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

Abstract

(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 gamma-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-HT(1B) 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 D(2) 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 GABA(A) 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.

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

“…Curran and her colleagues have found that these effects are manifested not only by enhanced sociality while under the influence of the drug, but also by decreased aggressiveness (Curran et al, 2004;Verheyden et al, 2002). However, the same studies showed that aggressive mood was elevated during the mid-week period following a weekend of Ecstasy use, a phenomenon that could be related to MDMA-induced depletion of 5-HT (Krakowski, 2003;Miczek et al, 2002). In accordance with the human literature, rats given relatively low doses of MDMA showed increased social interaction and decreased aggressive behavior while the drug is still 'on board' (Morley and McGregor, 2000), whereas 5-HT-depleting doses of MDMA produced later increases in aggressiveness in the social interaction test (Ando et al, 2006), though not in the resident-intruder paradigm (Kirilly et al, 2005).…”

Exploring the Association Between Anxiety and Conduct Problems in a Large Sample of Twins Aged 2–4

“…Although this study was not designed to identify genes common to anxiety and conduct problems, those involved in dopaminergic or serotonergic function are regarded as strong candidates for the association between internalizing and externalizing problems. For example, some studies associate low levels of plasma dopamine-β-hydroxylase with undersocialised conduct disorder (Bowden, Deutsch, & Swanson, 1988;Rogeness, Hernandez, Macedo, & Mitchell, 1982); and neural circuits involving dopamine are considered important in both animal and human aggression (Miczek, Fish, de Bold, & de Almeida, 2002). Furthermore, dopaminergically mediated striatal circuits are postulated to be important in social anxiety disorder (Stein, Westenberg, & Liebowitz, 2002).…”

Neural and Behavioral Correlates of Alcohol-Induced Aggression Under Provocation

“…Moreover, alcohol might exert its effects on aggression by increasing dopamine levels in the ventral striatum (Dichiara and Imperato, 1986;Boileau et al, 2003;Heinz et al, 2011), a potential neural mechanism underlying experimentally induced aggression in animals (Miczek et al, 2002;Ferrari et al, 2003;Nelson and Trainor, 2007) and humans (Krämer et al, 2011;Beyer et al, 2014). Using fMRI, alcohol-induced increased dopamine levels might be reflected by increased activation of the ventral striatum in humans (cf, Gilman et al, 2008).…”