Flibanserin and 8‐OH‐DPAT Implicate Serotonin in Association between Female Marmoset Monkey Sexual Behavior and Changes in Pair‐Bond Quality

Introduction.  Psychopathological origins of personally distressing, hypoactive sexual desire disorder (HSDD) in women are unknown, but are generally attributed to an inhibitory neural regulator, serotonin (5‐HT). Flibanserin, a 5‐HT 1A agonist and 5‐HT 2A antagonist, shows promise as a treatment for HSDD. Aim.  To test the hypothesis that female marmoset sexual behavior is enhanced by flibanserin and diminished by 8‐OH‐DPAT, in order to evaluate the efficacy of serotonergic modulation of female sexual behavior in a pairmate social setting comparable to humans. Methods.  Sexual and social behavior were examined in eight female marmoset monkeys receiving daily flibanserin (15 mg/kg), 8‐OH‐DPAT (0.1 mg/kg), or corresponding vehicle for 15–16 weeks in a counterbalanced, within‐subject design, while housed in long‐term, stable male–female pairs. Main Outcome Measures.  Marmoset pairmate interactions, including sexual and social behavior, were scored during weeks 5–6 of daily flibanserin, 8‐OH‐DPAT or vehicle treatment. 24‐hour pharmacokinetic profiles of the drugs and their metabolites, as well as drug‐induced acute symptoms of the 5‐HT behavioral syndrome were also assessed. Results.  Two‐way analysis of variance reveals that flibanserin‐treated females attract more male sexual interest ( P  = 0.020) and trigger increased grooming ( P  = 0.001) between partners. In contrast, 8‐OH‐DPAT‐treated females show increased rejection of male sexual advances ( P  = 0.024), a tendency for decreased male sexual interest ( P  = 0.080), and increased aggression with their male pairmates ( P  = 0.049). Conclusions.  While 8‐OH‐DPAT‐treated female marmosets display decreased sexual receptivity and increased aggressive interactions with their male pairmates, flibanserin‐treated female marmosets demonstrate increased affiliative behavior with their male pairmates. Such pro‐affiliation attributes may underlie flibanserin's effectiveness in treating HSDD in women. Aubert Y, Gustison ML, Gardner LA, Bohl MA, Lange JR, Allers KA, Sommer B, Datson NA, and Abbott DH. Flibanserin and 8‐OH‐DPAT implicate serotonin in association between female marmoset monkey sexual behavior and changes in pair‐bond quality. J Sex Med 2012;9:694–707.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90344/1/j.1743-6109.2011.02616.x.pd

Identification of essential and non-essential single-stranded DNA-binding proteins in a model archaeal organism

Single-stranded DNA-binding proteins (SSBs) play vital roles in all aspects of DNA metabolism in all three domains of life and are characterized by the presence of one or more OB fold ssDNA-binding domains. Here, using the genetically tractable euryarchaeon Haloferax volcanii as a model, we present the first genetic analysis of SSB function in the archaea. We show that genes encoding the OB fold and zinc finger-containing RpaA1 and RpaB1 proteins are individually non-essential for cell viability but share an essential function, whereas the gene encoding the triple OB fold RpaC protein is essential. Loss of RpaC function can however be rescued by elevated expression of RpaB, indicative of functional overlap between the two classes of haloarchaeal SSB. Deletion analysis is used to demonstrate important roles for individual OB folds in RpaC and to show that conserved N- and C-terminal domains are required for efficient repair of DNA damage. Consistent with a role for RpaC in DNA repair, elevated expression of this protein leads to enhanced resistance to DNA damage. Taken together, our results offer important insights into archaeal SSB function and establish the haloarchaea as a valuable model for further studies

Blood plasma B vitamins in depression and the therapeutic response to electroconvulsive therapy

A growing body of research has indicated a role for B vitamins in depression, with some previous studies suggesting that B vitamin status in patients with depression can impact on antidepressant response. Here we aimed to investigate B vitamin plasma concentrations in medicated patients with depression (n ​= ​94) compared to age- and sex-matched healthy controls (n ​= ​57), and in patients with depression after electroconvulsive therapy (ECT) in a real-world clinical setting. Our results show that nicotinamide (vitamin B3), N1-methylnicotinamide (vitamin B3 metabolite), and pyridoxal 5′-phosphate (PLP; vitamin B6) concentrations were significantly reduced in patients with depression compared to controls. The Cohen’s d effect sizes for nicotinamide, N1-methylnicotinamide, and PLP were moderate–large (−0.47, −0.51, and −0.59, respectively), and likely to be of clinical relevance. Functional biomarkers of vitamin B6 status (PAr index, 3-hydroxykynurenine: hydroxyanthranilic acid ratio, 3-hydroxykynurenine: xanthurenic acid ratio, and HKr) were elevated in depressed patients compared to controls, suggestive of reduced vitamin B6 function. Over 30% of the patient cohort were found to have low to deficient PLP concentrations, and exploratory analyses revealed that these patients had higher IL-6 and CRP concentrations compared to patients with PLP levels within the normal range. Treatment with ECT did not alter B vitamin concentrations, and B vitamin concentrations were not associated with depression severity or the therapeutic response to ECT. Overall, reduced plasma PLP, nicotinamide, and N1-methylnicotinamide concentrations could have wide ranging effects on pathways and systems implicated in depression. Further studies are required to understand the reasons why patients with depression present with low plasma B vitamin concentrations

Tryptophan catabolites and depression in the general population: results from the Gutenberg Health Study

Abstract Previous studies reported significantly altered tryptophan catabolite concentrations in major depression. Thus, tryptophan catabolites were considered as potential biomarkers of depression and their modulators as potential targets for psychopharmacotherapy. However, the results were based mainly on studies with small sample sizes limiting their generalizability. Against this background, we investigated the relationship of peripheral tryptophan catabolites with depression in a population-based sample with n = 3,389 participants (with fasting status ≥ 8 h and C-reactive protein < 10 mg/L). N = 248 had clinically significant depression according to a PHQ-9 score of ≥ 10, n = 1,101 subjects had mild depressive symptoms with PHQ-9 scores between 5 and 9, and n = 2,040 had no depression. After multivariable adjustment, clinically significant depression was associated with lower kynurenine and kynurenic acid. Spearman correlation coefficients of the tryptophan catabolites with the severity of depression were very small (rho ≤ 0.080, p ≤ 0.015). None of the tryptophan catabolites could diagnostically separate depressed from not depressed persons. Concerning linear associations, kynurenine and kynurenic acid were associated only with the severity and the cognitive dimension of depression but not its somatic dimension. Tryptophan catabolites were not associated with persistence or recurrence of depression at the 5 year follow-up. The results replicated the association between kynurenine and kynurenic acid with depression. However, the associations were small raising doubts about their clinical utility. Findings underline the complexity of the relationships between depression and tryptophan catabolites. The search for subgroups of depression with a potentially higher impact of depression might be warranted