Role of Substance P in Post-Traumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is a chronic, debilitating disorder that places a significant burden on individuals and society. Abnormalities in the serotonergic and noradrenergic systems and dysregulation of the hypothalamic-pituitary adrenal (HPA) axis have been proposed as neurobiological mechanisms in the development of the disorder, however the exact underpinnings of the neurobiology of the disorder must be elucidated.

Distribution of substance P (SP) and its receptor, neurokinin 1 (NK1) receptor, includes regions implicated in the pathophysiology of PTSD, namely the amygdala, hippocampus, hypothalamus, and locus ceruleus. There is a considerable spatial (and therefore functional) overlap between the SP-NK1 receptor system and other neurotransmitter (e.g., norepinephrine, serotonin) pathways with well established roles in anxiety. Preclinical studies indicate that stress regulates levels of SP in several brain regions. In addition, in several animal models, NK1 receptor antagonists demonstrate anxiolytic-like property. These anxiolytic-like effects seem to involve different mechanisms than those of currently available anxiolytics.

In this protocol, we will use a PET ligand that acts as an NK1 receptor antagonist, [18F]SPA-RQ ([18F]-labeled Substance P Antagonist Receptor Quantifier). Using this tracer, we will look for regional differences in NK1 receptor binding in 20 patients with PTSD and 20 healthy controls. The goal of the present study is to demonstrate the involvement of SP in PTSD, and thereby, further our understanding of its role in the psychopathology of this illness.

Inclusion criteria

PTSD Samples:

Twenty subjects (age 18-65) with current PTSD, as defined by DSM-IV criteria, of any ethnicity without other significant medical conditions will be selected.

Healthy Control Samples:

Twenty healthy subjects (age 18-65) without a known personal or family history of psychiatric disorders in first-degree relatives will be selected.

A control subject will be matched to each subject with PTSD for age, gender, and handedness, respectively.

They must not be actively using illicit drugs or engaged in heavy consumption of alcohol, had no metallic implants that are ferromagnetic, and competent to sign consent forms to participate in the study.

Exclusion criteria

Patients must not have taken antidepressant or other medications likely to alter SP-NK1 receptor system. Effective medications will not be discontinued for the purpose of this study.

Subjects will be excluded if they have:

• DSM-IV Axis I diagnostic criteria other than PTSD and Major depression (All controls must not meet any of the Axis I diagnoses);
• DSM-IV criteria for psychoactive substance abuse/dependence within six months;
• take psychotropic medication in last 3 weeks (8 weeks for fluoxetine);
• abnormal MRI other than minor atrophy;
• abnormal laboratory test, including HIV test;
• are currently pregnant or breast feeding (as documented by pregnancy testing at screening or at days of the scanning);
• prior participation in other research protocols within the past year such that a radiation exposure together with the present study would exceed the annual limits (A total effective dose 5.0 rem in a year and a 5 rad per year to the lens of the eyes, gonads and blood-forming organs; and 15 rad annually for all other organs);
• are unable to lay on one's back for PET/MRI scans (PET and MRI scans take approximately 5 and 1 hour, respectively);
• any condition that increases risk for MRI (e.g., pacemaker, metallic foreign body in the eye, etc.);
• individuals who recently donated blood;
• serious suicidal ideation or behavior;
• Xylocaine allergy;
• positive HIV test.

For healthy subjects, exclusion criteria b) through m) are same to those for PTSD subjects. As for item a), subjects will be excluded if they meet any current DSM-IV Axis I diagnostic criteria.