The Effect of Early Trauma Exposure on Serotonin Type 1B Receptor Expression Revealed by Reduced Selective Radioligand Binding

Abstract

Context Serotonergic dysfunction is implicated in the pathogenesis of posttraumatic stress disorder (PTSD), and recent animal models suggest that disturbances in serotonin type 1B receptor function, in particular, may contribute to chronic anxiety. However, the specific role of the serotonin type 1B receptor has not been studied in patients with PTSD. Objective To investigate in vivo serotonin type 1B receptor expression in individuals with PTSD, trauma-exposed control participants without PTSD (TC), and healthy (non–trauma-exposed) control participants (HC) using positron emission tomography and the recently developed serotonin type 1B receptor selective radiotracer [11C]P943. Design Cross-sectional positron emission tomography study under resting conditions. Setting Academic and Veterans Affairs medical centers. Participants Ninety-six individuals in 3 study groups: PTSD (n=49), TC (n=20), and HC (n=27). Main Outcome Measure Regional [11C]P943 binding potential (BPND) values in an a priori–defined limbic corticostriatal circuit investigated using multivariate analysis of variance and multiple regression analysis. Results A history of severe trauma exposure in the PTSD and TC groups was associated with marked reductions in [11C]P943 BPND in the caudate, the amygdala, and the anterior cingulate cortex. Participant age at first trauma exposure was strongly associated with low [11C]P943 BPND. Developmentally earlier trauma exposure also was associated with greater PTSD symptom severity and major depression comorbidity. Conclusions These data suggest an enduring effect of trauma history on brain function and the phenotype of PTSD. The association of early age at first trauma and more pronounced neurobiological and behavioral alterations in PTSD suggests a developmental component in the cause of PTSD.

Translational Findings on Brain-Derived Neurotrophic Factor and Anxiety: Contributions from Basic Research to Clinical Practice

“…As the mechanisms of development are under both genetic and environmental control, studies in monkeys and rodents support the important role of gene-environment interactions in the etiology of anxiety [3]. Indeed, genetic variations in the promoter of the serotonin transporter gene [4], changes in the expression of the serotonin type 1B receptor [5] or a decrease in hippocampal volume [6] have been related to individuals more likely predisposed to develop anxiety disorders and depression when exposed to traumatic experiences. …”

Normative database of the serotonergic system in healthy subjects using multi-tracer PET

“…This system works in concert with various environmental and endogenous signals such as day light intensity and length and several hormones as cortisol , progesterone and dehydroepiandrosterone sulfate . Furthermore, it has shown an integral role in the pathophysiology of common neuropsychiatric disorders including major depression (Mann, 1999;Staley et al, 1998), bipolar disorder (Chee et al, 2001), obsessive compulsive disorder (Adams et al, 2005), anxiety disorders (Akimova et al, 2009;Lanzenberger et al, 2007;van der Wee et al, 2008), post-traumatic stress disorder (Davis et al, 1997;Murrough et al, 2011aMurrough et al, , 2011b, eating disorders (Bailer et al, 2005;Mayer and Walsh, 1998), sleep disturbance (Portas et al, 1998), attention deficit hyperactivity disorder (Quist et al, 2003), drug addiction (Carey et al, 2005;Muller et al, 2007), suicidal behavior (Mann, 1999), schizophrenia (Abi-Dargham, 2007;Aghajanian and Marek, 2000;Hurlemann et al, 2005;Hurlemann et al, 2008), Alzheimer (Ouchi et al, 2009), migraine (Panconesi, 2008) and epilepsy (Assem-Hilger et al, 2010).…”

In vivo occupancy of the 5-HT1A receptor by a novel pan 5-HT1(A/B/D) receptor antagonist, GSK588045, using positron emission tomography

“…In addition pre-clinical behavioural pharmacology studies (Sari, 2004), and more recently human positron emission tomography (PET) studies suggest a role for 5-HT 1B in the aetiology and treatment of post-traumatic stress disorder (Murrough et al, 2011), whilst genetic studies have suggested an association between 5-HT 1D and anorexia nervosa (Bergen et al, 2003).…”

“…[ 11 C] WAY100635 in particular has been used to aid early drug development by defining the relationship between administered dose and 5-HT 1A receptor occupancy (Rabiner et al, 2000(Rabiner et al, , 2002. More recently, a number of PET radioligands have become available for 5-HT 1B : [ 11 C]P943 (Nabulsi et al, 2010) and [ 11 C]AZ10419369 (Varnas et al, 2011). However, these ligands were not available to us at the time our study was conducted.…”