Pretreatment with benzodiazepine
receptor agonists or tricyclic antidepressant
drugs prevents the behavioral
syndrome of learned helplessness and
reduces 5-HT release. Treatment with
antidepressants such as selective 5-HT
reuptake inhibitors, and infusion of 5-HT
into the frontal cortex reverses the behavioral
pattern (Petty et al., 1997). Correspondingly,
administration of 5-HT
receptor antagonists produces behavioral
deficits resembling those of learned
helplessness (Petty et al., 1997).
Serotonin release may have both
anxiogenic and anxiolytic effects. This
apparently depends on the region of the
forebrain involved and the receptor
subtype that is predominantly stimulated.
Anxiogenic effects are mediated
via 5-HT2A receptor stimulation;
whereas stimulation of 5-HT1A receptors
is anxiolytic and may even provide
resilience to aversive events. Postsynaptic
5-HT1A receptor gene expression
is under tonic inhibition by adrenal
steroids in the hippocampus, apparently
mostly by mineralocorticoid receptors
(Lopez et al., 1998).
The 5HT1A receptor density and
mRNA levels decrease in response to
stress or cortisol administration and increase
following adrenalectomy (Lopez
et al., 1998). Stress-induced downregulation
of 5-HT1A receptor expression
is prevented by adrenalectomy, showing
the importance of circulating adrenal
steroids in mediating this effect. This
regulatory steroid effect is rapid, and
5-HT1AmRNA levels markedly decrease
within hours of mineralocorticoid receptor
stimulation (Lopez et al., 1998). Conversely,
5-HT2A receptor expression is
upregulated during chronic stress and
cortisol administration and downregulated
in response to adrenalectomy.
There is increasing evidence for abnormalities
in serotonergic function in
subjects with PTSD. Patients with
combat-related PTSD had decreased
platelet paroxetine (Paxil) binding,
suggesting alterations in the 5-HT transporter.
Challenge studies probing the
serotonergic system using mCPP suggested
that a subgroup of patients with
PTSD develops anxiety and flashbacks
upon provocation with this agent
(Southwick et al., 1999). However,
PTSD symptoms can be elicited also
by other compounds such as lactate (Rainey et al., 1987). This indicates that
induction of unspecific anxiety can
provoke symptoms characteristic for
PTSD. Davis et al. (1999) used the serotonin-
releasing agent and reuptake
inhibitor D-fenfluramine in PTSD
patients and demonstrated a significantly
lower prolactin response compared
to control subjects, suggesting
central serotonergic dysfunction
(Southwick et al., 1999).
Several recent studies suggest close
interactions between serotonergic and γ-
aminobutyric acid (GABA)-ergic systems.
Mice lacking the 5-HT1A receptor
display marked anxiety (Heisler et al.,
1998; Parks et al., 1998; Ramboz et al.,
1998), and animals exposed to stress
exhibit downregulation of 5-HT1A receptors
(McKittrick et al., 1995). Subordinate
rats in a dominance hierarchy
show severe anxiety accompanied
by reduced 5-HT1A receptor levels
(McKittrick et al., 1995). More recently
it was shown that 5-HT1A receptor knockout
mice show: 1) a reduction in the α1
and α2 subunits of the GABAA receptor
function; 2) reduced binding of both
benzodiazepine and non- benzodiazepine
GABAA receptor-ligand; and 3) benzodiazepine-resistant anxiety (Sibille et
al., 2000). This suggests a pathological
pathway originating from 5-HT1A receptor
deficit leading towards dysfunctions
within GABAergic systems, resulting in
increased levels of anxiety.
Therefore, a logical next step in the
evaluation of brain systems possibly involved
in the pathophysiology of PTSD
was a study to determine 5-HT1A receptor
expression in patients with PTSD
versus controls. We acquired PET images of 5-HT1A receptor binding using
PET imaging on 12 unmedicated PTSD
subjects and 11 healthy controls without
a history of trauma using [18F]fluorocarbonyl-WAY-100635, a highly
selective 5-HT1A receptor radioligand
(Bonne et al., 2005).
Unexpectedly, we found no difference
in 5-HT1A receptor expression between the groups (Figure 2). This
result suggests no direct role for the 5-
HT1A receptor in the pathophysiology
of PTSD; however it does not exclude
its relevance in mediating the effects of
SSRIs in the treatment of PTSD by
involving other transmitter systems and
It has to be noted that sertraline (Zoloft)
is the only FDA-approved medication
for PTSD. Therefore, all the belowdescribed
uses of medications for PTSD
are off-label. While treatment with tricyclic
antidepressants improved depressive,
anxiety and intrusive symptoms,
it did not significantly change all the core
symptom clusters in PTSD (Davidson
et al., 1990; Frank et al., 1988; Reist et
al., 1989). Two controlled trials with
phenelzine (Nardil) showed contradictory
results (Frank et al., 1988; Shestatzky
et al., 1988), while open trials with
propranolol (Betachron ER, Inderal) and
clonidine (Catapres) helped reduce
symptoms only in the reexperiencing and
1.Bonne O, Vythilingham M, Bain E et al. (2005), No
change in serotonin 1A receptor imaging in posttraumatic
stress disorder. Am J Psychiatry 162(2):
Brady K, Pearlstein T, Asnis GM et al. (2000), Efficacy
and safety of sertraline treatment of posttraumatic
stress disorder: a randomized controlled trial. JAMA
283(14):1837-1844 [see comment].
Braun P, Greenberg D, Dasberg H, Lerer B (1990),
Core symptoms of posttraumatic stress disorder
unimproved by alprazolam treatment. J Clin
Breslau N, Kessler RC (2001), The stressor criterion
in DSM-IV posttraumatic stress disorder: an empirical
investigation. Biol Psychiatry 50(9):699-704.
Davidson J, Kudler H, Smith R et al. (1990), Treatment
of posttraumatic stress disorder with amitriptyline and placebo. Arch Gen Psychiatry 47(3):259-266.
Davis LL, Clark DM, Kramer GL et al. (1999), Dfenfluramine
challenge in posttraumatic stress disorder.
Biol Psychiatry 45(7):928-930.
Frank JB, Kosten TR, Giller EL Jr, Dan E (1988), A
randomized clinical trial of phenelzine and imipramine
for posttraumatic stress disorder. Am J
Gelpin E, Bonne O, Peri T et al. (1996), Treatment
of recent trauma survivors with benzodiazepines: a
prospective study. J Clin Psychiatry 57(9):390-394.
Heisler LK, Chu HM, Brennan TJ et al. (1998),
Elevated anxiety and antidepressant-like responses
in serotonin 5-HT1A receptor mutant mice. Proc Nat
Acad Sci U S A 95(25):15049-15054 [see comment].
Inoue T, Tsuchiya K, Koyama T (1994), Regional changes
in dopamine and serotonin activation with various intensity
of physical and psychological stress in the rat brain.
Pharmacol Biochem Behav 49(4):911-920.
Lopez JF, Chalmers DT, Little KY, Watson SJ (1998),
A.E. Bennett Research Award. Regulation of serotonin1A,
glucocorticoid, and mineralocorticoid receptor in rat and
human hippocampus: implications for the neurobiology
of depression. Biol Psychiatry 43(8):547-573.
Marshall RD, Beebe KL, Oldham M, Zaninelli R
(2001), Efficacy and safety of paroxetine treatment
for chronic PTSD: a fixed-dose, placebo-controlled
study. Am J Psychiatry 158(12):1982-1988.
McKittrick CR, Blanchard DC, Blanchard RJ et al. (1995),
Serotonin receptor binding in a colony model of chronic
social stress. Biol Psychiatry 37(6):383-393.
Parks CL, Robinson PS, Sibille E et al. (1998), Increased
anxiety of mice lacking the serotonin1A receptor. Proc
Nat Acad Sci U S A 95(18):10734-10739.
Petty F, Kramer GL, Wu J (1997), Serotonergic
modulation of learned helplessness. Ann N Y Acad
Rainey JM Jr, Aleem A, Ortiz A et al. (1987), A laboratory
procedure for the induction of flashbacks. Am
J Psychiatry 144(10):1317-1319.
Ramboz S, Oosting R, Amara DA et al. (1998),
Serotonin receptor 1A knockout: an animal model
of anxiety-related disorder. Proc Natl Acad Sci U S
A 95(24):14476-14781 [see comment].
Reist C, Kauffmann CD, Haier RJ et al (1989), A
controlled trial of desipramine in 18 men with posttraumatic
stress disorder. Am J Psychiatry 146(4):
513-516 [see comments].
Shestatzky M, Greenberg D, Lerer B (1988), A
controlled trial of phenelzine in posttraumatic stress
disorder. Psychiatry Res 24(2):149-155.
Sibille E, Pavlides C, Benke D, Toth M (2000), Genetic
inactivation of the serotonin1A receptor in mice
results in downregulation of major GABAA receptor
subunits, reduction of GABAA receptor binding, and
benzodiazepine-resistant anxiety. J Neuroscience
Southwick SM, Paige S, Morgan CA 3rd et al. (1999),
Neurotransmitter alterations in PTSD: catecholamines
and serotonin. Semin Clin Neuropsychiatry
van der Kolk BA, Dreyfuss D, Michaels M et al (1994),
Fluoxetine in posttraumatic stress disorder. J Clin
Psychiatry 55(12):517-522 [see comments].