Alterations in adolescent brain serotonin (5HT)1A, 5HT2A, and dopamine (D)2 receptor systems in a nonhuman primate model of early life adversity

Abstract

Stress affects brain serotonin (5HT) and dopamine (DA) function, and the effectiveness of 5HT and DA to regulate stress and emotional responses. However, our understanding of the long-term impact of early life adversity (ELA) on primate brain monoaminergic systems during adolescence is scarce and inconsistent. Filling this gap in the literature is critical, given that the emergence of psychopathology during adolescence has been related to deficits in these systems. Here, we use a translational nonhuman primate (NHP) model of ELA (infant maltreatment by the mother) to examine the long-term impact of ELA on adolescent 5HT_1A, 5HT_2A and D₂ receptor systems. These receptor systems were chosen based on their involvement in stress/emotional control, as well as reward and reinforcement. Rates of maternal abuse, rejection, and infant's vocalizations were obtained during the first three postnatal months, and hair cortisol concentrations obtained at 6 months postnatal were examined as early predictors of binding potential (BP) values obtained during adolescence using positron emission tomography (PET) imaging. Maltreated animals demonstrated significantly lower 5HT_1A receptor BP in prefrontal cortical areas as well as the amygdala and hippocampus, and lower 5HT_2A receptor BP in striatal and prefrontal cortical areas. Maltreated animals also demonstrated significantly lower D₂ BP in the amygdala. None of the behavioral and neuroendocrine measurements obtained early in life predicted any changes in BP data. Our findings suggest that early caregiving experiences regulate the development of brain 5HT and DA systems in primates, resulting in long-term effects evident during adolescence.

Fig. 1. 5HT_1A Receptor BPND.

5HT_1A receptor binding potential (average ± SEM) averaged for maltreated (gray filled in bars) and control (open bars) animals in the anterior cingulate cortex (ACC), amygdala (Amyg), caudate (Caud), hippocampus (Hipp), nucleus accumbens (NAcc), orbitofrontal cortex (OFC), putamen (Put), subgenual cingulate cortex (SGC), dorsolateral prefrontal cortex (dlPFC), medial prefrontal cortex (mPFC), ventrolateral prefrontal cortex (vlPFC), and ventromedial prefrontal cortex (vmPFC). *indicates a significant difference between Maltreated and Control animals in that brain area (p < 0.05).

Fig. 2. 5HT_2A Receptor BPND.

5HT_2A receptor binding potential (average ± SEM) averaged for maltreated (gray filled in bars) and control (open bars) animals in the anterior cingulate cortex (ACC), amygdala (Amyg), caudate (Caud), hippocampus (Hipp), nucleus accumbens (NAcc), orbitofrontal cortex (OFC), putamen (Put), subgenual cingulate cortex (SGC), dorsolateral prefrontal cortex (dlPFC), medial prefrontal cortex (mPFC), ventrolateral prefrontal cortex (vlPFC), and ventromedial prefrontal cortex (vmPFC). *Indicates a significant difference between Maltreated and Control animals in that area of the brain (p < 0.05).

Fig. 3. 5HT_2A Receptor BPND in OFC and Putamen.

5HT_2A receptor binding potential (average ± SEM) averaged for maltreated males (gray filled in bars), maltreated females (gray checkered bars), control males (open bars), and control females (white checkered bars) animals in the orbitofrontal cortex (OFC) and the Putamen. The bottom panel demonstrates 5HT_2A receptor binding potential in the putamen separated by laterality (gray bars represent the left hemisphere, and red bars represent the right hemisphere). *Indicates a significant difference between Control males and all other groups (top panels) (p < 0.05). Note that a significant ELA by sex by laterality interaction was detected in the bottom panel but did not survive multiple comparison testing.

Fig. 4. D₂ Receptor BPND.

D₂ receptor binding potential (average ± SEM). The left panel demonstrates BP averaged for left (black open bars) and right (red open bars) hemispheres of the ACC (left panel). The middle panel demonstrates BP averaged for the left hemisphere (black filled in bars for males, black and white checkered for females) and the right hemisphere (red open bars for males, red and white checkered for females) in the SGC. The left panel demonstrates BP averaged for maltreated males (gray filled in bars), maltreated females (gray checkered bars), control males (open bars), and control females (white checkered bars) animals in the amygdala. *Indicates a significant difference between left and right hemispheres (left panel), left and right male and females (middle panel), and between maltreated and control animals (right panel). Note that the middle and right panels demonstrated a significant ELA by sex by laterality interaction (middle panel) and a significant ELA by sex interaction (right panel), but did not survive multiple comparison testing.