XWH - 08 - 1 - 0083 TITLE : Glutamate Transmission Enhancement for Treatment of PTSD

Objective/Hypothesis: Although now considered to be the most effective treatment for post traumatic stress disorder (PTSD), extinctionbased therapies require substantial time and investment for both the patient and provider, averaging 10 sessions or more of approximately 1h each to achieve significant beneficial effects. Thus, treatments that enhance the efficacy of extinction therapies and reduce the number of required sessions for remission would be of great benefit. Ideally, such adjunctive treatments may reduce the need for long term medication. Preclinical studies have demonstrated that glutamate transmission in the amygdala is necessary for long term extinction of fearmemories. Furthermore, d-cycloserine (DCS), a partial NMDA receptor agonist acting on the glycine modulator site, significantly enhances fear extinction (fear extinction). DCS treatment has also been shown to significantly enhance efficacy of extinction-based therapy across a number of anxiety disorders. However, efficacy of DCS may be limited, as its effects diminish over repeated dosing and it is not effective in all subjects or protocols. Here we will examine the efficacy of 2 novel classes of compounds which enhance glutamate signal to facilitate fear extinction. First, we will examine the efficacy of Org-24598, a glycine transporter 1 (GLYT1) inhibitor to increase fear extinction. GLYT1 inhibition has been shown to facilitate glutamate transmission in limbic regions that modulate emotional processes, and are more efficacious in facilitating glutamate signal than DCS. Second we will examine the efficacy of CX546, a positive allosteric modulator of AMPA receptors to increase fear extinction. Methods: To assess the effects of these compounds on fear extinction, we proposed to use the FPS model of fear conditioning and extinction in mice. We will compare dose responses of both compounds to vehicle controls in their ability to facilitate fear extinction and examine if these effects were maintained with repeated testing. These initial studies characterizing and comparing the longevity of our test compounds on fear extinction will be important to inform clinical studies of the relative utility of these compounds to facilitate extinction-based therapies. Results: Our preliminary results in the mouse model of fear extinction showed that unlike in rats, DCS, the positive control, does not enhance fear extinction. We thus switched to utilization of the FPS model in rats which has been shown previously to be sensitive to DCS. We found that DCS significantly enhanced fear extinction as previously reported in rats, indicating we had established a protocol sensitive to fear extinction enhancement by glutamatergic drugs. TheGLYT1 inhibitor Org-24598 (3, 10 mg/kg) significantly increased fear extinction in rats. Unlike the GLYT1 inhibitor, the AMPAKINE CX546 (3, 30 mg/kg) did not affect fear extinction. Conclusions: These data indicate that the GLYT1 inhibitor Org-24598 but not the AMPAKINE CX546 facilitates fear extinction similar to DCS.