Psychoticism/Impulsivity/Sensation Seeking/Conscientiousness/Constraint 97found in anxiety disorders only when activated by an imme-
diate stressor.
Molecular Genetics
Lesch, Bengal, Hells, and Sabol (1996) found an association
between a serotonin transporter gene (5-HTTLPR) and the trait
of neuroticism, as assessed by three different scales including
the NEO N scale and Cloninger’s TCI harm avoidance scale.
Individuals with either one or two copies of the short form had
higher N scores than individuals homozygous for the long vari-
ant of the gene. The association was limited to the N factor
of the NEO and the harm avoidant factor of the TCI; none of
the other factors in these test was associated with the genetic
variant. However, in a second study by this group (Hamer,
Greenberg, Sabol, & Murphy, 1999) the association of the gene
with harm avoidance was weaker, and associations were found
with TCI traits of cooperativeness and self-directiveness.
Several other studies have not been able to replicate the re-
lationship between the gene variants and N or harm avoidance.
This is a common outcome in the hunt for specific genes asso-
ciated with personality traits or types of psychopathology,
even when studies have adequate power and use good method-
ology. Population differences may account for some of these
failures. Even in the studies that are significant the particular
gene accounts only for a small portion of the genetic variance.
In the Lesch et al. study the 5-HTT polymorphism accounted
for 3% to 4% of the total variance for the trait and 7% to 9% of
the genetic variance, and 10 to 15 more genes were estimated
to be involved. If there is any replication of a gene-trait associ-
ation, that finding should not be immediately dismissed by
subsequent failures of replication, particularly if the finding
has a theoretical basis. In this case Cloninger’s theory has sug-
gested the involvement of serotonin in harm avoidance.
The short form of the gene, which is associated with high
neuroticism, reduces serotonin uptake and therefore in-
creases serotonergic transmission. Reduced uptake has been
associated with anxiety in animal and human models, but
paradoxically the serotonin uptake inhibitors are therapeutic
agents in depressive disorders and several forms of anxiety
disorders. These drugs could achieve their results through the
inhibitory effects of serotonin on other systems such as the
noradrenergic ones.
Summary
A sudden intense surge in anxiety is characterized by
arousal of the sympathetic branch of the autonomic nervous
system as expressed in elevated heart and breathing rates,
blood pressure, sweating, and other signs of activation
of this system. This led to the expectation that N or trait
anxiety would be related to measures of these indicators
either in the basal state or in reaction to stress. Research has
generally failed to support this correlational hypothesis.
EEG and brain scan studies also fail to reveal a difference in
arousal levels as a trait distinguishing high- and low-N indi-
viduals. However, PET scan studies, done primarily on pa-
tients with anxiety disorders in reaction to fearful stimuli,
show heightened reactivity of frontal, insular, and temporal
cortex and anterior cingulate to such stimuli. Evidence from
studies of animals has implicated the amygdala as a center
for organization of the fear response, but brain imaging
studies in humans have not yet supplied evidence for this
localization.
Much of the research on other species identifies activation
of the dorsal ascending noradrenergic system originating in
the locus coeruleus as an alarm system activating the entire
cortex in states of fear or anxiety. Reactivity of this system is
a characteristic of panic disorders during panic attacks com-
pared to the reactions of other types of anxiety disorders and
normal controls. Correlational studies of norepinephrine
metabolites and N-type trait measures in the basal state have
not found a relationship, but at least one study has found a re-
lationship between N and reactivity of a norepinephrine
metabolite and response to stress. A hypothesized relation-
ship with the monoamine serotonin has also shown no rela-
tionship with N in the basal state and no consistent findings
relating N to reactions to drugs that stimulate serotonergic ac-
tivity. Initial findings of a relationship between a serotonin
transporter gene and N-type scales have not been replicated.
Hormones like testosterone and cortisol show similar nega-
tive findings in the basal state and few findings relating N to
reactivity to stress.
The research attempting to find a biological basis for N has
had a disappointing outcome, particularly in view of the posi-
tive results in experimental research with animals and with
humans that suffer from anxiety and mood disorders. Longi-
tudal research has shown that N is a personality precursor of
these disorders, so why does N not show relationships with
some of the same biological indicators that characterize the
disorders? There may be a kind of threshold effect so that the
dysregulation of neurotransmitter systems characteristic of
the disorders only emerges at some critical level of persistent
stress that is not reproducible in controlled laboratory studies.PSYCHOTICISM/IMPULSIVITY/SENSATION
SEEKING/CONSCIENTIOUSNESS/CONSTRAINTThe third major personality factor goes under a variety of
names depending on the various trait classification systems.
Our factor analyses of personality scales have shown that