Search

Glutamate delta receptor 1 (GluD1) is a unique synaptogenic molecule expressed at excitatory and inhibitory synapses. The lateral habenula (LHb), a subcortical structure that regulates negative reward prediction error and major monoaminergic systems, is enriched in GluD1. LHb dysfunction has been implicated in psychiatric disorders such as depression and schizophrenia, both of which are associated with GRID1, the gene that encodes GluD1. Thus, disruption in GluD1 synaptic signaling may contribute to LHb dysfunction and the pathophysiology of LHb-associated disorders. Despite its strong cellular expression, little is known about the subsynaptic and subcellular localization of GluD1 in LHb neurons. Given that GluD1 is involved in the development and/or regulation of glutamatergic and GABAergic synapses in various brain regions, a detailed map of GluD1 synaptic localization is essential to elucidate its role in the LHb. To address this issue, we used immunoelectron microscopy methods in rodents and monkeys. In both species, GluD1 immunoreactivity was primarily expressed in dendritic profiles, with lower expression in somata, spines, and glial elements. Pre- and post-embedding immunogold experiments revealed strong GluD1 expression in the core of symmetric GABAergic synapses. Albeit less frequent, GluD1 was also found at the edges (i.e., perisynaptic) of asymmetric, putative glutamatergic synapses. Through the combination of anterograde tracing with immunogold labeling in rats, we showed that axon terminals from the entopeduncular nucleus and the lateral hypothalamus express postsynaptic GluD1 immunolabeling in the LHb. Our findings suggest that GluD1 may play a critical role in modulating GABAergic transmission in the rodent and primate LHb., (© 2025 The Author(s). The Journal of Comparative Neurology published by Wiley Periodicals LLC.)

Introduction: The tobacco-specific nitrosamines (TSNAs) are an important group of carcinogens found in tobacco and tobacco smoke. To describe and characterize the levels of TSNAs in the Population Assessment of Tobacco and Health (PATH) Study Wave 1 (2013-2014), we present four biomarkers of TSNA exposure: N'-nitrosonornicotine, N'-nitrosoanabasine, N'-nitrosoanatabine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) which is the primary urinary metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone., Methods: We measured total TSNAs in 11 522 adults who provided urine using automated solid-phase extraction coupled to isotope dilution liquid chromatography-tandem mass spectrometry. After exclusions in this current analysis, we selected 11 004 NNAL results, 10 753 N'-nitrosonornicotine results, 10 919 N'-nitrosoanatabine results, and 10 996 N'-nitrosoanabasine results for data analysis. Geometric means and correlations were calculated using SAS and SUDAAN., Results: TSNA concentrations were associated with choice of tobacco product and frequency of use. Among established, every day, exclusive tobacco product users, the geometric mean urinary NNAL concentration was highest for smokeless tobacco users (993.3; 95% confidence interval [CI: 839.2, 1147.3] ng/g creatinine), followed by all types of combustible tobacco product users (285.4; 95% CI: [267.9, 303.0] ng/g creatinine), poly tobacco users (278.6; 95% CI: [254.9, 302.2] ng/g creatinine), and e-cigarette product users (6.3; 95% CI: [4.7, 7.9] ng/g creatinine). TSNA concentrations were higher in every day users than in intermittent users for all the tobacco product groups. Among single product users, exposure to TSNAs differed by sex, age, race/ethnicity, and education. Urinary TSNAs and nicotine metabolite biomarkers were also highly correlated., Conclusions: We have provided PATH Study estimates of TSNA exposure among US adult users of a variety of tobacco products. These data can inform future tobacco product and human exposure evaluations and related regulatory activities., (Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2020.)