Effects of early-life stress on serotonin(1A) receptors in juvenile Rhesus monkeys measured by positron emission tomography

Abstract

Background: Traumatic experiences in early childhood are associated with increased risk for developing mood and anxiety disorders later in life. Low serotonin(1A) receptor (5-HT(1A)R) density during development has been proposed as a trait-like characteristic leading to increased vulnerability of stress-related neuropsychiatric disorders.

Methods: To assess the relationship between early-life stress and alterations in the serotonin system during development, we used positron emission tomography to measure in vivo 5-HT(1A)R density and apparent dissociation constant (K(D)(app)) in the brain of juvenile Rhesus monkeys exposed to the early-life stress of peer-rearing.

Results: In general, 5-HT(1A)R density and K(D)(app) were decreased in peer-reared compared with control mother-reared animals. However, increase in receptor density was found in the dorsomedial prefrontal cortex of peer-reared females.

Conclusions: These findings suggest that exposure to an adverse early-life environment during infancy is associated with long-term alterations in the serotonin system and support previous studies suggesting that reduced 5-HT(1A)R density during development might be a factor increasing vulnerability to stress-related neuropsychiatric disorders. Furthermore, alterations in the serotonin system seemed to be gender- and region-specific, providing a biological basis for the higher prevalence of affective disorders in women.

Figure 1

Representative images of Rhesus monkey brain in transaxial (top panel), coronal (middle panel) and sagittal (bottom panel) view. On the left – T1 MRI scans used for co-registration with parametric BP_ND maps for ROI placement (middle panel). Parametric BP_ND maps were calculated from bolus plus infusion PET studies with [¹⁸F]FPWAY and PMOD (right panel). Pseudocolor bar represents BP_ND values (arbitrary unit).

Figure 2

Time-activity curves (TAC) (a) and Scatchard plots (b) from brain areas of a single animal. A: Y-axis - standard uptake value (SUV) (fraction of injected dose/g body weight/g tissue), X-axis – time after [¹⁸F]FPWAY administration onset. [¹⁸F]FPWAY was injected as a bolus followed by a constant infusion (B/I) to reach radioactivity equilibrium distribution. 120 min after the B/I of [¹⁸F]FPWAY, unlabelled FPWAY was co-injected as bolus plus constant infusion (B/I) for another 90 min to reach a second equilibrium state. B: Two points for Scatchard analysis were obtained from TAC, averaging the data from 90 to 120 min after the start of [¹⁸F]FPWAY injection; second point - 50 to 90 min after the beginning of unlabelled FPWAY administration, respectively (see Methods for details). HC - hippocampus, MCC - medial cingulate cortex, ACC - anterior cingulate cortex, AMY - amygdala, dmPFC - dorsomedial prefrontal cortex, and RN - raphe nuclei (midbrain).

Figure 2

Time-activity curves (TAC) (a) and Scatchard plots (b) from brain areas of a single animal. A: Y-axis - standard uptake value (SUV) (fraction of injected dose/g body weight/g tissue), X-axis – time after [¹⁸F]FPWAY administration onset. [¹⁸F]FPWAY was injected as a bolus followed by a constant infusion (B/I) to reach radioactivity equilibrium distribution. 120 min after the B/I of [¹⁸F]FPWAY, unlabelled FPWAY was co-injected as bolus plus constant infusion (B/I) for another 90 min to reach a second equilibrium state. B: Two points for Scatchard analysis were obtained from TAC, averaging the data from 90 to 120 min after the start of [¹⁸F]FPWAY injection; second point - 50 to 90 min after the beginning of unlabelled FPWAY administration, respectively (see Methods for details). HC - hippocampus, MCC - medial cingulate cortex, ACC - anterior cingulate cortex, AMY - amygdala, dmPFC - dorsomedial prefrontal cortex, and RN - raphe nuclei (midbrain).

Figure 3

Coronal view of BP_ND parametric maps obtained with [18F]FPWAY in four representative animals. Top row: MR animals - bottom row: PR animals - left column: females - right column: males. Images correspond to coronal slices at the level 15–16 mm from the interaural line(36). Pseudocolor bar represents BP_ND values (arbitrary unit).