Review
Escalated aggressive behavior: Dopamine, serotonin and GABA

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Abstract

The ethical dilemma in aggression research is how to reconcile two divergent objectives, namely to avoid harm and injury as much as possible and, at the same time, how to study behavioral phenomena that validly represent the essence of the neurobiology of aggression. Clinical and preclinical aggression research focuses on different types of aggression. Preclinical studies are usually stimulated by an ethological approach and focus on the phylogeny, ontogeny, survival value and neural mechanisms of ritualized displays and signals. On the other hand, clinical studies focus on violent individuals and pathologically excessive forms of aggressive behavior.

This review emphasizes research on escalated forms of aggression in animals and humans and their pharmacotherapy. The current experimental models to generate escalated levels of aggressive behavior in laboratory rely on social instigation, frustrative non-reward and alcohol drinking. These types of aggression are modulated by canonical neurotransmitters like dopamine, serotonin (5-HT) and GABA. It continues to be a main goal of much neurobiological research to find potential targets of pharmacological agents that interact with dopaminergic, GABAergic and serotonergic systems and have high efficacy and selectivity to reduce excessive levels of aggressive and violent behaviors without side-effects. While the mesocorticolimbic dopamine system is implicated in the initiation, execution, termination and consequences of aggressive behavior, drugs with a high affinity for dopamine D2 receptors lack specificity for reducing aggressive behavior. Current investigations point to 5-HT1B receptor subtypes as particularly relevant. First, they are differentially expressed in aggression-prone individuals relative to those who are not excessively aggressive. Second, these and also other 5-HT receptor subtypes emerge to be significant targets for anti-aggressive interventions. Positive modulators of GABAA receptors with specific subunit configuration may be relevant for heightening aggression, and these sites may be targets for intervention. A prerequisite for rational pharmacotherapies will be adequate characterization of serotonergic and GABAergic receptor regulation in individuals exhibiting escalated aggression.

Section snippets

Definitions and ethics

In most general terms, aggressive behavior can be considered as a behavior that inflicts harm and injury or threatens to do so (Berkowitz, 1983). One important class of aggressive behavior is characterized by its instrumentality, typically in a reproductive context; males achieve dominance in a social setting by engaging in aggressive displays; in other animal species, males patrol and defend territories in order to secure the resources that attract breeding partners, while females suppress the

Approaches to study aggression

It is ethically not acceptable to recreate clinically relevant types of aggressive behavior in the experimental human laboratory in real time. Most studies use simulations of symbolic and moderate forms of aggression towards a fictitious competitor (Cherek and Steinberg, 1987), neuroimaging of individuals who have displayed in the past high levels of aggressive behavior (Soloff et al., 2005, George et al., 2004). Alternatively, individuals with a criminal history or in drug abusers are studied (

Preclinical aggression research

Early laboratory studies of animal aggression began by inducing intense aggressive and defensive reactions in otherwise placid laboratory animals by brain lesions or electrical brain stimulation, by provoking animals with noxious painful stimuli or housing them in isolation for prolonged periods, or by exposing them to frustrating experiences (e.g., Valzelli, 1973, Yen et al., 1959, Ulrich, 1966, Ulrich and Azrin, 1962, Azrin et al., 1966, Hess and Brugger, 1943, Koolhaas, 1978, Brady and

Types of escalated aggression

In social species, the aggressive behavior can serve an important adaptive function. Nevertheless, when this type of behavior exceeds the species-typical pattern, it becomes maladaptive. Escalated or excessive levels of aggressive behavior can be induced in laboratory animals or humans by (a) pharmacological (alcohol-heightened aggression), (b) environmental (social instigation), (c) behavioral (frustration-induced aggression) means or (d) by genetic selection (de Boer and Koolhaas, 2005—this

Escalated forms of aggression and neurotransmitters

The role of neurotransmitters and their receptors and transport sites in preclinical studies of aggression has guided much of the development of pharmacotherapeutic interventions during the past decades (Miczek et al., 2002). The focus on the canonical aminergic transmitters such as dopamine, norepinephrine and serotonin, while still the basis for current drug treatments of violent individuals, has been complemented by a better understanding of modulatory influences by glutamate and GABA as

Conclusions

From an ethological perspective, the term “violence” is not relevant, since its focus is on adaptive forms of aggressive behavior, which are significant in terms of the individual's survival and reproduction. Animal models of hostile and violent symptoms in psychiatric disorders are necessary in order to be relevant to the study of the neurobiological basis of human violence.

The recent observations point to serotonin receptor subtypes such as the 5-HT1B receptor as particularly important for

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