Dopamine Enhancement of Fear Extinction Learning in PTSD (1R21MH108753)

Current state-of-the art treatments for posttraumatic stress disorder (PTSD) are lacking in
efficacy. There are two main evidence-based psychological treatments for PTSD. Prolonged
Exposure (PE) is a largely-exposure based intervention that has been found efficacious for
the reduction of PTSD symptoms; however, PE is associated with post-treatment remission rates
of only ~53-60%. Cognitive Processing Therapy (CPT) is also a widely studied and efficacious
psychological treatment for PTSD, which focuses both on exposure to the trauma memory as well
as cognitive therapy techniques. As with PE, post-treatment remission rates for CPT are only
~53-60%, thus also indicating need for improvement in overall efficacy and consistency of
response across individuals.

There is emerging research demonstrating that dopamine is critical to the consolidation and
subsequent recall of fear extinction learning. A recent study of healthy adult humans
demonstrated that oral administration of 150 mg L-DOPA after fear extinction learning led to
decreased fear responding, even when tested in a new context. Further, this study also found
that resting-state functional connectivity, measured ~45 minutes after post-extinction
learning L-DOPA administration, between the ventral tegmental area (VTA) and mPFC was
correlated with magnitude of medial prefrontal cortex (mPFC) recruitment during recall of the
fear extinction learning. This latter finding suggests that the mechanism by which L-DOPA
boosts consolidation of fear extinction learning is through acutely reorganized dopaminergic
resting-state networks. Indeed, other studies have demonstrated an acute effect of L-DOPA
administration on resting-state functional connectivity within dopaminergic neural networks.
Thus, agents that increase dopamine transmission acutely during the post-extinction learning
consolidation window, and thereby acutely altering organization of dopaminergic neural
networks, show promise for boosting the consolidation of fear extinction memories and
decreasing fear responding.

Genetic variation is a primary contributor to individual differences in baseline dopamine
neurotransmission. Individuals with specific alleles in genes coding for high baseline
dopamine demonstrate better performance on tasks probing working memory, cognitive control,
and social cognition. Genetic variants in baseline dopamine neurotransmission would therefore
be expected to modulate performance-enhancing effects of L-DOPA, such that individuals with
low endogenous would be expected to have increased performance upon exogenously increasing
dopamine neurotransmission; whereas individuals with high endogenous dopamine would be
expected to have performance deteriorate from exogenously increasing dopamine
neurotransmission. In support of this hypothesis, a recent study found an interaction between
L-DOPA administration and endogenous dopamine neurotransmission (as indicated by a polygenic
score pooled across catechol-O-methyltransferase (COMT), dopamine transporter protein (DAT),
dopamine D1 receptor (DRD1-3)) on motor learning performance, such that individuals with a
combination of alleles coding for higher baseline dopamine demonstrated a weaker learning
benefit from L-DOPA, whereas individuals with a combination of alleles coding for lower
baseline dopamine demonstrated a stronger learning benefit from L-DOPA. These data
demonstrate the non-linear relationship between performance and dopamine levels, suggesting
that any investigation of potential effects of boosting dopamine neurotransmission as a means
of boosting learning needs to account for baseline dopamine neurotransmission.

Overall, the proposed project seeks to demonstrate the engagement of post-extinction dopamine
neurotransmission and downstream acute reorganization of dopaminergic resting-state neural
networks as a means of increasing consolidation of generic fear extinction learning in adult
women with PTSD.

Inclusion Criteria:

- 25-50 years of age

- PTSD related to physical or sexual assault

- Medically healthy

- English speaking

Exclusion Criteria:

- Claustrophobia, or the inability to lie still in a confined space

- Major medical disorders (e.g., HIV, cancer)

- Magnetic metallic implants (such as screws, pins, shrapnel remnants, aneurysm clips,
artificial heart valves, inner ear (cochlear) implants, artificial joints, and
vascular stents)

- Electronic or magnetic implants, such as pacemakers

- Permanent makeup or tattoos with metallic dyes

- Currently pregnant

- A self-reported history of loss of consciousness (greater than 10 minutes)

- Physical disabilities that prohibit task performance (such as blindness or deafness)

- Psychotic disorders (e.g., schizophrenia)

- Any other condition that the investigator believes might put the participant at risk