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

The purpose of this study is to investigate a new use for a medication called levodopa (L-DOPA). L-DOPA has been approved for use in Parkinson 's disease, but not for Posttraumatic Stress Disorder (PTSD). L-DOPA is thought to enhance certain cognitive abilities that the investigators believe may be affected among women with PTSD. It is hypothesized that L-DOPA may enhance fear extinction learning to a conditioned fear stimulus. If this is true, L-DOPA may improve outcomes for those undergoing certain types of therapy for PTSD, though that aim is beyond the scope of this project. Additionally, the investigators are testing whether an individual's genetic profile affects how well L-DOPA works to enhance cognitive abilities.

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.

Posttraumatic Stress Disorder, functional Magnetic Resonance Imaging, Levodopa (L-DOPA), Exposure Therapy, Fear Extinction

Differential galvanic skin response will be assessed with respect to the conditioned stimulus versus the control stimulus. The investigators will compare, at an aggregate level, the differential galvanic skin response between the placebo, 100 mg, and 200 mg L-DOPA groups.

Amygdala is the part of the brain which controls emotions, survival instincts, and memory. PTSD patients exhibit hyperactivity in the amygdala in response to stimuli. Differential functional activation of the amygdala will be assessed with respect to the conditioned stimulus versus the control stimulus. The investigators will compare, at an aggregate level, the differential functional activation between the placebo, 100 mg, and 200 mg L-DOPA groups.

Differential functional activation of the anterior cingulate cortex will be assessed with respect to the conditioned stimulus versus the control stimulus. The investigators will compare, at an aggregate level, the differential functional activation between the placebo, 100 mg, and 200 mg L-DOPA groups.

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

Ahrenholtz R, Hiser J, Ross MC, Privratsky A, Sartin-Tarm A, James GA, Cisler JM. Unique neurocircuitry activation profiles during fear conditioning and extinction among women with posttraumatic stress disorder. J Psychiatr Res. 2021 Sep;141:257-266. doi: 10.1016/j.jpsychires.2021.07.007. Epub 2021 Jul 6.