Vol. 8, No. 4, 2002 Page 3


New research sheds additional light on the relationship between aggression and the neurotransmitter serotonin.

Andrew Holmes and colleagues studied the behavior of normal male mice and male mice lacking either one or both copies of the serotonin transporter (5-HTT) gene. "The 5-HTT," the researchers note, "is a key regulator of central serotonergic activity," controlling reuptake of the neurotransmitter and thus terminating its activity at the synapse.

To study the behavior of the 5-HTT "knockout" mice (those lacking both copies of the gene), the researchers introduced intruder mice into their cages. They report that the knockout mice were significantly less aggressive than mice with both copies of the 5-HTT gene, waiting longer to attack intruders and attacking them less frequently. Interestingly, they say, mice with only one 5-HTT gene copy showed intermediate levels of aggression, attacking intruders with less frequency than mice with two copies of the gene but attacking just as quickly.

The researchers conducted a second intruder test, in which mice with two copies of the 5-HTT gene responded by escalating their aggression (a normal response for mice). In contrast, the knockout mice showed no significant increase in aggression, while the mice with one copy of the gene increased their aggression but not to the levels exhibited by the mice with two gene copies.

The knockout mice were also significantly less active, while the mice with one copy of the gene were not. However, the researchers say, the knockout mice showed normal levels of non-aggressive social behaviors such as sniffing and grooming, "suggesting that low aggression in these mice was not confounded by overall inhibition of behavior in this test."

A drug challenge test indicated that the knockout mice exhibited desensitization of 5-HT1A/5-HT1B receptor function, which the researchers suggest "most likely constitutes a compensatory response to the chronically elevated levels of synaptic serotonin." They note other research showing that 5-HTT knockout mice show significant increases in basal levels of extracellular serotonin.

"High serotonergic activity in 5-HTT knockout mice," Holmes et al. say, "is in excellent agreement with the literature demonstrating that pharmacological manipulations known to increase serotonin activity reduce aggressive behavior in animal models, and [with] the negative relationship between serotonin availability and aggression in humans."


"Reduced aggression in mice lacking the serotonin transporter," Andrew Holmes, Dennis L. Murphy, and Jacqueline N. Crawley, Psychopharmacology, Vol. 161, 2002, 160-7. Address: Andrew Holmes, Section on Behavioral Genomics, National Institute of Mental Health, Building 10, Room 4D11, Bethesda, MD 20892-1375.

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