Alteration
of 5-HT1A signal transduction
pathways in brain of suicide victims
If
reduced levels of the neurotransmitter serotonin
(5-HT) in the brains of depressed suicide
victims is well accepted, the consequences of
such a reduction on 5-HT-receptor-activated
downstream signaling are not well understood. A
recent study examined distinct activities of
second messengers stimulated by 5-HT-1A
receptors in postmortem brain samples from
depressed suicide victims.
Psychological autopsy procedure using DSM III-R
criteria established the postmortem diagnosis.
The occipital cortex samples from six suicide
victims who suffered from major depression and
six matched controls was dissected and stored
frozen until membrane preparation and
measurement of several parameters linked to
5-HT-1A receptor activation.
Binding of
[35S]GTPgS
to Gai/o
was lower in the occipital cortex of suicide
victims and a decrease coupling of 5-HT-1A
receptor to adenylyl cyclase was observed. There
were no group differences in the expression
levels of Gai/o,
Gaq/11
or Gas
proteins, or in the activity of cAMP-dependent
protein kinase A. The activity of
phosphatidylinositol 3-kinase and its downstream
effector, protein kinase B, were decreased, and
an increase in phosphatase and tensin homolog
deleted on chromosome 10, which is the
phosphatase that hydrolyzes phosphatidylinositol
3,4,5-triphosphate, was observed. The activation
of extracellular signal-regulated kinases 1 and
2 was reduced in suicide victims.
These results support the involvement of
serotonergic dysfunction in suicidal behavior
and show the multi-faceted sites of
dysregulation of 5-HT. It is suggested that the
alteration of the complex system of 5-HT-1A
receptor transduction pathways may have fatal
consequences and better understanding the role
of these components to maintain normal
serotonergic transmission is essential to fully
characterize the pathophysiology of depression
and suicide. Hsiung
et al., 2003
Attenuated 5-HT1A receptor signaling in brains
of suicide victims: involvement of adenylyl
cyclase, phosphatidylinositol 3-kinase, Akt and
mitogen-activated protein
kinase. Neurochem 87: 182-194.