Positron emission tomography assessment of 8-OH-DPAT-mediated changes in an index of cerebral glucose metabolism in female marmosets

Abstract

As part of a larger experiment investigating serotonergic regulation of female marmoset sexual behavior, this study was designed to (1) advance methods for PET imaging of common marmoset monkey brain, (2) measure normalized FDG uptake as an index of local cerebral metabolic rates for glucose, and (3) study changes induced in this index of cerebral glucose metabolism by chronic treatment of female marmosets with a serotonin 1A receptor (5-HT(1A)) agonist. We hypothesized that chronic treatment with the 5-HT(1A) agonist 8-OH-DPAT would alter the glucose metabolism index in dorsal raphe (DR), medial prefrontal cortex (mPFC), medial preoptic area of hypothalamus (mPOA), ventromedial nucleus of hypothalamus (VMH), and field CA1 of hippocampus. Eight adult ovariectomized female common marmosets (Callithrix jacchus) were studied with and without estradiol replacement. In a crossover design, each subject was treated daily with 8-OH-DPAT (0.1mg/kg SC daily) or saline. After 42-49 days of treatment, the glucose metabolism radiotracer FDG was administered to each female immediately prior to 30 min of interaction with her male pairmate, after which the subject was anesthetized and imaged by PET. Whole brain normalized PET images were analyzed with anatomically defined regions of interest (ROI). Whole brain voxelwise mapping was also used to explore treatment effects and correlations between alterations in the glucose metabolism index and pairmate interactions. The rank order of normalized FDG uptake was VMH/mPOA>DR>mPFC/CA1 in both conditions. 8-OH-DPAT did not induce alterations in the glucose metabolism index in ROIs. Voxelwise mapping showed a significant reduction in normalized FDG uptake in response to 8-OH-DPAT in a cluster in medial occipital cortex as well as a significant correlation between increased rejection of mount attempts and reduced normalized FDG uptake in an overlapping cluster. In conclusion, PET imaging has been used to measure FDG uptake relative to whole brain in marmoset monkeys. Voxelwise mapping shows that 8-OH-DPAT reduces this index of glucose metabolism in medial occipital cortex, consistent with alterations in female sexual behavior.

Fig. 1

MRI template. Mean of aligned images (n=8) used as MRI template (Every fourth 0.5 mm coronal slice shown). Whole brain mask is overlaid (red). The template is freely available upon request to the corresponding author.

Fig. 2

Aligned images. Axial, coronal, and sagittal slices of MRI template (A, n=8 subjects), MRI of one subject (B, cj1022), mean FDG image (C, n=8 subjects×2 conditions), and FDG image of one subject (cj1022) in Saline condition D and 8-OH-DPAT condition E. Contour is on whole brain mask trimmed to avoid contributions from radioactivity uptake outside of the brain. Color scale indicates whole brain normalized radioactivity concentration shown in C–E.

Fig. 3

Anatomical identification. Fusion image (center column) of coregistered brain atlas (left column) and MRI template (right column). Representative coronal slices showing regions of interest (ROIs) for medial prefrontal cortex (mPFC), medial preoptic area of the hypothalamus (mPOA), ventromedial hypothalamic nucleus (VMH), field CA1 of the hippocampus (CA1), and dorsal raphe nucleus (DR). Atlas images courtesy of Springer Science+Business Media (Palazzi and Bordier, 2008).

Fig. 4

ROI analysis of response to 8-OH-DPAT treatment. Scatter plot showing individual ROI results (whole brain normalized radioactivity) in 8-OH-DPAT and saline conditions (A). Bar plot shows difference in whole brain normalized radioactivity (8-OH-DPAT minus saline) for each ROI and each subject (B). No ROI shows a significant response to chronic 8-OH-DPAT treatment (p>0.3 for each region; paired t test, 2-tailed; n=8).

Fig. 5

Glucose metabolism index decreases in medial occipital cortex in response to chronic 8-OH-DPAT treatment. The color scale indicates the mean difference in whole brain normalized radioactivity, ΔFDG=8-OH-DPAT minus Saline. White contour marked by arrows delineates a significant negative 3D cluster in the corresponding t map, shown at Bregma −11.2 mm (2-tailed paired t test, p_uncorrected<0.05, extent=60 μL, p_corrected=0.004). Mean difference arbitrarily thresholded at 0.02<|ΔFDG |<0.10.

Fig. 6

Rejection of mounts. Between-condition difference in normalized FDG uptake (8-OH-DPAT - Saline) plotted against alteration in behavior for the eight subjects. Voxelwise analysis found two significant clusters (Suppl. Fig. 6), one with a positive correlation (◊) left ventral cerebellum) and one with a negative correlation (□) medial occipital cortex).

Fig. 7

Glucose metabolism index and behavior respond to 8-OH-DPAT treatment in concert. Orthogonal views of MRI template at medial occipital cortex. Cluster of voxels with significant reduction in FDG radioactivity during 8-OH-DPAT condition compared to Saline condition (red; paired t test, 2-tailed p_uncorrected<0.05, extent 60 μL, p_corrected=0.004). Cluster of voxels with significant negative correlation between alterations of FDG radioactivity and rejection of mount attempts between conditions (blue; Pearson r; 2-tailed p_uncorrected<0.05, extent 72 μL, p_corrected=0.001). The two clusters overlap (yellow). Part of significant cluster with positive correlation is seen in coronal view (light blue at ventral left edge of cerebellum).