Several receptor families and the 5-HT transporter (SERT) have been characterized in terms of their genetic basis and molecular features. Pharmacological and molecular genetics studies have begun to implicate the 5-HT and 5-HT2 receptor families and SERT in different types of aggressive behavior. Agonists of the 5-HT1A and 5-HT1B receptors reduce aggressive behavior; and the antiaggressive effects of the 1B receptor subtype are behaviorally specific and especially, effective in situations that engender escalated levels of aggressive behavior, although these effects remain to be translated to the clinic. Microinjection studies provide evidence that 5-HT1A and 5-HT1B receptor agonists can achieve their antiaggressive effects via action at either somatodendritic auto-receptors in the dorsal raphe nuclei or the presynaptic terminal autoreceptors or the postsynaptic heterorecep-tors (Fig. 2). If, in fact, the decrease in extracellular levels of corticolimbic 5-HT after 5-HT1A and 5-HT1B receptor stimulation constitutes a critical mechanism of action for the antiaggressive effects, a significant revision of the serotonin deficiency hypothesis is required. Genetic deletion studies of 5-HT1A and 5-HT1B receptors generate a more complex pattern of results that appears to be influenced by the genetic background of the mouse or by developmental compensations in mutant mice. Similarly, associations between ► polymorphisms of 5-HT1A and 5-HT1B receptors and aggressive traits in humans remain inconsistent.
Antagonism of 5-HT2A receptors represents the mechanism via which some atypical antipsychotic compounds achieve their calming effects in patients with diagnoses that range from schizophrenia, dementia, depression, and posttraumatic stress disorders (PTSD). Yet, the side-effect profile of these agents highlights the problematic nature of this new class of antipsychotic agents. Preclinical studies of the 5-HT2A and 5-HT2C receptors have to await the development of more selectively acting molecular tools, since at present it is not possible to differentiate between the antiaggressive effects of agonists and antagonists at these receptor subtypes. Similarly, linkage studies between polymorphisms in the 5-HT2A receptor and impulsive-aggressive or antisocial traits require replication.
Blockade of the reuptake mechanism for 5-HT via the SERT reduces aggressive episodes in most patients, especially when given over extended periods. Large meta-analyses have identified the exceptional nature of the occasional reports of increased aggressivity and suicidal tendencies among those treated with selective serotonin reuptake inhibitors (SSRI). Preclinical studies have shown that acute and chronic treatment with SSRIs reduces aggressive behavior in species ranging from invertebrates to primates. Chronic SSRI administration can also restore competent agonistic
Aggression. Fig. 2. Modulation of aggressive behaviors in rodents by microinjections of 5-HT1A, 5-HT1B, and 5-HT2A/2c receptor agonists. Text boxes show that local injections of 5-HT1A receptor (1A), 5-HT1B receptor (IB), or 5-HT2A/2C receptor (2A/2C) agonist increases (|), decreases (J,), or has no effect ("0") on territorial, escalated, maternal, and defensive aggressive behaviors. Serotonergic neurons originate from the raphe nuclei and project to several brain areas.
interactions in placid laboratory strains of rats that do not show intact species-typical aggressive behavior.
The short-length allele in the serotonin-transporter gene-linked polymorphic region (5-HTTLPR) leads to lower SERT expression and lower serotonergic activity relative to those with the long-length allele. Some evidence supports the association of the short allele with increased hostility, impulsivity, and aggressiveness, primarily in males. The contribution of the 5-HTTLPR to the variation in aggressive personality traits is relatively small and appears to depend on epistatic influences and on environmental triggers. Early stressful life experiences in monkeys and humans may increase the probability of escalated aggression toward others and themselves, particularly in those individuals who carry the short-length allele. A more adequate understanding of SERT expression in corticolimbic regions promises to be relevant for the display of aggressive personality traits.
Brain serotonin modulates and is modulated by other amines, amino acids, and also neuropeptides and neuro-steroids. For example, serotonergic projections in specific hypothalamic nuclei may regulate the release and action of vasopressin (VP), a neuropeptide that is associated with high rates of aggressive behavior in several animal species via action at 5-HT1A and 5-HT1B receptors. Similarly, the modulation of serotonergic neurons by corticotrophic releasing factor (CRF) and opioid peptides provides the anatomical basis for functional interactions that appear relevant to aggressive behavior. The promising information on CRF, GABA, and glutamate in amygdaloid connections with hypothalamic and brainstem structures during displays of intense emotion should prompt a detailed examination of these mechanisms in escalated types of aggressive behavior.
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