The quetiapine active metabolite N-Desalkylquetiapine and the neurotensin NTS1 receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats

Major depressive disorder (MDD) is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that are apparent following one week of quetiapine treatment, and it is possible that the active metabolite N-Desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 are suggestive of antidepressant efficacy, but the effects of a NTS1 receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of the N-Desalkylquetiapine, the neurotensin NTS1 receptor agonist PD14916, quetiapine, the tricylic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate (DRL) 72 s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. The typical antipsychotic drug raclopride decreased both reinforcers and responses. These data suggest that N-Desalklyquetiapine likely contributes to quetiapine’s antidepressant efficacy and identifies NTS1 receptor activation as a potential novel pharmacologic strategy for antidepressant drugs

Systemic administration of the neurotensin NTS1 receptor agonist PD149163 improves performance on a memory task in naturally deficient male Brown Norway rats

Agonists for neurotensin NTS1 receptor consistently exhibit antipsychotic effects in animal models without producing catalepsy, suggesting that NTS1 receptor agonists may be a novel class of drugs to treat schizophrenia. Moreover, studies utilizing NTS1 agonists have reported improvements in some aspects of cognitive functioning, including prepulse inhibition and learning procedures, that suggest an ability of NTS1 receptor agonists to diminish neurocognitive deficits. The present study sought to assess both baseline delay-induced memory performance and the effects of NTS1 receptor activation on learning and memory consolidation in male Long Evans and Brown Norway rats using a delayed non-match to position radial arm maze task. In the absence of drugs, Brown Norway rats displayed a significant increase in spatial memory errors following a 3, 7, and 24 hour delay, whereas Long Evans rats exhibited an increase in spatial memory errors following only a 7 and 24 hour delay. With Brown Norway rats, administration of PD149163 before or after an information trial significantly reduced errors during a retention trial after a 24 hour delay. Administration of the NTS1/2 receptor antagonist SR142948 prior to the information trial did not affect retention trial errors. These data are consistent with previous findings that Brown Norway rats have natural cognitive deficits and that they may be useful for assessing putative antipsychotic drugs for cognitive efficacy. Moreover, this study supports previous findings suggesting that NTS1 receptor agonists may improve some aspects of cognitive functioning

Human Milk-Fed Piglets Have a Distinct Small Intestine and Circulatory Metabolome Profile Relative to That of Milk Formula-Fed Piglets.

The impact of human milk (HM) feeding compared with cow's milk formula (MF) feeding on small intestinal and circulatory metabolome patterns has not been fully investigated. Therefore, 2-day-old male piglets were fed HM or MF (n = 26/group) from postnatal day 2 (PND 2) through 21 and were weaned to a solid diet until PND 51. The small intestine (gastrointestinal [GI]) contents, serum, and urine were collected from subsets of piglets at PND 21 and PND 51. Samples were subjected to primary metabolomics analyses at the West Coast Metabolomics Center, UC Davis. The metabolome data assessment and the statistical analyses were performed with MetaboAnalyst software. Compared with MF feeding, at PND 21, HM feeding resulted in a higher abundance of fucose in the jejunum and urine and a greater concentration of myo-inositol in serum. In HM-fed piglets, 1,5-anhydroglucitol was higher in the duodenum, serum, and urine at PND 21. Additionally, the HM group had higher levels of urinary kynurenic acid at PND 21. Correlations between bacterial genera and altered metabolites in ileum revealed that Turicibacter sp. and Campylobacter sp. were positively correlated with maltotriose and panose at PND 21, while ileal Campylobacter sp. was negatively correlated with fumaric acid. At PND 51, no significant metabolites were identified between HM and MF diet groups. The metabolites associated with the neonatal diets may serve as the substrates and signals that contribute to the physiological effects in HM and MF during infancy, with a subset reflecting diet-associated differences in microbial metabolism and ecology.IMPORTANCE Exclusive HM feeding for newborns is recommended at least for the first 6 months of life. However, when breastfeeding is not possible, MF is recommended as a substitute. Due to the challenges associated with sample collection from infants fed HM or MF, their gut metabolism is poorly understood. Thus, an established piglet model from our team was used to determine the metabolite profile in relation to host, diet, and microbiota. The current study is the first to provide novel insights across the small intestine metabolism and its association with circulatory metabolites in the HM group relative to the MF group at the weaning and postweaning period. Data also demonstrate that during the neonatal period, diet, host, and microbial metabolism contribute to the lumen and circulatory metabolite profile. Furthermore, small intestinal lumen metabolome can be tracked in the urine as a biomarker of dietary differences, which would be a useful tool for clinical interventions

Neonatal Diet Impacts the Large Intestine Luminal Metabolome at Weaning and Post-Weaning in Piglets Fed Formula or Human Milk.

The impact of human milk (HM) or dairy milk-based formula (MF) on the large intestine's metabolome was not investigated. Two-day old male piglets were randomly assigned to HM or MF diet (n = 26/group), from postnatal day (PND) 2 through 21 and weaned to a solid diet until PND 51. Piglets were euthanized at PND 21 and PND 51, luminal contents of the cecum, proximal (PC) and distal colons (DC), and rectum were collected and subjected to metabolomics analysis. Data analyses were performed using Metaboanalyst. In comparison to MF, the HM diet resulted in higher levels of fatty acids in the lumen of the cecum, PC, DC, and rectum at PND 21. Glutamic acid was greater in the lumen of cecum, PC, and DC relative to the MF group at PND 21. Also, spermidine was higher in the DC and rectal contents of HM relative to MF at PND 21. MF diet resulted in greater abundances of amino acids in the cecal lumen relative to HM diet at PND 21. Additionally, several sugar metabolites were higher in various regions of the distal gut of MF fed piglets relative to HM group at PND 21. In contrast, at PND 51, in various regions there were higher levels of erythritol, maltotriose, isomaltose in HM versus MF fed piglets. This suggests a post weaning shift in sugar metabolism that is impacted by neonatal diet. The data also suggest that infant diet type and host-microbiota interactions likely influence the lower gut metabolome

Neonatal Diet Impacts the Large Intestine Luminal Metabolome at Weaning and Post-Weaning in Piglets Fed Formula or Human Milk.

The impact of human milk (HM) or dairy milk-based formula (MF) on the large intestine's metabolome was not investigated. Two-day old male piglets were randomly assigned to HM or MF diet (n = 26/group), from postnatal day (PND) 2 through 21 and weaned to a solid diet until PND 51. Piglets were euthanized at PND 21 and PND 51, luminal contents of the cecum, proximal (PC) and distal colons (DC), and rectum were collected and subjected to metabolomics analysis. Data analyses were performed using Metaboanalyst. In comparison to MF, the HM diet resulted in higher levels of fatty acids in the lumen of the cecum, PC, DC, and rectum at PND 21. Glutamic acid was greater in the lumen of cecum, PC, and DC relative to the MF group at PND 21. Also, spermidine was higher in the DC and rectal contents of HM relative to MF at PND 21. MF diet resulted in greater abundances of amino acids in the cecal lumen relative to HM diet at PND 21. Additionally, several sugar metabolites were higher in various regions of the distal gut of MF fed piglets relative to HM group at PND 21. In contrast, at PND 51, in various regions there were higher levels of erythritol, maltotriose, isomaltose in HM versus MF fed piglets. This suggests a post weaning shift in sugar metabolism that is impacted by neonatal diet. The data also suggest that infant diet type and host-microbiota interactions likely influence the lower gut metabolome

Neonatal diet alters fecal microbiota and metabolome profiles at different ages in infants fed breast milk or formula

BackgroundNeonatal diet has a large influence on child health and might modulate changes in fecal microbiota and metabolites.ObjectivesThe aim is to investigate fecal microbiota and metabolites at different ages in infants who were breastfed (BF), received dairy-based milk formula (MF), or received soy-based formula (SF).MethodsFecal samples were collected at 3 (n = 16, 12, and 14, respectively), 6 (n = 20, 19, and 15, respectively), 9 (n = 12, 11, and 12, respectively), and 12 mo (n = 14, 14, and 15, respectively) for BF, MF, and SF infants. Infants that breastfed until 9 mo and switched to formula were considered as no longer breastfeeding at 12 mo. Microbiota data were obtained using 16S ribosomal RNA sequencing. Untargeted metabolomics was conducted using a Q-Exactive Hybrid Quadrupole-Orbitrap mass spectrometer. The data were analyzed using R (version 3.6.0) within the RStudio (version 1.1.463) platform.ResultsAt 3, 6, and 9 mo of age BF infants had the lowest α-diversity, SF infants had the highest diversity, and MF was intermediate. Bifidobacterium was 2.6- to 5-fold lower in SF relative to BF infants through 1 y of life. An unidentified genus from Ruminococcaceae higher in the SF (2%) than in the MF (0.4%) and BF (0.08%) infants at 3 mo of age was observed. In BF infants higher levels of butyric acid, d-sphingosine, kynurenic acid, indole-3-lactic acid, indole-3-acetic acid, and betaine were observed than in MF and SF infants. At 3 mo Ruminococcaceae was positively correlated to azelaic, gentisic, isocitric, sebacic, and syringic acids. At 6 mo Oscillospira was negatively correlated with 3-hydroxybutyric-acid, hydroxy-hydrocinnamic acid, and betaine whereas Bifidobacterium was negatively associated with 5-hydroxytryptamine. At 12 mo of age, Lachnospiraceae was negatively associated with hydroxyphenyllactic acid.ConclusionsInfant diet has a large impact on the fecal microbiome and metabolome in the first year of life.This study was registered at clinicaltrials.gov as NCT00616395