Interaction of nitric oxide and serotonin in aggressive behavior

Abstract

Nitric oxide (NO) modulates many behavioral and neuroendocrine responses. Genetic or pharmacological inhibition of the synthetic enzyme that produces NO in neurons evokes elevated and sustained aggression in male mice. Recently, the excessive aggressive and impulsive traits of neuronal NO synthase knockout (nNOS Ϫ/Ϫ ) mice were shown to be caused by reductions in serotonin (5-HT) turnover and deficient 5-HT 1A and 5-HT 1B receptor function in brain regions regulating emotion. The consistently high levels of aggression observed in nNOS Ϫ/Ϫ mice could be reversed by 5-HT precursors and by treatment with specific 5-HT 1A and 5-HT 1B receptor agonists. The expression of the aggressive phenotype of nNOS Ϫ/Ϫ knockout mice requires isolated housing prior to testing. The effects of social factors such as housing condition and maternal care can affect 5-HT and aggression, but the interaction among extrinsic factors, 5-HT, NO, and aggression remains unspecified. Taken together, NO appears to play an important role in normal brain 5-HT function and may have significant implications for the treatment of psychiatric disorders characterized by aggressive and impulsive behaviors.

Evidence for the Contribution of NOS1 Gene Polymorphism (rs3782206) to Prefrontal Function in Schizophrenia Patients and Healthy Controls

“…First, we found significant associations between rs3782206 and working memory and attentional control, both of which have been associated with some symptoms of schizophrenia, such as distractibility, loosening of associations, disorganization, anger, aggression, and other socially inappropriate behaviors (Braver et al, 1999). In the previous animal studies, NOS1 gene knockout mice have showed very high levels of impulsive and aggressive behaviors (Chiavegatto et al, 2001;Chiavegatto and Nelson, 2003;Nelson et al, 2006). In the previous human studies, Reif et al (2009) found an association between a VNTR in the promoter region and many disorders characterized by impulsivity, such as attention deficit hyperactivity disorder, SCZ, and suicide attempt.…”

Increased Plasma Nitric Oxide Metabolites in Suicide Attempters

“…Some animal studies reported that aggressive behavior was diminished in endothelial NO synthase-defi cient mice [23] , whereas it was increased in neuronal NO synthase-defi cient mice [23,24] . 5-HT, a key neurotransmitter system in aggression and impulsivity, has accounted for the relationship between aggressive behavior and NO synthase isoforms [25] . Moreover, mice lacking endothelial NO synthase showed enhanced 5-HT turnover in the frontal cortex and ventral striatum and increased 5-HT metabolite in the cerebellum [26] .…”

Changes in attack behavior and activity in EphA5 knockout mice

“…Accumulated evidence has suggested an inverse relationship between serotonin level in cerebrospinal fluid (CSF) and brain with impulsivity, or escalated aggression, and suicide (Lee and Coccaro, 2001;van Praag, 1998). In rodents, some studies have shown a similar relationship with decreased serotonin and 5-HIAA levels associated with increased offensive aggression (Chiavegatto et al, 2001;Chiavegatto and Nelson, 2003;Ferrari et al, 2005;van der Vegt et al, 2003).…”

“…This type of offensive aggression can also be modulated by serotonin activity and drugs (Chiavegatto et al, 2001;Fish et al, 1999;Lyons et al, 1999;Miczek et al, 1998). Genetic manipulations that target serotonin-related genes, and on genes that affect serotonin receptor numbers also can change this form of aggression in rodents (Chiavegatto et al, 2001;Chiavegatto and Nelson, 2003;Dulawa et al, 2000;Fischer et al, 2000;Liu et al, 2007;Nelson et al, 2006;Saudou et al, 1994;Schiller et al, 2006;Stork et al, 2000;Wersinger et al, 2007). We also assessed defensive aggression by using the target-biting paradigm.…”