Dopamine binding

Abstract: Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration (p < 5 × 10−8; 43 loci at p < 6 × 10−9). Replication is observed for PAX8, VRK2, and FBXL12/UBL5/PIN1 loci in the CHARGE study (n = 47,180; p < 6.3 × 10−4), and 55 signals show sign-concordant effects. The 78 loci further associate with accelerometer-derived sleep duration, daytime inactivity, sleep efficiency and number of sleep bouts in secondary analysis (n = 85,499). Loci are enriched for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission and plasticity, among others. Genetic correlation indicates shared links with anthropometric, cognitive, metabolic, and psychiatric traits and two-sample Mendelian randomization highlights a bidirectional causal link with schizophrenia. This work provides insights into the genetic basis for inter-individual variation in sleep duration implicating multiple biological pathways.

Abstract: [ 3 H]Haloperidol and [ 3 H]dopamine bind in saturable fashion to membranes from calf brain with high affinity and other characteristics indicating an association with post-synaptic dopamine receptors. Kinetic analysis of rates of association and dissociation yields K D values in agreement with equilibrium measurements. Regional variations in [ 3 H]dopamine and [ 3 H]haloperidol binding are parallel and correspond to regional differences in dopaminergic innervation. Drug specificity does not appear to differ between limbic and striatal areas. The relative potencies of various agonists and antagonists on the binding of the two ligands parallel their pharmacological actions at dopamine receptor sites. Dopamine agonists have 6-38 times more affinity for [ 3 H]dopamine than [ 3 H]haloperidol binding sites. By contrast, dopamine antagonists have 20-12,000 times more affinity for [ 3 H]haloperidol than [ 3 H]dopamine binding sites. Ergot derivatives, including d -lysergic acid diethylamide, and other serotonin antagonists have substantial affinity for both types of binding.

Abstract: To test the dopamine hypothesis of schizophrenia the authors measured specific 3H-neuroleptic/dopamine binding sites in three dopamin-rich regions of 59 postmortem normal human brains and 50 postmortem brains from schizophrenic patients using 3H-haloperidol and 3H-spiperone. The binding of 2 nM 3H-haloperidol and of 1 nM 3H-spiperone was significantly elevated in the brains from schizophrenic patients. The brain regions from patients who had no history of being treated with neuroleptic drugs also exhibited significantly higher binding of the 3H-neuroleptics. These results are compatible with the hypothesis that schizophrenia may be associated with an overactivity of postsynaptic dopamine receptors.

Abstract: Using serial [(11)C]SCH 23390- and [11C]raclopride-PET, we have measured the rate of loss of striatal dopamine D1 and D2 receptor binding over a mean of 40 months in nine asymptomatic adult Huntington's disease mutation carriers, four patients with symptomatic disease, seven mutation-negative controls and three subjects at risk for the disease. Eight of the nine asymptomatic Huntington's disease mutation carriers had serial [11C]raclopride-PET and showed a mean annual loss of striatal D2 binding of 4.0%. Only five of these eight, however, showed active progression, and they had a mean annual loss of D2 binding of 6.5%. All nine asymptomatic mutation carriers had serial [11C]SCH 23390-PET and showed a mean annual loss of striatal D1 binding of 2. 0%. Four of these subjects demonstrated active progression and they had a mean annual loss of 4.5%. Our four symptomatic Huntington's disease patients showed a mean annual loss of D2 binding of 3.0% and of D1 binding of 5.0%. Loss of striatal D1 and D2 binding was significantly greater in the known mutation carriers than in the combined at-risk and gene-negative groups (P < 0.05). At follow-up PET all subjects were clinically assessed using the Unified Huntington's Disease Rating Scale. Scores for motor function and total functional capacity correlated with PET measures of striatal dopamine receptor binding both in the asymptomatic mutation carriers (D1, P < 0.01) and across the combined asymptomatic and clinically affected Huntington's disease mutation carrier group (D1 and D2, P < 0.001). We conclude that PET measures of striatal D1 and D2 dopamine binding can be used to identify asymptomatic Huntington's disease mutation carriers who are actively progressing and who would thus be suitable for putative neuroprotective therapies. Measures of disease progression rates in Huntington's disease patients and asymptomatic mutation carriers will be of critical importance in future trials of experimental restorative treatments.