Brain serotonin dysfunction accounts for aggression in male mice lacking neuronal nitric oxide synthase

Abstract

Genetically engineered mice with targeted disruption of the neuronal nitric oxide synthase (nNOS) gene established the inhibitory role of nitric oxide (NO) in male impulsive aggressive behavior. This was later confirmed by using selective nNOS inhibitors in male wild-type mice. The molecular mechanisms accounting for the aggressive behavior caused by the lack of neuronally derived NO is not known. Recent studies suggest that central serotonergic neuronal circuits and particularly 5-HT1A and 5-HT1B receptors play a prominent role in the regulation of aggression. Accordingly, we investigated whether the aggressiveness caused by the lack of nNOS might be because of alterations in serotonergic function. We now demonstrate that the excessive aggressiveness and impulsiveness of nNOS knockout mice is caused by selective decrements in serotonin (5-HT) turnover and deficient 5-HT1A and 5-HT1B receptor function in brain regions regulating emotion. These results indicate an important role for NO in normal brain 5-HT function and may have significant implications for the treatment of psychiatric disorders characterized by aggressiveness and impulsivity.T he gene encoding neuronal nitric oxide synthase (nNOS) was disrupted and inactivated by homologous recombination to clarify the functional role of nitric oxide (NO) as a messenger molecule in the nervous system (1). Mice lacking the gene for nNOS (nNOS Ϫ/Ϫ ) exhibit a variety of abnormalities including enlargement of the stomach (1), hypertrophied urinary bladders (2), reduced parasympathetic tone (3), and nocturnal motor deficits (4). In addition, male nNOS Ϫ/Ϫ mice display dramatic increases in aggressive and sexual behavior (5). Pharmacological treatment of male wild-type (WT) mice with selective nNOS inhibitor also evokes an increase in impulsive aggressive behavior to the levels displayed by nNOS Ϫ/Ϫ mice (6), indicating that the aggressive behavior is caused by loss of neuronally derived NO and not developmental abnormalities. nNOS is enriched throughout the limbic system (7, 8), an area important in emotional and agonistic behaviors and thus nNOS-derived NO is appropriately positioned to play a prominent role in regulating impulsive and aggressive behavior. Despite the evidence which implicates neuron-derived NO in the modulation of aggressive behavior, the molecular mechanisms by which NO regulate aggression are not known. Plasma androgen concentrations can affect the display of aggressive behavior in male mice, but testosterone concentrations in nNOS Ϫ/Ϫ and WT mice are similar (9).Previous studies of the brain mechanisms underlying aggression reveal that central serotonergic neuronal circuits are prominent in the regulation of aggression. For instance, a negative correlation exists between serotonin (5-hydroxytryptamine; 5-HT) metabolites and impulsive aggressiveness in humans (10-12) and rodents (13,14). Pharmacological manipulations that increase 5-HT neurotransmission decrease the severity of aggressiveness in humans (15) and reduce aggression in animal models ...

An Alternative Promoter of the Human Neuronal Nitric Oxide Synthase Gene Is Expressed Specifically in Leydig Cells

“…64 Recent evidence implicates selective decreases in serotonic (5-HT) turnover and deficient 5-HT 1a and 5-HT 1b receptor function in these mice. [65][66][67] Of great interest for the current work, this aggressive behavior required testosterone, but serum testosterone levels did not vary between the (ϩ/ϩ) and (Ϫ/Ϫ) mice. It is appreciated that although testosterone is required for normal erectile function, it is permission and does not play a direct role.…”

A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function

“…This notion is further supported by the finding that NOS-I knockout mice feature marked changes in serotonergic function: 5HT turnover is impaired, 5HT receptors are desensitized, and 5HTT expression in the brain stem neurons is decreased. 73 Regarding dopaminergic signaling, it has been shown that NO regulates striatal output by modulating the firing pattern of striatal neurons. 74 Taken together, NO appears to be a link between glutamatergic transmission on the one hand and monoaminergic system on the other, thus being centered in key pathways previously shown to be involved in the pathophysiology of SCZ.…”

Inhibition of neuronal nitric oxide reduces anxiety-like responses to pair housing

“…Most research on the role of NO in social behaviours has focused on aggression [5,13,29,31,41]. Male mice lacking the gene that encodes nNOS (nNOS-/-) are highly aggressive and do not relent in response to submissive postures of wildtype (WT) males [29].…”