Gaba

By distinction from glutamate, GABA and particularly, the GABAa receptor complex have been consistently implicated in the neural control of several types of aggressive behavior. Especially positive ► allosteric modulators of the GABAA receptors such as benzodiazepines, barbiturates, ethanol, and progestin-derived neurosteroids can increase aggressive behavior after low acute doses or after tolerance to the sedative doses has developed (Fig. 1). At moderate and higher doses, the antiaggressive effects of these substances are accompanied by sedation and motor impairment. The bidirectional effects of allosteric positive modulators of the GABAA receptors depend not only on the dose, but also on the context and the prior experience with aggressive behavior. When social consequences lower the rate of aggressive behavior, benzodiazepines and etha-nol are more likely to increase its occurrence. In spite of the consistent epidemiological evidence linking alcohol to two thirds of all violent crimes, the neurobiological mechanism of action for these alcohol effects remains elusive. The current challenge is to understand how an individual's prior experiences with aggressive behavior modify the GABAA receptor complex so that proaggressive effects of GABAA positive modulators emerge. The prevalent current hypothesis attributes the divergent effects of GABAA positive modulators on aggressive behavior to differential expression of genes encoding the subunits that form the pentameric GABAA receptor complexes. Emerging data from gene deletion and pharmacological antagonism studies suggest a structural dissociation between the anxiety-attenuating, sedative, and aggression-heightening effects of GABAA receptor positive modulation, primarily due to the differential role of alpha subunits. In addition to the GABAA receptor, the GABAB receptors are widely distributed throughout the neuroaxis. The population of GABAB receptors in the dorsal raphe nucleus modulates serotonin cells, and this may be the mechanism via which GABAB receptor agonists can increase aggressive behavior in mice.

Norepinephrine

Catecholaminergic and serotonergic pathways contain reciprocal anatomical links which provide the basis for extensive functional interactions. Particularly, intense arousal that is associated with salient life events, among them certain types of aggressive behavior on just observing a fight, is based on elevated activity in noradrenergic cell

Aggression. Fig. 1. GABAa positive allosteric modulators and aggression. Biphasic effects of GABAa receptor positive modulators on aggression in rats (fop) and mice (bottom). Low doses of alcohol (filled hexagon), the benzodiazepines diazepam (filled diamonds, rats only) and midazolam (filled circles), and the neurosteroid allopregnanolone (filled triangles, mice only) increase the mean (±SEM, vertical lines) number of attack bites, expressed as a percentage of vehicle control, while higher doses decrease this measure of aggression. Triazolam (filled upward triangles) increases attack bites in rats but not mice. No increase in aggression was seen after treatment with zolpidem, the alphal-preferring agonist (filled downward triangles, mice only). The dotted horizontal line represents the baseline at 100%. (From Miczek et al. 2007.)

bodies in locus coeruleus and cortical noradrenergic terminals. Pharmacological blockade of beta receptors may achieve its calming effects in patients with intensely aggressive, hostile outbursts by reducing noradrenergic hyperac-tivity, although alternatively, beta blockers also act as antagonists at 5-HT1A receptors. Molecular manipulations of the genes encoding for the noradrenergic transporters, or metabolic enzymes such as COMT have so far resulted in inconsistent results with regard to aggressive behavior and traits.

Dopamine

Specific dopamine (DA) pathways and DA receptor subtypes critically contribute to the neurobiological mechanisms of species-typical and escalated, pathological types of aggressive behavior. Anatomical and pharmacological data provide evidence for serotonergic receptors on soma of DA neurons in the VTA and substantia nigra suggesting modulation of ascending DA pathways by 5-HT.

The most widespread option for pharmacotherapeutic management of aggressive individuals relies on antipsy-chotic medication that acts via blockade of dopamine (DA) D2 receptors, although the antiaggressive effects of

► first-generation antipsychotics such as ► haloperidol or ► chlorpromazine are embedded in sedative and motor-incapacitating side effects. At present, the so-called

► atypical antipsychotic drugs with more complex mechanisms appear to be preferred as antiaggressive medication on account of a more favorable side-effect profile. Clearly, there continues to be a need for more satisfactory medication development.

Case studies point to ► amphetamine intoxication as a potentially triggering event for lethal violence. At intermediate doses, amphetamine disrupts many types of social behavior and at lower doses, it may increase aggressive behavior, probably due to its antifatigue and arousing effects. Increased corticolimbic DA can be detected via in vivo measurement and imaging techniques in individuals who react defensively to an aggressive confrontation and who prepare for such an event. Anatomical and temporal analysis with higher resolution may enable a more precise delineation of DA activity in different phases and types of aggressive behavior.

Genetic disruption of the genes that are critically involved in the inactivation of ► catecholamines, COMT, and MAO-A can promote aggressive behavior in male mice. It is tempting to relate these preclinical data to the specific polymorphism in the gene for COMT which is associated with increased aggressive behavior in schizophrenic men.

Was this article helpful?

0 0
Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

Get My Free Ebook


Post a comment