Rosa Maria Martins de Almeida

Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and γ-aminobutyric acid systems

Abstract Background and rationale. Aggressive outbursts that result in harm and injury present a major problem for the public health and criminal justice systems, but there are no adequate treatment options. Obstacles at the level of social policy, institutional regulation, and scientific strategy in developing animal models continue to impede the development of specific anti-aggressive agents for emergency and long-term treatments. Objective. To be more relevant to the clinical situation, preclinical aggression research has begun to focus on the neurobiological determinants of escalated aggressive behavior that exceeds species-typical patterns. It is the goal of this review to examine novel pharmacological and molecular tools that target the neural mechanisms for different kinds of aggressive behavior more selectively than previously possible and to outline potential pharmacotherapeutic options. Results and conclusions. (1) The preclinical focus on the behavioral characteristics and determinants of intense aggression promises to be most relevant to the clinical distinction between the proposed impulsive-reactive-hostile-affective subtypes of human aggression and the controlled-proactive-instrumental-predatory subtypes of aggression. The neural circuits for many types of human and animal aggression critically involve serotonin, dopamine and γ-aminobutyric acid (GABA) and specific receptor subtypes. (2) The dynamic changes in frontal cortical serotonin that are triggered by engaging in aggressive behavior imply that serotonergic drug effects are largely determined by the functional state of the receptors at the time of drug treatment. Of the numerous 5-HT receptors currently identified, the 5-HT1B receptors offer a promising target for reducing impulsive aggressive behavior, particularly if the action can be limited to sites in the central nervous system. (3) Aggressive confrontations are salient stressors, both for the aggressor as well as the victim of aggression, that are accompanied by activation of the mesocorticolimbic but not the striatal dopamine system. Dopaminergic manipulations, particularly targeting the D2 receptor family, can influence aggressive behavior in animals and human patients, suggesting that mesocorticolimbic dopamine may have important enabling or permissive functions. (4) GABA is critical in the neurochemical control of aggressive behavior as evidenced by studies that directly modify GABAergic neurotransmission and neurochemical studies that correlate GABA measurements with aggressive behavioral responses in several animal species. The GABAA receptor complex is a mechanism through which certain benzodiazepines and alcohol enhance and inhibit aggressive behaviors. Social and pharmacological experiences decisively determine the effects of GABAergic positive modulators on aggression.

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.

Brain serotonin receptors and transporters: initiation vs. termination of escalated aggression

RationaleRecent findings have shown a complexly regulated 5-HT system as it is linked to different kinds of aggression.ObjectiveWe focus on (1) phasic and tonic changes of 5-HT and (2) state and trait of aggression, and emphasize the different receptor subtypes, their role in specific brain regions, feed-back regulation and modulation by other amines, acids and peptides.ResultsNew pharmacological tools differentiate the first three 5-HT receptor families and their modulation by GABA, glutamate and CRF. Activation of 5-HT1A, 5-HT1B and 5-HT2A/2C receptors in mesocorticolimbic areas, reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT1A and 5-HT1B receptors in the medial prefrontal cortex or septal area can increase aggressive behavior under specific conditions. Activation of serotonin transporters reduce mainly pathological aggression. Genetic analyses of aggressive individuals have identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g., Neuropeptide Y, αCaMKII, NOS, BDNF). Dysfunction in genes for MAOA escalates pathological aggression in rodents and humans, particularly in interaction with specific experiences.ConclusionsFeedback to autoreceptors of the 5-HT1 family and modulation via heteroreceptors are important in the expression of aggressive behavior. Tonic increase of the 5-HT2 family expression may cause escalated aggression, whereas the phasic increase of 5-HT2 receptors inhibits aggressive behaviors. Polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT modulate aggression, often requiring interaction with the rearing environment.

Escalated Aggressive Behavior: New Pharmacotherapeutic Approaches and Opportunities

Abstract: Psychopharmacologic studies of aggressive behavior in animals under controlled laboratory conditions have been instrumental in developing and evaluating specific and effective novel drug treatments that reduce aggressive behavior. An initial contribution of this research is to create experimental conditions that enable the display of aggressive and defensive acts and postures in species that engage in either dominance or territorial or maternal aggression. Quantitative ethological analyses allow the precise delineation of the sequential organization of aggressive bursts, providing a benchmark for assessing excessive or pathological forms of aggressive behavior. A second contribution of preclinical research is the development of experimental models of escalated forms of aggressive behavior, such as focusing on genetic predispositions or social provocations and frustrative experiences. A critical role of preclinical research is in the pharmacological and neurochemical analysis of aggressive behavior; for example, a host of undesirable side effects prompted a shift from classic dopaminergic neuroleptic compounds to the more recently developed atypical neuroleptics with effective and more specific anti‐aggressive effects. The long‐established role of brain serotonin in impulsive and escalated forms of aggressive behavior continues to be a focus of preclinical studies. New evidence differentiates dynamic state changes in corticolimbic serotonergic neurons during the termination of aggressive behavior from the deficient‐serotonin trait in violence‐prone individuals. It can be anticipated that currently developed tools for targeting the genes that code for specific subtypes of serotonin receptors will offer new therapeutic options for reducing aggressive behavior, and the 5‐HT1B receptor appears to be a promising target. The modulation of GABA and GABAA receptors by 5‐HT in corticolimbic neurons promises to be particularly relevant for specific forms of escalated aggressive behavior such as alcohol‐heightened aggression.

8-OH-DPAT in the median raphe nucleus decreases while in the medial septal area it may increase anxiety in female rats

The experiment evaluated the effects of 8-OH-DPAT on the activity of virgin female rats (diestrus) in the elevated plus maze. The 5-HT1A receptor agonist was infused into the median raphe nucleus (N = 60) and medial septal area (N = 68) 10 min before the test. Five groups for each brain area were analyzed: intact, saline (0.2 microl) and 8-OH-DPAT (0.2; 0.5 and 2.0 microg rat(-1)). The following measures were recorded: number of entries onto open and enclosed arms and time spent on the open and enclosed arms. In addition, the frequency of stretch-attend and head-dipping were also evaluated. The results showed that in the median raphe nucleus only the highest dose of 8-OH-DPAT (2.0 microg) increased the percentage of time spent on the open arms. On the other hand, in medial septal area 8-OH-DPAT in the dose of 0.5 microg decreased the percentage of time spent on the open arms, while the doses of 0.2 and 2.0 microg had no significant impact on anxiety. Data suggest that 8-OH-DPAT acting on 5-HT1A somatodendritic autoreceptors decreases anxiety. However, at a specific dosage and acting on postsynaptic receptors of the medial septal area, 8-OH-DPAT can increase anxiety.

Effects of intracerebroventricular administration of 5-HT receptor agonists on the maternal aggression of rats

This study attempted to analyze the effects of 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), TFMPP (1-(3-trifluoromethyl-phenyl)piperazine hydrochloride), and DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) on maternal aggressive behavior. Female Wistar rats were divided into 4 groups of 12 animals each. They received an intracerebroventricular (i.c.v.) injection of: (1) saline, (2) 8-OH-DPAT (20 micrograms/rat), (3) TFMPP (100 micrograms/rat), and (4) DOI (100 micrograms/rat). 5-HT1A (8-OH-DPAT) and 5-HT2 (DOI) receptor agonists decreased the frequency of attack 15 but not 55 min after i.c.v. injection. The 5-HT1B/D receptor agonist (TFMPP), in the dose studied, showed no significant difference as compared to saline. Pup care and non-aggressive social interaction with the intruder were not affected by any drug. These data suggest that 5-HT1A and 5-HT2 receptor agonists can specifically inhibit maternal aggression without affecting maternal care; however, this effect is of short duration.

Dependência de Álcool, Cocaína e Crack e Transtornos Psiquiátricos

This study investigated the frequency of psychiatric disorders in two groups of drug users, cocaine/crack and alcohol/cocaine/crack, by means of the Mini International Neuropsychiatric Interview (M.I.N.I Plus). The participants, 32 men, had an average age of 27.65 (SD=7.38) years. Most of them had not completed Fundamental School (34.37%), were single (81.25 %) and reported a family history of alcohol consumption (76.5% - cocaine/crack; 53.3% - alcohol/ cocaine/crack). On average, the time of abstinence was 33.05 (SD=19.52) days. The results showed a high frequency of Mood Disorders in both groups. Although the difference was not statistically significant, the alcohol/cocaine/crack group presented, additionally, high frequency of Personality Disorder, suggesting the need of a distinct treatment for that population.

Historical Development and Methodological Foundations of Cognitive Neuropsychology

The cognitive neuropsychology is presented in its historical development and main methodological changes. The ontological debates are distinguished on the relations between mind and brain in the history of psychology. The appearance of neuropsychology is described as a result of the studies concerning the relations between aphasia and cerebral injuries. The research in cognition, a strong movement in psychology in the last four decades, is recognized as a contribution to the understanding of human mental operations. Such developments strengthened the relations between brain and mind. The main methodological proposals in cognitive neuropsychology are discussed with special emphasis for the following aspects: debate between case and groups studies; dissociations between cognitive tasks; and advances and limitations of the neuroimaging techniques. Finally, the historical process of scientific and professional organization of the area is described.

Behavioural, hormonal and neurobiological mechanisms of aggressive behaviour in human and nonhuman primates

Aggression is a key component for social behaviour and can have an adaptive value or deleterious consequences. Here, we review the role of sex-related differences in aggressive behaviour in both human and nonhuman primates. First, we address aggression in primates, which varies deeply between species, both in intensity and in display, ranging from animals that are very aggressive, such as chimpanzees, to the nonaggressive bonobos. Aggression also influences the hierarchical structure of gorillas and chimpanzees, and is used as the main tool for dealing with other groups. With regard to human aggression, it can be considered a relevant adaptation for survival or can have negative impacts on social interaction for both sexes. Gender plays a critical role in aggressive and competitive behaviours, which are determined by a cascade of physiological changes, including GABAergic and serotonergic systems, and sex neurosteroids. The understanding of the neurobiological bases and behavioural determinants of different types of aggression is fundamental for minimising these negative impacts.

On the dual nature of maternal aggression in rats

Presentation of a natural predator, a cat, was used to differentiate elements of maternal attack by female rats on a male intruder. Following exposure (without direct physical contact) of post-partum females to a cat or to a toy stuffed cat (control group), the females were replaced in their home cages and presented with a male intruder rat. Cat exposure reliably decreased lateral attack to the intruder, as well as locomotion, but had no effect on either jump attack or an upright defensive posture (boxing). Since predator exposure produces a somewhat durable increase in defense, along with inhibition of nondefensive behavior, these results suggest that maternal aggression represents a mixture of offensive, usually related to competition, and defensive (protective) behaviors. The results indicate that maternal aggression, as a parental care behavior, appears to be at least partially resistant to fear.