Program & Abstract Book - EPFL Latsis Symposium 2009

EPFL Latsis Symposium 2009: Understanding Violence
60
P-6
February 11-13 2009
se r o t o n e r g i c a u t o r e g u l a t o r y m e c h a n i s m s
in v i o l e n t m i c e
Caramaschi, Doretta 1 3 Natarajan, Deepa 1 3 ; de Weerd,
Henk 2 ; van der Want, Han 2 ; Mulder, Kees C. 1 ; de Boer, Sietse
F. 1 ; Koolhaas, Jaap M. 1
1 Biologisch Centrum, Dept. Behavioral Physiology, University of
Groningen, Haren, The Netherlands; 2 University Medical Center
Groningen, Molecular Imaging and Electron Microscopy, Dept.
Cell Biology, University of Groningen, Groningen, The Netherlands;
3 These authors contributed equally
Human violence has been traditionally linked to a lowered functionality
of the central serotonin (5-HT) system. Despite the vast accumulation
of data linking reduced brain 5-HT activity to pathological aggressive
behavior, information about the possible mechanisms underlying such a
decreased 5-HT functioning is virtually absent. A major obstacle in this
respect is the lack of relevant animal models of violence, and in particular
the omission of objective criteria for assessing violence in preclinical studies.
We recently established, using a rigorous ethological methodology,
that feral mice originally genetically selected for Short Attack Latency (SAL
line) show distinct characteristics of pathological aggression comparable to
human violence.
Employing this mouse model, we have investigated extensively the serotonergic
system, focusing in particular on the autoregulatory control
mechanisms.
First, in line with the 5-HT deficiency hypothesis of aggression, we found
that the pugnacious SAL mice have lower frontolimbic 5-HT levels than
their docile Long Attack Latency (LAL) counterparts. However, this difference
only appeared after the animals had acquired experience with repeated
social conflicts and was not visible beforehand when animals were
naïve with resident-intruder testing. This difference in 5-HT level seems
not to be due to the activity of either the 5-HT-synthesis limiting enzyme
tryptophan-hydroxylase or the main 5-HT-degrading enzyme monoamineoxidase.
Rather, SAL mice showed less functional 5-HTT activity (serotonin
transporter), regardless of the exposure to social experience. Moreover,
SAL mice showed enhanced 5-HT1A autoreceptor and heteroreceptor functionality,
which seems to correlate to the social experience and the escalation
of aggression levels.
These data suggest that the combination of a constitutionally low 5-HT
reuptake functionality and (experience-driven) high 5-HT autoinhibitory
activity leads to disrupted aggression regulation and accompanying lower
levels of 5-HT.