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.