment, no tolerance to the antiaggressive effects of zopiclone and zolpidem was developed. It is concluded that omega sites at the GABAA receptor could be involved in the control of aggression. Aggr. Behav. 28:416–425, 2002. © 2002 Wiley‐Liss, Inc.

Aggression Escalated by Social Instigation or by Discontinuation of Reinforcement (“Frustration”) in Mice: Inhibition by Anpirtoline: A 5-HT1B Receptor Agonist

Experiments with social instigation or the omission of scheduled reinforcement show that serotonergic mechanisms may be involved in escalated aggression in animals. 5-HT1B receptor agonists have anti-aggressive effects in individuals who show moderate as well as high levels of aggression. The present study compared the effects of the 5-HT1B agonist anpirtoline (0.125–1.5 mg/kg) on (1) species-typical aggressive behavior in male mice, (2) aggression “instigated” or primed by prior exposure to the opponent, and (3) aggression heightened by “frustration” caused by omission of scheduled reinforcement. The effects of anpirtoline on species-typical behavior were also assessed after pretreatment with the 5-HT1B/1D receptor antagonist GR127935 (10 mg/kg). Anpirtoline, like other 5-HT1B agonists (CP-94,253, zolmitriptan), decreased both instigated and frustration-heightened aggression, while motor behavior was unaffected. The aggression-inhibiting effects of anpirtoline were blocked by pretreatment with GR127935. The current results indicate that the 5-HT1B receptor is critically involved in the modulation of escalated aggression.

Effects of cocaine and putative atypical antipsychotics on rat social behavior: An ethopharmacological study

The effects of cocaine, amperozide, clozapine, olanzapine and cocaine/atypical antipsychotic combinations on aggression, affiliation and defensive behaviors was examined. Acute cocaine (30.0 mg/kg) decreased basal aggression and affiliation yet increased basal defense. Amperozide (1.0, 3.0 and 5.0 mg/kg) decreased basal aggression, affiliation and defense had no effect on the cocaine-induced decrease in affiliation, and accentuated the cocaine-induced decrease in aggression. Near basal levels of defense were observed for animals treated with either amperozide, clozapine (3.0 and 10.0 mg/kg but not 30.0 mg/kg) or olanzapine followed by cocaine. Clozapine (3.0, 10.0 and 30.0 mg/kg) decreased basal aggression and affiliation. Clozapine (30.0 mg/kg but not 3.0 or 10.0 mg/kg) decreased basal defense. Clozapine attenuated the cocaine-induced decrease in aggression. Although 3.0 and 10.0 mg/kg clozapine attenuated the cocaine-induced decrease in affiliation, 30.0 mg/kg clozapine accentuated this cocaine-induced effect. Olanzapine (1.0, 3.0 and 10.0 mg/kg) decreased basal aggression, affiliation and defense. Olanzapine had no effect on the cocaine-induced decrease in aggression. Olanzapine (3.0 mg/kg but not 1.0 or 10.0 mg/kg) attenuated the cocaine-induced decrease in affiliation. Thus, acute cocaine administration had an antiaggressive effect, suppressed affiliative behavior and enhanced defensive behavior. Amperozide, clozapine and olanzapine have anticonflict and anxiolytic effects, as well as potent and specific antiaggressive effects.

Recent advances in 5-HT1B/1D receptor antagonists and agonists and their potential therapeutic applications.

The human 5-HT(1B) and 5-HT(1D) receptors are especially similar in sequence despite being encoded by two distinct genes. Although, human 5-HT(1B) and 5-HT(1D) receptors have been pharmacologically differentiated using nonselective 5-HT(1B/D) receptor antagonists such as ketanserin (1), ritanserin (2) and methiothepin (3), the precise function of these receptors remains undefined, and progress toward this has been hampered by the lack of selective ligands. The interest of the major pharmaceutical companies in 5-HT(1B/1D) antagonists increased by the discovery of potent and selective tools, combined with the fact that the blockade of terminal 5-HT(1B) receptors by selective antagonists has been proposed as a new approach for more efficient and/or fast-acting antidepressant drugs, since the acute blockade of these 5-HT autoreceptors will, in theory, immediately mimic their desensitization. Furthermore, it has been also suggested that supersensitive 5-HT(1B/1D) receptors may be involved in the pathophysiology of obsessive compulsive disorders (OCD). In the 5-HT(1B/1D) agonist field, since the discovery of sumatriptan (26) (a 5-HT(1B/1D) receptor agonist) as an effective treatment for migraine headache, intensive research in this area has led to several second-generation compounds, a few of which have either entered the market place or are in late clinical trials. Beside the antimigraine activity of the 5-HT(1B/1D) agonists in clinical evaluation or already on the market, other potential therapeutic evaluations (such as gastric motor effect, bipolar disorder, autism, anti-aggressive effects) with these drugs are being investigated. This article highlights and reviews the research advances published in the 5-HT(1B/1D) antagonist and agonist literature. The article is supplemented with selected references on the design, synthesis and development of novel 5-HT(1B/1D) agents, and on studies to understand their mechanism and pathophysiology. Emphasis is given to recent advances in the potential therapeutic applications of 5-HT(1B/1D) serotonergic agents. By no means has any attempt been made to exhaustively review the literature but rather, primary references along with citations to recent literature reviews have been included in each section.

Memantine does not block antiaggressive effects of morphine in mice.

The action of the noncompetitive N-methyl-D-aspartate (NMDA) receptor blocker memantine (5, 10, 20 and 40 mg/kg) was evaluated during social encounters in mice. Although a dose-dependent increase in locomotion was observed, only with the highest dose did it reach statistical significance. Aggressive behavior was decreased with 20 and 40 mg/kg of memantine, social contacts being increased only with 20 mg/kg. Subsequently, the effect of these memantine doses on the antiaggressive actions of morphine (10 mg/kg) was evaluated. None of the doses affected the antiaggressive action of morphine. As memantine administration produced an antiaggressive effect only at doses that affected locomotion, it is unlikely that the glutamatergic system mediates the antiaggressive actions of morphine.

The GABAergic effect of low doses of lorazepam on social behavior

AbstractThe aim of this work was to test the antiaggressive effects of lorazepam and to determine whether these effects were mediated by benzodiazepine receptors. In a first experiment, male mice were injected with lorazepam in a range of low doses (0.05, 0.1, 0.2, and 0.6 mg/kg) or saline solution. In a second experiment, 1 mg/kg of Ro 15‐1788, a benzodiazepine receptor antagonist, and a saline solution were injected before the behavioral test. Results showed that 0.6 mg/kg of lorazepam was the only dose that decreased the total duration of threat (P < .01) and social investigation (P < .05) and that 1 mg/kg of Ro 15‐1788 had no effects. In the third experiment, animals received two injections: 0.6 mg/kg of lorazepam plus 1 mg/kg of Ro 15‐1788, 0.6 mg/kg of lorazepam plus saline solution, or saline solution plus saline solution. Those treated with lorazepam and saline solution spent less time digging (P < .001), threatening (P < .001), and attacking (P < .05) and more time avoiding the opponent (P < .01) or being immobile (P < .001) than the controls. Ro 15‐1788 was successful in completely antagonizing the behavior modulated by lorazepam. Aggr. Behav. 28:248–256, 2002. © 2002 Wiley‐Liss, Inc.

Modulation by 5-HT2A Receptors of Aggressive Behavior in Isolated Mice

The present study examines whether isolation-rearing affects sensitivity of 5-hydroxy-tryptamine (5-HT)2A receptors and the functional interaction between 5-HT1A and 5-HT2A receptors in mice. The 5-HT2A-receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)-induced head twitch response was significantly greater in isolated mice than in grouped mice. DOI increased isolation-induced aggressive behavior, and the 5-HT2A-receptor antagonist ritanserin decreased it. The 5-HT1A-receptor agonist (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242) inhibited the DOI-enhanced aggressive behavior. MKC-242 inhibited DOI-induced head twitch response. These findings suggest that 5-HT2A receptors play a role in aggressive behavior in isolated mice and imply that the antiaggressive effect of MKC-242 may be mediated partly by the inhibition of 5-HT2A-receptor function.

Involvement of benzodiazepine binding sites in an antiaggressive effect by 5-HT 1A receptor activation in isolated mice

The effect of the benzodiazepine receptor antagonist flumazenil was examined on an antiaggressive effect of ( S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3- benzodioxole HCl (MKC-242), a 5-HT 1A receptor agonist. MKC-242 (0.1–1.0 mg/kg, p.o.) selectively reduced isolation-induced aggressive behavior in a dose-dependent manner. Flumazenil (10 mg/kg, i.p.) antagonized the antiaggressive effects of MKC-242 and diazepam, although it alone did not affect the behaviors of isolated mice. These findings suggest that a γ-aminobutyric acid A (GABA A) receptor system is involved in the antiaggressive effect by 5-HT 1A receptor activation.

Oral drug self-administration in the home cage of mice: alcohol-heightened aggression and inhibition by the 5-HT1B agonist anpirtoline.

In order to model heightened aggression after alcohol consumption and to study the inhibitory influence of 5-HT1B receptors on drinking and fighting, an experimental procedure should enable self-administration of precise amounts of alcohol in a limited period of time before an aggressive confrontation. To design a new device that can reinforce operant responding by the delivery of sweet alcohol in the resident mouse home cage, where aggressive behavior toward an intruder can subsequently be examined, and to demonstrate inhibition of alcohol-heightened aggression by 5-HT1B receptor agonist treatment. Within one experimental session, all singly housed CFW male mice (n=26) performed a nose-poke response that was reinforced by 0.05 ml sucrose. Using the sucrose fading technique, eventually the mice consumed a 6% ethanol/4% sucrose solution after each fifth nose poke during daily 15-min experimental sessions. The number of ethanol reinforcements was adjusted so that 0.6, 1.0, 1.7, and 3.0-g/kg doses were consumed in 15 min or less. Assays confirmed blood alcohol levels at 68.1 mg/dl for intake of 1.0 g/kg. After consuming a specific dose of ethanol in the form of a fixed number of response-dependent deliveries, the response panel was removed from the home cage and, 15 min later, the resident confronted a male intruder. Anpirtoline was administered either before alcohol self-administration or before the aggressive confrontation. After being reinforced with 1.0 g/kg or 1.7 g/kg sweet ethanol, the mice significantly increased attack and threat behavior relative to their aggressive behavior following sucrose or water consumption only. Treatment with the 5-HT1B receptor agonist anpirtoline (0.125, 0.25, 0.5 mg/kg, i.p.) before the confrontation decreased alcohol-heightened aggression and species-typical aggression in the absence of changes in other elements of the behavioral repertoire. Anpirtoline affected ethanol-reinforced behavior only at doses that were 5-10 times higher than those producing anti-aggressive effects. Self-administration of alcohol in the home cage of mice is readily accomplished with the aid of a simple, removable panel. The effective inhibition of high levels of aggressive behavior due to alcohol consumption after anpirtoline treatment confirm the 5-HT1B receptor as a critical site in the termination of aggression.

Antiaggressive and motor effects of the DA release inhibitor CGS 10746B

AbstractIn the present study the effects of a wide range of doses of the dopamine release inhibitor CGS 10746B were evaluated in spontaneous activity and in aggressive behaviour using the paradigm of isolation‐induced aggression. The two higher doses (8 and 16 mg/kg) produced a decrease in spontaneous motor activity. Antiaggressive effects were observed after administration of doses from 4 mg/kg upwards. At this dose, CGS 10746B diminished threat and attack, and although an increase in immobility was observed, no impairment of other motor behaviours was presented. With higher doses, aggression was practically abolished but with a concomitant effect on many other behaviours. When animals were separated depending on their latency of attack, those that showed a long attack latency (LAL) presented a stronger response to 4 mg/kg than those that had a short attack latency (SAL), which were not affected in their aggression by this dose. We can conclude that presynaptic dopamine function is necessary for the normal expression of aggressive behaviours, since CGS 10746B reduces aggression at doses that do not affect spontaneous motor activity. Aggr. Behav. 27:382–390, 2001. © 2001 Wiley‐Liss, Inc.

Zolmitriptan - a 5-HT 1B/D agonist, alcohol, and aggression in mice

Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D receptors. It penetrates into the central nervous system and, like other 5-HT1B/D agonists, its pharmacotherapeutic profile may include significant anti-aggressive effects. To examine whether zolmitriptan has potential anti-aggressive effects by studying two kinds of aggressive behavior in mice--species-typical and aggression under the influence of alcohol. A second objective was to study whether pre- or post-synaptic receptors mediate these anti-aggressive effects. Initially, the anti-aggressive effects of zolmitriptan were studied in male CFW mice during 5-min resident-intruder confrontations. To confirm the 5-HT1B receptor as a critical site of action for the anti-aggressive effects, the zolmitriptan dose-effect determinations were repeated after pretreatment with GR 127935 (10 mg/kg, i.p.). In further experiments, mice were treated concurrently with alcohol (1.0 g/kg, p.o.) and zolmitriptan (1-30 mg/kg, i.p.) in order to compare the effects of this agonist on species-typical and alcohol-heightened aggression. Finally, mice were infused with the neurotoxin 5,7-DHT (10 microg) into the raphé area to eliminate somatodendritic and presynaptic autoreceptors. The anti-aggressive effects of zolmitriptan (17 mg/kg, i.p.) or CP-94,253 (10 mg/kg, i.p.) were assessed 10 days after the lesion, and levels of 5-HT and 5-HIAA were measured in the hippocampus and prefrontal cortex. Zolmitriptan exerted behaviorally specific anti-aggressive effects. The reduction in aggression was antagonized by GR 127935, indicated by a rightward shift in the dose-effect curves of zolmitriptan, showing the specificity for the 5-HT1B receptors. Zolmitriptan also decreased alcohol-heightened aggression with equal efficacy. The anti-aggressive effects of CP-94,253 and zolmitriptan remained unaltered by 5,7-DHT lesions that depleted cortical and hippocampal 5-HT by 60-80%. Zolmitriptan proved to be an effective and behaviorally specific anti-aggressive agent in situations that engender moderate and alcohol-heightened levels of aggression. These effects are potentially due to activation of post-synaptic 5-HT1BD receptors.

Antiaggressive and motor effects of the DA release inhibitor CGS 10746B

In the present study the effects of a wide range of doses of the dopamine release inhibitor CGS 10746B were evaluated in spontaneous activity and in aggressive behaviour using the paradigm of isolation-induced aggression. The two higher doses (8 and 16 mg/kg) produced a decrease in spontaneous motor activity. Antiaggressive effects were observed after administration of doses from 4 mg/kg upwards. At this dose, CGS 10746B diminished threat and attack, and although an increase in immobility was observed, no impairment of other motor behaviours was presented. With higher doses, aggression was practically abolished but with a concomitant effect on many other behaviours. When animals were separated depending on their latency of attack, those that showed a long attack latency (LAL) presented a stronger response to 4 mg/kg than those that had a short attack latency (SAL), which were not affected in their aggression by this dose. We can conclude that presynaptic dopamine function is necessary for the normal expression of aggressive behaviours, since CGS 10746B reduces aggression at doses that do not affect spontaneous motor activity. Aggr. Behav. 27:382–390, 2001. © 2001 Wiley-Liss, Inc.

Behavioral and neurochemical effects of anpirtoline and citalopram in isolated and group housed mice

1. Acute effects of serotonergic drugs acting via different mechanisms were investigated by a social interaction test and subsequent determination of serotonin and dopamine metabolisms in mice housed in groups or isolated for 6 weeks. 2. A resident / intruder test was performed with anpirtoline (5-HT 1B receptor agonist in rodents; 1 mg/kg), citalopram (SSRI; 0.5 mg/kg) and saline treatment before animals were decapitated and different brain regions were frozen for subsequent HPLC-analyses. 3. Behavioral investigations indicated a strong increase of aggressive behavior after 6 weeks of isolation housing. Acute citalopram treatment did not influence behavioral parameters of isolated and group housed mice. In contrast, anpirtoline antagonized isolation induced aggressive behavioral components in a specific manner. 4. Analysis of dopamine and serotonin metabolism revealed that citalopram treatment did not affect dopamine metabolism, but reduced serotonin metabolism in the striatum, hippocampus, cortex and midbrain independent of housing conditions. 5. In contrast, anpirtoline treatment increased dopamine metabolism in cortex, striatum and midbrain as well as influenced serotonin metabolism in a structure- and state-specific manner. Whereas anpirtoline decreased serotonin metabolism in the cortex, the midbrain and the hippocampus independent of housing conditions, in the striatum anpirtoline abolished the isolation induced decrease of serotonin metabolism. 6. These results indicate that anpirtoline might induce antiaggressive effects via postsynaptic receptor- and structure- specific activation of serotonergic but also dopaminergic processes, whereas structure independent increase of synaptic serotonin via citalopram was ineffective to reverse aggressivity in isolated mice.

Development of tolerance to the antiaggressive effects of morphine.

Many reports have demonstrated that there is a development of tolerance to many effects produced by morphine. This study was conducted with the aim of determining whether the antiaggressive actions of morphine develop tolerance after chronic administration. Acute morphine administration produced antiaggressive effects which disappeared after chronic (7 days) treatment in isolated mice. An increase in non-social exploration was observed, representing morphine-induced hyperactivity, after acute treatment, which was not present after chronic administration. In conclusion, there is a development of tolerance to the antiaggressive and motor effects of morphine.

Additive Effect of Clonidine and Fluoxetine on Apomorphine-Induced Aggressive Behavior in Adult Male Wistar Rats

Background Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to be superior in its antiaggressive properties as compared with other antidepressants. The objective of the study was to investigate whether the effect of a minimal effective dose of fluoxetine could be potentiated by the α2-adrenergic agonist clonidine. Methods Vehicle (1.0 mL/kg), clonidine (0.1 mg/kg), fluoxetine (10 mg/kg), and their combination [clonidine (0.1 mg/kg) plus fluoxetine (10 mg/kg)] were injected into apomorphine-pretreated (1.0 mg/kg, once daily during 12 days) aggressive adult male Wistar rats. Results Repeated apomorphine treatment induced a gradual development of aggressive behavior. Combined clonidine and fluoxetine treatment attenuated the intensity of aggressive behavior, while these drugs alone had only a weak tendency toward reduction of aggression. Latency before the first attack was unchanged. Conclusions Our experiments confirm that combined clonidine and fluoxetine treatment elicits an additive antiaggressive effect on apomorphine-induced aggressive behavior in rats.

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

AbstractThe 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 Antiaggressive Action of Combined Haloperidol-Propranolol Treatment in Schizophrenia

Psychopharmacological interventions for managing aggression in schizophrenia have thus far yielded inconsistent results. This study evaluates the antiaggressive efficacy of combined haloperidol-propranolol treatment. Thirty-four newly admitted schizophrenic patients were studied in a controlled double-blind trial. Following a 3-day drug-free period and 7 days of haloperidol treatment, patients were randomly assigned to receive either haloperidol-propranolol or haloperidol-placebo for eight consecutive weeks. Doses of medications were adjusted as necessary; biperiden was administered if required. Rating scales were applied to assess aggression, anger, psychosis, depression, anxiety and extrapyramidal symptoms. The mean daily dose of haloperidol was 21 mg (SD = 6.4) in the research group and 29 mg (SD = 6.9) in the controls. Mean and maximal daily doses of propranolol were 159 mg (SD = 61) and 192 mg (SD = 83), and of placebo, 145 mg (SD = 50) and 180 mg (SD = 70), respectively. Compared with the controls, the scores for the research patients decreased significantly from baseline, particularly after 4 weeks of treatment, for some dimensions of anger, psychosis, anxiety, and neuroleptic-induced parkinsonism. A tendency for reduced aggression was shown in the combined haloperidol-propranolol group for some dimensions but not others. These patients also required significantly less biperiden. The tendency toward elevated antiaggressive effect of combined haloperidol-propranolol treatment compared to haloperidol alone may be explained by a simultaneous decrease in aggression, psychotic symptomatology, and anxiety.