Effects of d,l-fenfluramine on aggressive and impulsive responding in adult males with a history of conduct disorder

Rationale: The role of serotonin in aggression and impulsivity was examined by administering the serotonin-releasing drug, d,l-fenfluramine and measuring effects on aggressive and impulsive responding under controlled laboratory conditions. Methods: Ten male subjects with a history of conduct disorder and criminal behavior participated in experimental sessions, which measured aggressive and impulsive responses. Aggression was measured using the Point subtraction Aggression paradigm (PSAP), which provides subjects with an aggressive, escape and monetary reinforced response options. Impulsive responses were measured using a paradigm which provided subjects with choices between small rewards after short delays versus larger rewards have long delays. Results: Acute challenge doses (0.2,0.4 and 0.8 mg/kg) of d,l-fenfluramine produced significant dose-dependent decreases in aggressive and impulsive responses. Escape and monetary reinforced responses were not significantly changed. Decreases in aggressive responses were therefore selective, because escape responses were not affected, and could not be attributed to a non-specific sedative action because monetary reinforced responses were slightly increased. Conclusions: Release of serotonin and/or reuptake blockade by d,l-fenfluramine is the possible mechanism for reductions in aggression and impulsivity. These results are consistent with a large body of data linking reduced serotonin function and aggressive behavior and impulsivity. Received: 5 March 1999 / Final version: 2 June 1999     

Acute effects of lorazepam on laboratory measures of aggressive and escape responses of adult male parolees

Acute benzodiazepine administrations typically decrease aggressive responding, but increases in aggression have been reported in some studies. The benzodiazepine lorazepam has been studied less frequently than other benzodiazepines in aggression research, although it is often used to suppress violent aggression in patients. The present study was designed to investigate the effects of acute administrations of lorazepam on aggressive responding in adult humans on a laboratory aggression task. Eight adult males participated in experimental sessions on the Point Subtraction Aggression Paradigm (PSAP), which provided subjects with aggressive, escape and monetary-reinforced response options. Acute oral doses (1, 2 and 4 mg) of lorazepam decreased both aggressive responding and monetary-reinforced responding in seven of eight subjects. In one subject, lorazepam produced dose-dependent increases in aggressive responding. The effects of lorazepam on escape responding were the same as the effects on aggressive responding. The results are consistent with prior research using the PSAP and clinical data showing that benzodiazepines generally decrease aggression, and contrast with other studies that have shown that benzodiazepines can increase aggression. Since lorazepam affected both aggressive and escape responding, it is suggested that while lorazepam often produces sedation, it also modifies human aggressive responding, in part, by suppressing reactions to aversive stimuli.     

Effects of chronic paroxetine administration on measures of aggressive and impulsive responses of adult males with a history of conduct disorder

RATIONALE:The role of serotonin in human aggression and impulsivity was evaluated by administering paroxetine or placebo for 3 weeks and comparing the effects on laboratory measures of aggression and impulsivity among male subjects with a history of conduct disorder. METHODS: Twelve male subjects with a history of criminal behavior participated in experimental sessions, which measured aggressive and impulsive responses. Six subjects were assigned to placebo treatment and six subjects to placebo and paroxetine treatment. Aggression was measured using the point subtraction aggression paradigm (PSAP), which provides subjects with an aggressive and monetary reinforced response options. Impulsive responses were measured using a paradigm that gives subjects choices between small rewards after short delays versus larger rewards after longer delays. RESULTS:Chronic administration of paroxetine (20 mg/day) for 21 days produced significant decreases in impulsive responses. Decreases in aggressive responses were evident only at the end of paroxetine treatment. Decreases in impulsive and aggressive responses could not be attributed to a non-specific sedative action because monetary reinforced responses were not decreased as has been observed following CNS sedation. CONCLUSIONS: Inhibition of serotonin reuptake by paroxetine is the possible mechanism for reductions in aggressive and impulsive responses. These results support other data linking serotonin function and aggression and impulsivity.     

A further examination of gender differences in alcohol-related aggression

OBJECTIVE: The purpose of this investigation was to replicate and extend findings from a previous study on the acute effects of alcohol on aggressive behavior in men and women in a laboratory setting. METHOD: Subjects were 234 (111 men and 123 women) healthy social drinkers between 21 and 35 years of age. They were randomly assigned to either an alcohol or a placebo group. Aggression was measured using a modified version of the Taylor Aggression Paradigm, in which electric shocks are received from and administered to a fictitious opponent during a supposed competitive interpersonal task. Aggression was operationalized as the intensity and duration of shocks that subjects administered to their "opponent." RESULTS: Provocation was a stronger elicitor of aggression than either gender or alcohol. Overall, alcohol increased aggression for men but not for women. CONCLUSIONS: In conjunction with other laboratory investigations on alcohol-related aggression, this study suggests that alcohol increases aggression for men but not for women. This finding may be due to gender-related differences in liability thresholds for aggression as well as discrepancies in how men and women respond to different forms of provocation.     

Effects of acute tiagabine administration on aggressive responses of adult male parolees

Experimental and clinical studies have supported a relationship between gamma-aminobutyric acid (GABA) and aggressive behavior in non-humans and humans. Tiagabine is a GABA uptake inhibitor that has been shown to produce acute behavioral effects in animals. In addition, tiagabine has been shown to decrease aggression in agitated patients when administered chronically. The present study was designed to investigate the effects of acute administration of tiagabine on aggressive responding on a laboratory task in adult humans. Ten adult males participated in experimental sessions on the Point Subtraction Aggression Paradigm (PSAP), which provided subjects with aggressive, escape, and monetary-reinforced response options. All subjects received four acute oral doses of Tiagabine (4, 8, 12 and 16 mg) separated by placebo sessions. Tiagabine decreased aggression at doses that either did not affect, or affected to a lesser extent, monetary-reinforced responding. The results are consistent with some prior research using the PSAP showing a possible unique role for GABA in the regulation of human aggression. A possible behavioral mechanism for the rate-decreasing effects on aggressive responding produced in the present study is that tiagabine may modify aggressive responding by suppressing reactions to aversive stimuli.     

Acute effects of D-fenfluramine on simultaneous measures of aggressive escape and impulsive responses of adult males with and without a history of conduct disorder

RATIONALE: The role of serotonin in human aggression was evaluated by administering D-fenfluramine and comparing the effects on laboratory measures of aggression, escape and impulsivity among subjects with and without a history of conduct disorder. METHODS: Ten male subjects with a history of criminal behavior participated in experimental sessions that measured aggressive and impulsive responses. Five subjects had a history of childhood conduct disorder (CD+) and five control subjects did not. Aggression was measured using the Point Subtraction Aggression Paradigm (PSAP), which provides subjects with an aggressive, escape and monetary reinforced response options. Impulsive responses were measured using a paradigm that gives subjects choices between small rewards after short delays versus larger rewards after long delays. RESULTS: Acute doses (0.1, 0.2 and 0.4 mg/kg) of D-fenfluramine produced significant decreases in aggressive responses in CD+ subjects and large decreases in escape responses for CD+ subjects and smaller decreases for control subjects. Impulsive responses were decreased slightly and monetary reinforced responses were not changed in either group. Decreases in aggressive responses were not selective, since escape responses were also decreased, but such effects could not be attributed to a non-specific sedative action because monetary reinforced responses were increased and reaction times were decreased, indicative of central nervous system stimulation. CONCLUSIONS: Release of serotonin by D-fenfluramine is the possible mechanism for reductions in aggressive responses. These results are consistent with a large body of data linking reduced serotonin function and aggressive behavior.     

Tryptophan depletion and aggressive responding in healthy males

In order to study the effect of decreasing plasma tryptophan levels on aggressive responding in a controlled laboratory setting, we administered two doses (25 g and 100 g) of a tryptophan-free amino acid mixture to ten healthy male subjects after 24 h of a low tryptophan diet. Subjects were screened for current or past psychiatric, or non-psychiatric medical illness. Aggressive responding on a free-operant laboratory measure of aggression (the Point Subtraction Aggression Paradigm) and plasma tryptophan levels were measured before and after drinking the amino acid mixture. There was a significant increase in aggressive responding 5 h after the 100 g mixture and a significant increase in aggressive responding 6 h after the 25 g mixture compared to a baseline day when no drink was administered. There was also a significant decrease in plasma tryptophan at 5 hours after ingestion compared to baseline for both doses of amino acid mixture. This study supports the hypothesis that tryptophan depletion increases aggressive responding in healthy males in a laboratory setting; probably by decreasing brain serotonin.     

Testosterone, 5 alpha-dihydrotestosterone and cortisol in men with and without alcohol-related aggression

OBJECTIVE: The present investigation was designed to study steroid hormones, alcohol and aggression interactions in men with a history of alcohol-related aggression (AGG+) and in a cross-sectional control population (AGG-). METHOD: AGG+ (n = 40) and AGG- (n = 44) male volunteers completed the Buss-Perry Aggression Questionnaire and the revised Michigan Alcoholism Screening Test (MAST), after which plasma-free and total testosterone, 5alpha-dihydrotestosterone (DHT) and cortisol were determined. RESULTS: The AGG+ men displayed significantly (p < .05) higher aggression and MAST measures compared with the AGG- men; however, no significant group differences were observed regarding the hormone values. Independently of the steroid hormones, MAST correlated positively with the hostility subscale in both AGG- and AGG+ groups. Free and total testosterone correlated positively with anger and DHT correlated positively with verbal aggression and anger, whereas cortisol correlated negatively with physical aggression and anger in the AGG- group. No significant correlations between steroid hormones and aggression parameters were observed in the AGG+ group. The age factor explained part of the MAST and steroid hormone correlations with aggression. A hormone and MAST independent moderation effect of age upon aggression was also found. CONCLUSIONS: The present study demonstrates an association between alcohol drinking and self-reported sober-state aggression, which implies that the etiology of alcohol misuse and aggressive behavior may involve common biological and/or social factors. These mechanisms, as well as age, androgens and cortisol, all represent factors that, in combination, regulate human aggression.     

Impulsiveness and the prolactin response to d-fenfluramine

Rationale: A number of studies have reported abnormalities of serotonin function in aggressive and impulsive behaviours in psychiatric and forensic populations. It is unknown whether this is because serotonin function plays a part in determining the dimension of trait impulsiveness in the general population or whether this is restricted to these behaviourally extreme groups. Method: The prolactin response to d-fenfluramine was measured in subjects scoring high and low on a scale of impulsiveness selected from a panel of healthy volunteers screened for impulsiveness. Measures included the I7 impulsiveness scale, State Trait Anger Expression Inventory (STAngXI) and the Tridimensional Personality Questionnaire (TPQ). Plasma cortisol was also determined along with fenfluramine and its metabolite norfenfluramine. Results: The high impulsive group had reduced AUC (PRL) compared with the low impulsive group; this remained significant after adjusting for baseline prolactin, cortisol and drug levels. There was no significant association between impulsiveness, the harm avoidance subscale of the TPQ or trait anger (STAngXI) and prolactin rise. Repeated serum prolactin measures were not significantly different between the two groups. Conclusions: This study provides some support to the hypothesis that reduced serotonin function contributes to high trait impulsiveness and is not restricted to behaviourally extreme populations. Received: 12 July 1999 / Final version: 2 November 1999     

Long-term citalopram maintenance in mice: selective reduction of alcohol-heightened aggression

Background Selective serotonin reuptake inhibitors (SSRIs) alleviate many affective disturbances in human clinical populations and are used in animal models to study the influence of serotonin (5-HT) on aggressive behavior and impulsivity. Objective We hypothesized that long-term SSRI treatment may reduce aggressive behavior escalated by alcohol consumption in mice. Therefore, aggression was tested in male CFW mice to determine whether repeated citalopram (CIT) administration reduces alcohol-heightened aggression. Materials and methods Resident male mice self-administered alcohol by performing an operant response on a panel placed in their home cage that delivered a 6% alcohol solution. Mice repeatedly confronted an intruder 15 min after self-administration of either 1 g/kg alcohol (EtOH) or water (H₂O). Aggressive behaviors were higher in most mice when tests occurred after EtOH intake relative to H₂O. Once baseline aggression was established, animals were injected (i.p.) twice daily with 10 mg/kg CIT or saline (SAL) for 32 days. Every 4 days throughout the CIT treatment period, aggressive encounters occurred 6 h after CIT injections, with testing conditions alternating between EtOH and H₂O intake. Results Aggression was only modestly affected by CIT in the first 2 weeks of treatment. However, by day 17 of CIT treatment, alcohol-heightened aggressive behavior was abolished, while baseline aggression remained stable. These data lend support for the role of the 5-HT transporter in the control of alcohol-related aggressive behavior, and the time course of effects suggests that a change in density of 5HT_1A autoreceptors is necessary before antidepressant drugs produce beneficial outcomes.     

Cognition, emotion, and the alcohol--aggression relationship: comment on Giancola (2000)

P. R. Giancola's (2000) thesis that the alcohol-aggression relationship can be explained by alcohol-induced disruption of executive cognitive functions mediated by the prefrontal cortex is critically examined. At moderate doses, alcohol has been reported to increase aggression in animals as diverse as fish, rats, cats, monkeys, and humans. Although alcohol depresses prefrontal cortex activity and disrupts executive cognitive performance in humans, alcohol's anxiolytic actions, and its disinhibiting effects on subcortical structures implicated in anger and aggression, may be at least as important as the higher cognitive functions cited by Giancola in accounting for the alcohol-aggression relationship. Other drugs that alter prefrontal cortex activity have also been reported to influence aggressive responding in humans and other animals, and implications of this are briefly discussed.     

精神分裂症患者攻击行为与5-HTTLPR多态性的关联研究

目的 探讨精神分裂症患者的攻击行为与5-HTTLPR多态性的相关性.方法 采用〈修订版外显攻击行为量表〉（MOAS）对符合美国〈精神障碍统计与诊断手册第4版〉（DSM-Ⅳ）的精神分裂症患者进行评定,99例MOAS加权总分≥4分者为有攻击行为组（攻击组）,96例MOAS加权总分0分者为无攻击行为组（非攻击组）.应用聚合酶链式反应-限制性片段长度多态性（PCR-RFLP）技术检测受试者的5-HTTLPR多态性.结果 攻击组的基因型分别为SS 38例、SL 44例、LL17例,等位基因频率分布分别为S 120例、L 78例;非攻击组间的基因型分别为SS40例、SL 39例、LL 17例,等位基因频率分布分别为S 119例、L73例,两组比较差异无显著性（P＞0.05）.按性别分层后分析,两组间的基因型和基因频率分布差异亦无显著性（P＞0.05）.结论 未见5-HTTLPR多态性与精神分裂症患者的攻击行为存在关联.     

Individual differences in aggressive responding to intravenous flumazenil administration in adult male parolees

Nonhuman and human studies have shown that benzodiazepine (BZD) receptor agonists can modify aggressive behaviour. However, it is unknown whether flumazenil, a BZD receptor antagonist, enhances or inhibits aggressive behaviour.The present study was designed to investigate the effects of acute administrations of flumazenil on aggressive responding in adult humans.Six adult males with histories of childhood conduct disorder (DSM IV R) participated in experimental sessions. Aggression was measured using the Point Subtraction Aggression Paradigm (PSAP; Cherek 1992), which provided subjects with aggressive and monetary-reinforced response options.Acute doses of flumazenil (2 and 3mg) did not produce statistically significant changes in either monetary-reinforced responding or aggressive responding. The analysis of individual subjects data revealed that aggressive responses varied across subjects.The results are discussed in terms of individual differences based on the previous history of BZD abuse. Additional laboratory research is needed to better clarify the behavioural mechanisms by which BZD receptor antagonists modify human aggressive responding.     

Effects of alcohol and trait anger on physical aggression in men

OBJECTIVE: According to recent theoretical models, the alcohol-aggression link is predicated on the interaction among many variables, including the drinker's personality. The few studies that investigated effects of personal dispositions on alcohol-related aggression have been inconclusive, possibly because the role of dispositions related to affect were largely ignored. As such, the purpose of this study was to investigate the interactive effect of alcohol and trait anger on physical aggression. METHOD: Participants were 136 male social drinkers who reported high, moderate, and low levels of trait anger and were nonrandomly assigned to an "alcohol" or "no-alcohol" control beverage group. Participants competed in an aggression paradigm in which electric shocks were received from and administered at will to a fictitious opponent during a competitive task. Shock intensity, duration, and proportion of highest shock served as indexes of aggression. RESULTS: Intoxicated participants with moderate trait anger selected higher shock intensity and had a greater proportion of highest shock, compared with their sober counterparts. Within the alcohol group, high- and moderate-anger participants were more aggressive than low-anger participants. Intoxicated participants selected longer shock durations following both low and high provocation, and they evinced a greater increase in shock duration from low to high provocation than their sober counterparts. Independent of beverage group, men who reported a high or moderate level of trait anger displayed more aggression on all measures, compared with those who reported low anger disposition. CONCLUSIONS: The present findings suggest that individuals who report low levels of trait anger may be more resistant to the potentiating effects of alcohol on aggression and that the effects of alcohol on aggression may be most pronounced in men who have a moderate level of trait anger. Furthermore, independent of intoxication, trait anger appears to be a risk factor for physical aggression in men.     

The effects of a cumulative alcohol dosing procedure on laboratory aggression in women and men.

OBJECTIVE: This study directly compared the effects of cumulative alcohol dosing procedure on aggression in both women and men. METHOD: Thirteen women and 13 men consumed three beverages 1 hour apart. There were two experimental conditions: (1) a placebo day, when subjects consumed three 240 ml beverages, each containing only 1 ml of alcohol; and (2) an alcohol day, when subjects consumed three 240 ml beverages, each containing 0.35 g/kg of 95% alcohol. Alcohol doses for women were reduced by 8%. Prior to beverage consumption, and periodically after consumption, subjects participated in 25-minute laboratory testing sessions designed to measure aggression. In this paradigm, subjects could earn points by responding on a button, or aggress toward a fictitious opponent who ostensibly subtracted earnings from them. RESULTS: Both women and men showed an increase in aggressive responding after drinking alcohol but not placebo. As a group the greatest increases were observed after consuming the second alcohol drink (BAC = 0.08%). Aggressive responding, however, remained elevated for several hours after alcohol consumption. A post hoc analysis of the data indicated that subjects with high aggression levels under placebo conditions showed the greatest increases in aggression under alcohol conditions. CONCLUSIONS: These results indicate that at least under these conditions, alcohol does increase aggression in both women and men. The aggression-increasing effects of alcohol appear to be long-lasting and specific to individuals with the higher aggressive tendencies while sober.     

Female alcohol consumption,motivations for aggression and aggressive incidents in licensed premises

Research into the relationship between alcohol and aggression has previously focused on men. However, in recent years there has been an increase in binge drinking and violent crime among women, behaviours which have been labelled ‘ladette’ culture in the UK. The current study advances the literature in this area by investigating the relationship between alcohol consumption and aggressive behaviour of females in licensed premises, including the type of aggression and motivations for aggressive incidents. Ninety-three female university students completed the Student Alcohol Questionnaire (SAQ; Engs, 2002), the Aggression Questionnaire (Buss & Perry, 1992) and a questionnaire developed to measure self-reported aggressive incidents. Females who had been involved in an aggressive incident reported spending more time on average in licensed premises per week and higher levels of aggression as well as consuming significantly more alcohol on the day of the incident than females who had not been involved in an aggressive incident. Contrary to expectations, however, those who had been involved in an aggressive incident did not report drinking more beer (a male-orientated drink) than those who had not. Verbally aggressive incidents were reported more than physically aggressive incidents, and aggression was commonly motivated by an emotional reaction or to address a grievance. The finding that average alcohol consumption per week was significantly associated with female aggression in licensed premises highlights the importance of developing interventions to reduce alcohol consumption among young females.     

Effects of smoking different doses of nicotine on human aggressive behavior

A new methodology was employed to study the effects of drugs on human aggressive behavior in a laboratory situation. The effects of not smoking, smoking a low nicotine dose (0.42 mg/cigarette), and smoking a high nicotine dose (2.19 mg/cigarette) on human nonaggressive and aggressive responding was determined. A nonaggressive response, which resulted in the accumulation of money, was continuously available to the subject. Two different aggressive responses were also available: the ostensible subtraction of money from, and the ostensible presentation of a 1-s blast of white noise to a (fictitious) person. Aggressive responding was elicited by subtracting money from the research subjects, which was attributed to a fictitious person paired with the research subject randomly each day. Nicotine, administered with experimental cigarettes, produced dose-dependent decreases in both types of aggressive responding elicited by low or high frequency subtractions of money attributed to another person. Generally, the more aggressive response option, i.e., subtraction of money from another person, decreased more following nicotine administration. Smoking the same doses of nicotine increased nonaggressive monetary reinforced responding. This indicates that the suppressant effect of nicotine on aggressive responding was not due to a nonspecific depressant action.Portions of these data have been previously reported at a regional meeting of the International Society for Research on Aggression held in Boston, MA, in August, 1981.     

Effect of citalopram treatment on relationship between platelet serotonin functions and the Karolinska scales of personality in panic patients

Using the Karolinska Scales of Personality (KSP), we investigated the effect of the selective serotonin reuptake inhibitor citalopram on personality traits and the relationship between personality traits and peripheral indexes for central serotonergic function in patients with panic disorder at baseline and after 6 months of treatment. The degree of anxiety and depression was assessed using the Beck Anxiety Inventory, the Beck Depression Inventory, the Clinical Anxiety Scale, and the Montgomery Asberg Depression Rating Scale. A reduction in anxiety and depression scores of 75% was observed after treatment in two thirds of the patients. Mean changes of 12% in the direction of normalization were observed in all KSP anxiety-related items (Somatic Anxiety, Muscular Tension, Psychic Anxiety, and Psychasthenia), the aggression and hostility related items (Inhibition of Aggression, Irritability, and Guilt) and the item of Socialisation. A positive correlation was found between Vmax for the platelet [14C]-serotonin uptake and Inhibition of Aggression before treatment, and a negative correlation was found between the affinity of serotonin uptake and Inhibition of Aggression after treatment. Negative childhood experiences influenced enhanced scores on some KSP items but not the serotonergic function. In panic patients treated with citalopram, effects were seen on personality traits, confirming an association between serotonergic activity and aggression.     

"Yes, I Do But Not With You"-Qualitative Analyses of Sexual/Romantic Overture-related Aggression in Bars and Clubs

Assaultive and aggressive behaviors related to sexual overtures are common in commercial drinking establishments (bars, pubs and clubs). In this paper, we examined the thematic content of 251 incidents of verbal and physical aggression related to sexual/romantic overtures documented by researcher-observers in a study of Toronto bar and clubs. Aggression was examined as it emerged in the following stages of the social interaction process: (a) sexual/romantic overtures that began aggressively; (b) initiators of sexual/romantic overtures who became aggressive later in the social interaction process; (c) aggression by targets of overtures; and (d) aggression by third parties. From these thematic analyses, we identify the distinctions between predatory and genuine overtures and explore the potential role of the effects of alcohol.In these social overtures, aggression occurred as part of the initial overture, during the interaction following the overture (i.e., aggression by the person who made the initial overture, by the target or third parties) and in response to rejection by the target. Targets of overtures responded aggressively to perceived inappropriate overtures; third parties played important aggressive and nonaggressive roles; and alcohol intoxication was identified as contributing to aggression in a number of ways. The theoretical significance and practical implications for prevention of the findings are discussed.     

Alcohol-related aggression in men and women: the influence of dispositional aggressivity

OBJECTIVE: The purpose of this study was to investigate the influence of dispositional aggressivity on the alcohol-aggression relation in men and women. METHOD: Subjects were 204 healthy social drinkers (111 men) between 21 and 35 years of age. Dispositional aggressivity was measured using the Buss-Perry Aggression Questionnaire. Following the consumption of either an alcohol or placebo beverage, subjects were tested on a modified version of the Taylor Aggression Paradigm, in which electric shocks are received from and administered to a fictitious opponent during a competitive task. Aggression was operationalized as the shock intensities administered to the fictitious opponent under conditions of low and high provocation. RESULTS: Of all the variables, provocation was the strongest elicitor of aggression. Overall, persons with high dispositional aggressivity exhibited more aggression than did those with low dispositional aggressivity. Alcohol increased aggression for persons with high, but not for those with low, dispositional aggressivity. This effect was stronger under conditions of low provocation. Furthermore, men and women with low dispositional aggressivity did not differ in aggression. Men with high dispositional aggressivity, however, were more aggressive than their female counterparts. CONCLUSIONS: This is the first investigation to examine the influence of dispositional aggressivity on the alcohol-aggression relation in men and women. The results highlight the fact that alcohol consumption does not increase aggression in all persons and in all situations. An important goal for future research is to identify which individual difference and contextual factors are most important in determining who will, and will not, behave in an aggressive manner when intoxicated.