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Background Gilts experiencing sustained hyperprolactinemia from d 90 to 109 of gestation showed an early onset of lactogenesis coupled with premature mammary involution. To better understand the molecular mechanisms underlying the premature mammary involution observed in these gilts, a transcriptomic analysis was undertaken. Therefore, this study aimed to explore the effect of hyperprolactinemia on the global transcriptome in the mammary tissue of late gestating gilts and identify the molecular pathways involved in triggering premature mammary involution. Methods On d 90 of gestation, gilts received daily injections of (1) canola oil until d 109 ± 1 of gestation (CTL, n  = 18); (2) domperidone (to induce hyperprolactinemia) until d 96 ± 1 of gestation (T7, n  = 17) or; (3) domperidone (until d 109 ± 1 of gestation (T20, n  = 17). Mammary tissue was collected on d 110 of gestation and total RNA was isolated from six CTL and six T20 gilts for microarray analysis. The GeneChip® Porcine Gene 1.0 ST Array was used for hybridization. Functional enrichment analyses were performed to explore the biological significance of differentially expressed genes, using the DAVID bioinformatics resource. Results The expression of 335 genes was up-regulated and that of 505 genes down-regulated in the mammary tissue of T20 vs CTL gilts. Biological process GO terms and KEGG pathways enriched in T20 vs CTL gilts reflected the concurrent premature lactogenesis and mammary involution. When looking at individual genes, it appears that mammary cells from T20 gilts can simultaneously upregulate the transcription of milk proteins such as WAP , CSN1S2 and LALBA, and genes triggering mammary involution such as STAT3 , OSMR and IL6R . The down-regulation of PRLR expression and up-regulation of genes known to inactivate the JAK-STAT5 pathway ( CISH , PTPN6 ) suggest the presence of a negative feedback loop trying to counteract the effects of hyperprolactinemia. Conclusions Genes and pathways identified in this study suggest that sustained hyperprolactinemia during late-pregnancy, in the absence of suckling piglets, sends conflicting pro-survival and cell death signals to mammary epithelial cells. Reception of these signals results in a mammary gland that can simultaneously synthesize milk proteins and initiate mammary involution.

There has been controversy over the cardiovascular safety of domperidone, attributable to the lack of a well-designed study as well as inconsistent results. This study aimed to examine the risk of severe domperidone-induced ventricular arrhythmia (VA), compared to mosapride, itopride, or non-use of all three prokinetics, in the general population. We conducted a population-based, self-controlled case series analysis. Enrolled subjects were individuals who were diagnosed with severe VA and were prescribed domperidone, mosapride, or itopride from 2003 to 2013 in the National Health Insurance Service-National Sample Cohort. The incidence rate ratio for severe VA was measured during exposure to prokinetics and compared with unexposed periods and itopride (no-proarrhythmic effect)-exposure periods, as control. A total of 2,817 subjects were included. Domperidone, mosapride, or itopride use was associated with increased risk of severe VA, compared with non-use (adjusted incidence rate ratios (IRR) of 1.342 (95% CI 1.096–1.642), 1.350 (95% CI 1.105–1.650), and 1.486 (95% CI 1.196–1.845), respectively). The risk of severe domperidone-induced VA was lower, compared to that of itopride [adjusted IRR of 0.548 (95% CI 0.345–0.870)]. Of the subjects who had been prescribed all three prokinetics, domperidone-exposure was associated with a lower risk of severe VA, compared to itopride-exposure (crude IRR, 0.571; 0.358–0.912). Mosapride-exposure did not show IRR difference for severe VA, compared to itopride-exposure. Domperidone, mosapride, or itopride use is associated with an increased risk of severe VA. However, the magnitude of association was modest and domperidone use does not increase further the risk, compared with other prokinetics.

The present study was designed to measure the potential antiemetic properties of nerolidol (NDL) via in vivo and in silico studies. To induce emesis copper sulfate pentahydrate (CuSO4.5H2O) was administered at a dose of 50 mg/kg (orally) to 2‐day‐old chicks. The test sample (NDL) was given at two doses of 50 and 100 mg/kg. b.w. orally. Additionally, aprepitant (16 mg/kg), domperidone (6 mg/kg), hyoscine (21 mg/kg), ondansetron (5 mg/kg), and diphenhydramine (10 mg/kg) were given also orally as positive controls. To observe the modulatory effects of the test sample, combination therapies with reference drugs were also administered to three different groups of animals. Molecular docking and visualization of ligand‐receptor interaction were performed against several emesis‐inducing receptors (5HT3, D2, D3, H1, and M1‐M5) using diverse computational tools. Pharmacokinetics and drug‐likeness of the selected ligands were also calculated. Findings demonstrated that NDL significantly (p <0.05) dose‐dependently lessens the mean number of retches and delays the emetic onset in the chicks. The combined drug therapy with ondansetron exposed better antiemetic activity. In addition, in silico analysis, NDL has greater binding affinity (−7.3 kcal/mol) against M2 and M3 receptors. In conclusion, NDL exerted mild antiemetic activity with synergistic properties through muscarinic receptors. Nerolidol shows prominent antiemetic activity and mitigates CuSO4.H2O‐mediated retching in chicks efficiently through its peripheral action. Additionally, the in silico studies have also shown possible antiemetic effects with greater binding affinity against muscarinic (specially, M2 and M3) and dopaminergic receptors.

Rationale The role of somatostatin and its receptors for the stress-related neuropsychiatric disorders has been widely raised. Recently, we have also demonstrated the involvement of somatostatin receptor type 2-sst2R and dopamine receptor type 2-D2R in stress. Objective In this context, we decided to find if these receptors are involved in response to antidepressant treatment in animal model of depression—chronic mild stress (CMS). Methods Here, we report data obtained following 7-week CMS procedure. The specific binding of [125I]Tyr3-Octreotide to sst2R and [3H]Domperidone to D2R was measured in the rat brain, using autoradiography. Additionally, the level of dopamine and metabolites was measured in the rat brain. Results In the final baseline test after 7 weeks of stress, the reduced consumption of sucrose solution was observed (controls vs the stressed animals (6.25 0.16 vs. 10.39 0.41; p  < 0.05). Imipramine was administered for the next 5 weeks, and it reversed anhedonia in majority of animals (imipramine-reactive); however, in some animals, it did not (imipramine-non-reactive). Two-way repeated measures ANOVA revealed significant effects of stress and treatment and time interaction [ F (16, 168) = 3.72; p  < 0.0001], n  = 10 per groups. We observed decreased binding of [125I]Tyr3-Octreotide in most of rat brain regions in imipramine non-reactive groups of animals. The decrease of D2R after stress in striatum and nucleus accumbens and no effect of imipramine were observed. In the striatum and prefrontal cortex, the significant role of stress and imipramine in dopamine levels was observed. Conclusions The results obtained in binding assays, together with dopamine level, indicate the involvement of sst2R receptors for reaction to antidepressant treatment. Besides, the stress context itself changes the effect of antidepressant drug.

The purpose of the present study was to develop an optimized gastric floating drug delivery system (GFDDS) containing domperidone as a model drug. Box-Behnken design was employed in formulating the GFDDS with three polymers: hydroxypropyl methylcellulose K4M (HPMC K4M) (X1), Carbopol 934P (X2) and sodium alginate (X3), as independent variables. Floating lag time (FLT), total floating time (TFT), time required to release 50% of the drug (t50) and diffusion exponent (n) were selected as dependent variables. Seventeen formulations were prepared, dissolution data obtained was fitted to the power law and floating profiles were analyzed. HPMC loading was found to be significant for floating properties. Carbopol loading had a negative effect on floating properties but was found helpful in controlling the release rate of the drug. No significant effect of sodium alginate on floating properties was observed but it was important for gel formation. The quadratic mathematical model developed could be used to predict formulations with desired release and floating properties. Cilj rada bio je razvoj i optimizacija plutajućih sustava za isporuku lijekova u želucu (GFDDS) s domperidonom kao modelom lijeka. Box-Behnkenovo dizajniranje korišteno je u formuliranju GFDDS. Nezavisne varijable u dizajniranju bila su tri polimera: hidroksipropil metilceluloza K4M (HPMC K4M) (X1), Carbopol 934P (X2) i natrijev alginat (X3), a zavisne varijable usporeno vrijeme plutanja (FLT), ukupno vrijeme plutanja (TFT), vrijeme potrebno za oslobađanje 50% lijeka (t50) i difuzijski eksponent (n). Pripravljeno je ukupno sedamnaest formulacija. Analizirani su podaci o oslobađanju ljekovite tvari. Količina HPMC značajno utječe na svojstva plutanja, dok količina karbopola ima negativni učinak na svojstvo plutanja, ali kontrolira oslobađanje ljekovite tvari. Natrijev alginat nema značajni učinak na svojstva plutanja, ali utječe na stvaranje gela. Kvadratni matematički model može se upotrijebiti za predviđanje formulacija sa željenim profilom oslobađanja i svojstvima plutanja.

Rationale Few studies have investigated neurobiological and biochemical differences between stress-resilient and stress-vulnerable experimental animals. Objectives We investigated alterations in mesolimbic dopamine D 2 receptor density and mRNA expression level in stressed rats at two time points, i.e. after 2 and 5 weeks of chronic mild stress (CMS). Methods We used the chronic mild stress paradigm because it is a well-established animal model of depression. Two groups of stressed rats were distinguished during CMS experiments: (1) stress reactive (70 %), which displayed a decrease in the drinking of a palatable sucrose solution during the stress regimen, and (2) stress resilient (30 %), which exhibited an unaltered drinking profile when compared with the unchallenged control group. [ 3 H]Domperidone was used as a ligand to label dopamine D 2 receptors, and a mixture of three specific oligonucleotides was used to evaluate dopamine D 2 receptor mRNA changes in various regions of the rat brain. Results CMS strongly affected the mesolimbic dopamine circuit in stress-resilient group after 2 weeks and stress-reactive group of rats after 5 weeks which exhibited a decrease in the level of dopamine D 2 receptor protein without alterations in D 2 mRNA expression. Stress-resilient animals, but not stress-reactive animals, effectively adapted to the extended stress and coped with it. The increase in D 2 mRNA expression returned the dopamine D 2 receptor density to control levels in stress-resilient rats after 5 weeks of CMS, but not in stress-reactive animals. Conclusions These results clearly demonstrate that, despite earlier blunting, the activation of dopamine receptor biosynthesis in the dopamine mesoaccumbens system in stress-resilient rats is involved in active coping with stressful experiences, and it exhibits a delay in time.

We characterized the binding of [125I]epidepride to dopamine D2-like and D3-like receptors in tissue sections of human striatum. The competition for binding of [125I]epidepride by domperidone, quinpirole, and 7-hydroxy-N,N-di(1-propyl)-2-aminotetralin (7-OH-DPAT) was best fit by assuming one site in the caudate but two sites in nucleus accumbens. Guanosine 5'-[beta, gamma-imido]triphosphate showed a large modulatory influence in agonist inhibition of [125I]epidepride binding in caudate but not in nucleus accumbens. The binding of [125I]epidepride in the presence of 7-OH-DPAT (1000-fold selective for D3-like versus D2-like sites) and domperidone (20-fold selective for D2-like versus D3-like sites) was used to quantify the numbers of D2-like and D3-like receptors in areas of human brain. The distribution of D2-like and D3-like receptors was largely nonoverlapping. Binding of [125I]epidepride to D3-like receptors was negligible in the dorsal striatum but was concentrated in islands of dense binding in the nucleus accumbens and ventral putamen that aligned with acetylcholinesterase-poor striosomes. Binding to D3-like receptors was also enriched in the internal globus pallidus, ventral pallidum, septum, islands of Calleja, nucleus basalis, amygdalostriatal transition nucleus of the amygdala, central nucleus of the amygdala, and ventral tegmental area. Binding of [125I]epidepride to D2 but not D3 receptors was detected in cortex and hippocampus.

A clone encoding a human D2 dopamine receptor was isolated from a pituitary cDNA library and sequenced. The deduced protein sequence is 96% identical with that of the cloned rat receptor with one major difference: the human receptor contains an additional 29 amino acids in its putative third cytoplasmic loop. Southern blotting demonstrated the presence of only one human D2 receptor gene. Two overlapping phage containing the gene were isolated and characterized. DNA sequence analysis of these clones showed that the coding sequence is interrupted by six introns and that the additional amino acids present in the human pituitary receptor are encoded by a single exon of 87 base pairs. The involvement of this sequence in alternative splicing and its biological significance are discussed.

Sodium ion (Na + ) influences binding of both dopamine agonists and antagonists to D 2 receptors in striatum and retina. Also, Na + markedly potentiates the loss of high-affinity agonist binding due to the GTP analogue p[NH]ppG. 2-Amino-6, 7-dihydroxy-1,2,3,4-tetrahydro[5,8- 3 H]naphthalene ([ 3 H]ADTN) binds exclusively to an agonist conformation of D 2 receptor in both striatum and retina, distinct from the antagonist conformation labeled by [ 3 H]spiroperidol or [ 3 H]domperidone in striatum or by [ 3 H]spiroperidol in retina. Na + is not required for interaction of [ 3 H]ADTN or antagonist radioligand sites with the selective D 2 agonist LY-141865, the D 2 antagonist domperidone, or nonselective dopamine agonists or antagonists; however, Na + is necessary for high affinity interaction of those radioligand sites with the D 2 antagonists molindone and metoclopramide. With Na + present, striatal sites for [ 3 H]ADTN, [ 3 H]spiroperidol, and [ 3 H]domperidone have similar affinities for antagonists but only [ 3 H]ADTN sites have high affinity for agonists. Na + further decreases the low affinity of dopamine agonists for [ 3 H]spiroperidol binding sites. Also, Na + enhances [ 3 H]spiroperidol and decreases [ 3 H]ADTN binding. Na + alone causes bound [ 3 H]ADTN to dissociate from at least 30% of striatal and 50% of retinal sites, and with Na + present [ 3 H]ADTN rapidly dissociates from the remaining sites upon addition of p[NH]ppG. It is proposed that D 2 receptors in striatum and retina exist in distinct but interconvertible conformational states, with different properties depending on the presence or absence of Na + and of guanine nucleotide. adenylate cyclase antipsychotic drugs neuroleptic drugs guanine nucleotide

The binding of [3H]domperidone and [3H]spiroperidol was examined in membranes prepared from rat striatum. Scatchard analysis of the binding of [3H]domperidone resulted in curvilinear plots consistent with the presence of multiple classes of binding sites. Nonlinear regression analysis of untransformed data showed that the curvature was best explained by the presence of two populations of binding sites. Scatchard plots of the binding of [3H]spiroperidol were linear, suggesting that this radioligand binds to a single class of receptors. However, results obtained in studies of the inhibition of [3H]spiroperidol binding by a number of competing ligands were not consistent with the interaction of these agents with a single class of binding sites. Computer-assisted analysis of the Hofstee plots of six competing ligands gave the same relative proportion for two classes of sites as determined by analysis of the binding of [3H]domperidone. The two classes of receptors labeled with [3H]spiroperidol had affinities for domperidone that were similar to those of the two populations of binding sites for [3H]domperidone. Furthermore, the number of binding sites for [3H]spiroperidol was equal to the total number of binding sites for [3H]domperidone. These findings suggest that the two radioligands bind to the same two classes of binding sites. It is unlikely that either of the two classes of striatal sites are receptors for serotonin. The approach described will make it possible to assess the effects of physiological or pharmacological manipulations on the densities or properties of subtypes of dopamine receptors.