ACNP 59th Annual Meeting: Poster Session III
The NIH Helping to End Addiction Long-term Initiative, or NIH HEAL Initiative, is a trans-agency effort to provide scientific solutions to the opioid crisis. As part of the NIH HEAL Initiative, the National Institute of Neurological Disorders and Stroke (NINDS) has been charged with enhancing pain management and accelerating the discovery and development of new non-addictive pain therapeutics. Toward this goal, NINDS created the Preclinical Screening Platform for Pain (PSPP) with the aim of
... lerating the preclinical development of nonopioid, non-addictive therapeutics for pain. PSPP is working with PsychoGenics to develop and validate preclinical models and endpoints to enable the screening and profiling of assets, including small molecules, biologics, natural products, and devices. Methods: The PSPP aims to screen and profile candidate therapeutics in a number of preclinical assays. Assets are evaluated in a tiered manner, starting with in vitro functional assays to rule out opioid receptor activity and to assess in vitro abuse liability. In vivo pharmacokinetic studies are then used to measure plasma and brain exposures to guide the dose range and pretreatment times for the side effect profile, in vivo efficacy, and in vivo abuse liability studies. All experiments are blinded, both sexes are included, group sizes are determined by power analysis, and data are reported in accordance with ARRIVE guidelines Results: A key component of the PSPP is to validate new and existing models and endpoints. In collaboration with key opinion leaders in the field, NINDS and PsychoGenics have been validating existing preclinical models of pain in rodents for inclusion in the PSPP workflow. This includes validation of models of nerve injury, chemotherapy-induced neuropathic pain, post-operative pain, pain associated with osteoarthritis, deep muscle pain, and migraine, as well as validation of existing endpoints, of evoked pain measures but more importantly, validating non-evoked endpoints for use in these models. For example, we aim to understand whether endpoints such as gait, wheel running, guarding, place escape avoidance paradigm (PEAP), and electroencephalogram (EEG) are useful endpoints in a model of nerve injury. Another exciting feature of the program that will be highlighted in this presentation will be assessment of abuse liability in the context of efficacy in pain endpoints. Advances in understanding these endpoints and representative data will be presented. Conclusions: This presentation will describe efforts to standardize models and endpoints to enhance rigor and reproducibility while evaluating potential non-opioid, non-addictive therapeutics for pain within the NINDS HEAL Initiative PSPP program. antagonist, blocked the effect of DETQ, while the NKCC1 inhibitor, bumetanide, which restores excitatory GABA to inhibitory GABA in scPCP mice (Kim et al, in press), also rescued NOR in the aged mice. The D1 positive allosteric modulator, DETQ, improves cognition and negative symptoms in aged mice as well as subchronic-PCP treated mice. A single dose of Mg threonate also restored NOR in aged and PCP treated mice. Conclusions: These preliminary results are promising and suggest D1PAM which is active in man may be of clinical value in treating age-associate memory impairment and related causes of cognitive decline. The effectiveness of D1 PAM in both normal aging and the PCP model of schizophrenia is noteworthy and suggests some common pathophysiology. The efficacy of bumetanide suggests depolarizing GABA may be important for both aging and schizophrenia. The combination of bumetanide and a D1PAM could be of clinical interest. with the long-term goal to restore memory function that is susceptible to decline with age. ACNP 59 th Annual Meeting: Poster Session III This work represents the most extensive molecular characterization of the acute stress response to date. It can serve as a roadmap in the endeavor to understand how various stressors can trigger similar or divergent, possibly maladaptive changes in different individuals. ACNP 59 th Annual Meeting: Poster Session III 282 Neuropsychopharmacology (2020) 45:278 -382 Background: Post-traumatic stress disorder has been frequently associated with increased immune activation, as shown by higher level of inflammatory markers (such as C-reactive protein, CRP) and abnormal functional connectivity of fronto-limbic pathways. However, little is known about how inflammation is associated with the integrity of white matter within these pathways, as well as the ways in which duration of illness may affect this relationship. As such, we assessed the relationship between CRP, PTSD and white matter structural integrity within two samples: a highly-traumatized population with chronic PTSD (Grady Trauma Project, GTP) and a population of acutely traumatized individuals recruited from the emergency department (ED). Methods: Clinical assessments, serum CRP, and diffusion tensor imaging (DTI) data were collected from both a cross-sectional study of chronic trauma (GTP) and as part of a longitudinal study of acutely traumatized people (recruited from the ED). With respect to the GTP sample, fifty-seven women aged 19-62 (Mean=38.7, SD=12.2) were recruited from primary care clinics of an inner-city hospital in Atlanta, Georgia; approximately half of the sample had clinically significant PTSD. Separately, twentyeight men and women aged 19-58 (Mean=33.1, SD=11.5) were recruited from the ED of a level 1 trauma center as part of an NIHfunded study of PTSD biomarkers and scanned at approximately 1 month post-trauma; 12 participants had clinically significant PTSD at this timepoint. In both samples, probabilistic tractography was used to examine structural integrity of white matter connections between the hippocampus and anterior cingulate cortex (cingulum bundle) and the amygdala and vmPFC (uncinate fasciculus). Mean fractional anisotropy (FA) values of these tracts were entered into statistical models. Results: In the GTP sample, Serum CRP was positively correlated with FA in the cingulum bundle in participants with clinically significant PTSD symptoms (r=.42, p=.03), but not in the low/no symptom group. In the ED sample, FA in the uncinate fasiculus was negatively associated with serum CRP in the high PTSD symptom group (r=-.7, p=.01), but no significant associations were observed in the low/no symptom group. Conclusions: These findings indicate distinct associations between white matter connectivity and CRP that may be moderated by chronicity of PTSD. Whereas higher CRP levels were associated with lower FA in fronto-limbic tracts in acutely traumatized people with PTSD symptoms, this association was reversed in people with more chronic PTSD and greater trauma exposure. Trauma exposure and symptom chronicity appears to be a moderator of associations between inflammatory markers and PTSD (Michopoulos et al., 2020, American Journal of Psychiatry; Bhatt et al., 2020, Nature Communications). These data suggest that symptom chronicity may have a moderating effect on immune activation and its relationship with white matter connections in fronto-limbic pathways. We will discuss the implications of these findings for acute versus chronic PTSD, elaborating on how immune dysregulation may differentially affect white matter connectivity at earlier vs later stages of PTSD symptom development. Background: Limbic regions, such as the amygdala and bed nucleus of the stria terminalis (BNST) play a crucial role in processing emotionally salient information, including fear and anxiety. They are involved in the initiation [basolateral amygdala] and maintenance [BNST] of anxiety-like states in response to potential threat. Changes in the underlying neural circuitry in anxiety and hypervigilance can be probed clinically in humans through use of the Fearful Face Task (FFT) in fMRI studies. ACNP 59 th Annual Meeting: Poster Session III Conclusions: Among trauma-exposed individuals, those with PTSD show deficits in fear extinction recall to previously threatening stimuli a week after extinction learning. Diagnosis may be a key factor in discerning learning deficits to future stimuli. Additionally, a three-task paradigm is appropriate to detect physiological differences among trauma-exposed individuals with and without PTSD.