Combat-related PTSD remains a significant and growing problem in the OIF/OEF veteran population. Understanding biological mechanisms that underlie risk for PTSD and modulate treatment responses will aid in (1) identification of novel treatment strategies and (2) enable individualized treatment approaches for PTSD. A polymorphism in the coding region of the catechol-o-methyltransferase (COMT) gene, COMTval158met, has recently been linked to risk for PTSD across 3 separate studies. Carriers homozygous for the methionine (Met) allele are more prevalent in PTSD patient populations, with the Met allele increasing risk of responding to moderate trauma exposure. Healthy Met/Met carriers exhibit abnormalities in fear extinction and Met/Met carriers with panic disorder exhibit reduced responses to exposure therapy. Hence, disruptions in fear extinction processes may explain why Met carriers exhibit increased risk for PTSD. The mechanisms by which COMTval158met alters risk for PTSD and affects fear learning processes are not understood. The COMTval158met polymorphism is a coding mutation in which subjects homozygous for the Met allele have reduced enzymatic activity with consequently reduced catecholamine degradation in frontal cortex. Recent studies suggest that dopamine (DA) signaling in the frontal cortex is necessary for fear extinction learning as well as for resiliency to long-term effects of stress. This project will use a novel humanized mouse model in which the human COMT gene with either the valine or methione coding sequence is knocked-in to the mouse Comt gene locus. This mutant model allows for direct comparison of the human COMT val and met allele effects on neural functions and behavior. This unique model will be used to determine (1) the DA receptor mechanism and neural circuits underlying Met/Met abnormalities in cued fear learning and extinction and (2) the role of COMTval158met in other PTSD-like symptoms and response to treatment. To enhance translation to the clinic, we will also test whether the COMTval158met polymorphism modulates the response to extinction-based treatments in veterans with PTSD. The overall hypothesis is that the Met polymorphism confers risk for PTSD and alters treatment response to exposure therapy due to alterations in catecholamine signaling in cortex and amygdala regions.
In aim 1 we use novel knockin mice for the human COMTval158met polymorphism and pharmacological tools to test the hypothesis that altered DA receptor D1, D2 and D4 signaling in the cortex and amygdala underlies the extinction deficits and increased fear retention in Met/Met mice.
In aim 2 we will use the predator stress model of PTSD in COMTval158met mice to determine if the Met allele increases responsivity to enduring effects of trauma on anxiety-like behaviors. We will also determine if methylphenidate, which preferentially enhances cortical DA signaling and is clinically available, blocks the anxiety responses induced by predator stress in COMTval158met mice.
In aim 3, we will determine if the COMTval158met genotype predicts treatment response in Veterans with PTSD undergoing either extinction-based or non-extinction based psychotherapy. The findings from this project will (1) advance our understanding of COMT and cortical DA system in the etiology and treatment of PTSD (2) support development of targeted treatments that normalize catecholamine signaling in the frontal cortex of Met carriers (3) determine the potential utility of methylphenidate as a novel treatment for PTSD and (4) determine if the COMTval158met genotype is predictive of treatment responses in Veterans with PTSD.
Advancing treatment of PTSD is a VA mission with clear relevance to Veteran's care. This proposal will advance our understanding of the etiology and treatment of PTSD. First, it will examine the mechanisms of a gene mutation that confers risk for PTSD and may also alter treatment response. Understanding how this mutation alters fear recovery will allow development of targeted treatments for those carrying the risk allele (Met allele of the COMTval158met polymorphism). Specifically, in the near future the animal model studies proposed for this project will support development of adjunctive treatments targeted for carriers of the Met allele with PTSD, and will inform the field of the potential utility of methylphenidate s a treatment for PTSD. Importantly, the human studies proposed in this project will rapidly inform the field as to whether COMTval158genotype is predictive of treatment response in veterans.
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