Binding of Pramipexole to Extrastriatal Dopamine D2/D3 Receptors in the Human Brain: A Positron Emission Tomography Study Using 11C-FLB 457

The purpose of this study was to determine the binding sites of pramipexole in extrastriatal dopaminergic regions because its antidepressive effects have been speculated to occur by activating the dopamine D2 receptor subfamily in extrastriatal areas. Dynamic positron emission tomography (PET) scanning using 11C-FLB 457 for quantification of D2/D3 receptor subtype was performed on 15 healthy volunteers. Each subject underwent two PET scans before and after receiving a single dose of pramipexole (0, 0.125, or 0.25 mg). The study demonstrated that pramipexole significantly binds to D2/D3 receptors in the prefrontal cortex, amygdala, and medial and lateral thalamus at a dose of 0.25 mg. These regions have been indicated to have some relation to depression and may be part of the target sites where pramipexole exerts its antidepressive effects

Continuum Approaches to Understanding Ion and Peptide Interactions with the Membrane

Experimental and computational studies have shown that cellular membranes deform to stabilize the inclusion of transmembrane (TM) proteins harboring charge. Recent analysis suggests that membrane bending helps to expose charged and polar residues to the aqueous environment and polar head groups. We previously used elasticity theory to identify membrane distortions that minimize the insertion of charged TM peptides into the membrane. Here, we extend our work by showing that it also provides a novel, computationally efficient method for exploring the energetics of ion and small peptide penetration into membranes. First, we show that the continuum method accurately reproduces energy profiles and membrane shapes generated from molecular simulations of bare ion permeation at a fraction of the computational cost. Next, we demonstrate that the dependence of the ion insertion energy on the membrane thickness arises primarily from the elastic properties of the membrane. Moreover, the continuum model readily provides a free energy decomposition into components not easily determined from molecular dynamics. Finally, we show that the energetics of membrane deformation strongly depend on membrane patch size both for ions and peptides. This dependence is particularly strong for peptides based on simulations of a known amphipathic, membrane binding peptide from the human pathogen Toxoplasma gondii. In total, we address shortcomings and advantages that arise from using a variety of computational methods in distinct biological contexts

Alterations in DNA Methylation and Hydroxymethylation Due to Parental Care in Rhesus Macaques

Early life is one of the most important and sensitive periods during the development of an individual. During this stage, the body and especially the brain are known to be greatly responsive to environmental cues, such as the early social environment. As a consequence, early life adverse social experiences in humans are associated with a wide range of health problems in adulthood. The broad range of phenotypes associated with early life stress (ELS) suggests a system-wide response of the organism, which is yet to be determined. In the last decade, increasing evidence suggests that epigenetic mechanisms underlie the effects of ELS on adult human health. However, there are critical challenges in delineating the direct effects of ELS on epigenetic profiles and phenotypes in human studies. It is impossible to randomize ELS and rare are the studies where complete information about past environmental insults is available, which would allow us to conclude on causality. Nonhuman primates offer several advantages in addressing these challenges. This chapter focuses on parental deprivation models in rhesus macaques which have been shown to produce an array of behavioral, physiological, and neurobiological deficits that parallel those identified in humans subjected to ELS. It describes the evidence for epigenetic alterations induced by differential rearing in this model and points out the differences between tissue-specific versus multi-tissue changes and outlines possible mechanisms for these to occur. In addition, it highlights the need for multi-omics longitudinal studies to better understand the epigenetic trajectories induced by ELS exposure and their impact on adult health