Acute continuous moderate-intensity exercise, but not low-volume high-intensity interval exercise, attenuates postprandial suppression of circulating osteocalcin in young overweight and obese adults.

Bone remodeling markers (BRMs) are suppressed following the consumption of a meal. Our findings indicate that a single session of continuous moderate-intensity exercise, but not low-volume high-intensity interval exercise, performed 1 h after a meal attenuates the postprandial suppression of BRMs. INTRODUCTION: Acute exercise transiently increases BRMs including osteocalcin (tOC) and the undercarboxylated form of osteocalcin (ucOC), a hormone that is implicated in glucose regulation. The effects of acute exercise and exercise-intensity on postprandial levels of tOC and ucOC are unknown. METHODS: Twenty-seven adults that were overweight or obese (age 30 ± 1 years; BMI 30 ± 1 kg∙m-2; mean ± SEM) were randomly allocated to perform a single session of low-volume high-intensity interval exercise (LV-HIIE; nine females, five males) or continuous moderate-intensity exercise (CMIE; eightfemales, five males) 1 h after consumption of a standard breakfast. Serum tOC, ucOC, and ucOC/tOC were measured at baseline, 1 h, and 3 h after breakfast consumption on a rest day (no exercise) and the exercise day (exercise 1 h after breakfast). RESULTS: Compared to baseline, serum tOC and ucOC were suppressed 3 h after breakfast on the rest day (- 10 ± 1% and - 6 ± 2%, respectively; p < 0.05), whereas ucOC/tOC was elevated (2.5 ± 1%; p = 0.08). Compared to the rest day, CMIE attenuated the postprandial-induced suppression of tOC (rest day - 10 ± 2% versus CMIE - 5 ± 2%, p < 0.05) and ucOC (rest day - 6 ± 4% versus CMIE 11 ± 2%, p < 0.05), and increased postprandial ucOC/tOC (rest day 3 ± 2% versus CMIE 15 ± 1%, p < 0.05). In contrast, LV-HIIE did not alter postprandial tOC, ucOC, or ucOC/tOC (all p > 0.1). CONCLUSIONS: Acute CMIE, but not LV-HIIE, attenuates the postprandial-induced suppression of tOC and ucOC. CMIE may be an effective tool to control the circulating levels of BRMs following meal consumption in overweight/obese adults.

Effects of calcium supplementation on circulating osteocalcin and glycated haemoglobin in older women.

One year of calcium supplementation in older women led to modest reductions in total osteocalcin and undercarboxylated osteocalcin (ucOC), with no changes in muscle or fat mass, or glycated haemoglobin. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control. INTRODUCTION: Total osteocalcin (TOC) is a marker of bone turnover, while its undercarboxylated form has beneficial effects on glucose metabolism in mice. This post hoc analysis of a randomised double-blind, placebo-controlled trial examined whether 1 year of calcium supplementation affected circulating TOC, undercarboxylated osteocalcin (ucOC) or glycated haemoglobin (HbA1c) in 1368 older community-dwelling women (mean age 75.2 ± 2.7 years). METHODS: Women enrolled in the Calcium Intake Fracture Outcome Study trial (1998-2003) were supplemented with 1.2 g/d of elemental calcium (in the form of calcium carbonate) or placebo. Circulating TOC, ucOC and HbA1c was measured at 1 year (1999). RESULTS: After 1 year of calcium supplementation, TOC and ucOC levels were 17% and 22% lower compared with placebo (mean 22.7 ± 9.1 vs. 27.3 ± 10.9 µg/L and 11.1 ± 4.9 vs. 13.0 ± 5.7 µg/L, both P < 0.001). Carboxylated osteocalcin/ucOC was 6% lower after calcium supplementation (P < 0.05). Despite this, no differences in HbA1c were observed (calcium, 5.2 ± 0.6 vs. placebo, 5.3 ± 0.8%; P = 0.08). Calcium supplementation did not affect BMI, whole body lean or fat mass. In exploratory analyses, total calcium (dietary and supplemental) was inversely related to TOC and ucOC, indicating calcium intake is an important dietary determinant of osteocalcin levels. CONCLUSION: One year of calcium supplementation in older women led to modest reductions in TOC and ucOC, with no changes in muscle or fat mass, or HbA1c. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control.

Individual personality differences in Port Jackson sharks Heterodontus portusjacksoni.

This study examined interindividual personality differences between Port Jackson sharks Heterodontus portusjacksoni utilizing a standard boldness assay. Additionally, the correlation between differences in individual boldness and stress reactivity was examined, exploring indications of individual coping styles. Heterodontus portusjacksoni demonstrated highly repeatable individual differences in boldness and stress reactivity. Individual boldness scores were highly repeatable across four trials such that individuals that were the fastest to emerge in the first trial were also the fastest to emerge in subsequent trials. Additionally, individuals that were the most reactive to a handling stressor in the first trial were also the most reactive in a second trial. The strong link between boldness and stress response commonly found in teleosts was also evident in this study, providing evidence of proactive-reactive coping styles in H. portusjacksoni. These results demonstrate the presence of individual personality differences in sharks for the first time. Understanding how personality influences variation in elasmobranch behaviour such as prey choice, habitat use and activity levels is critical to better managing these top predators which play important ecological roles in marine ecosystems.

Isavuconazole activity against Aspergillus lentulus, Neosartorya udagawae, and Cryptococcus gattii, emerging fungal pathogens with reduced azole susceptibility.

Isavuconazole is an extended-spectrum triazole with in vitro activity against a wide variety of fungal pathogens. Clinical isolates of molds Aspergillus lentulus and Neosartorya udagawae and yeast Cryptococcus gattii VGII (implicated in the outbreak in the Pacific Northwest, North America) exhibit reduced susceptibilities to several azoles but higher susceptibilities to isavuconazole.

Osteocalcin and its forms respond similarly to exercise in males and females.

INTRODUCTION: Acute exercise increases osteocalcin (OC), a marker of bone turnover, and in particular the undercarboxylated form (ucOC). Males and females differ in baseline levels of total OC and it is thought the hormonal milieu may be driving these differences. Males and females adapt differently to the same exercise intervention, however it is unclear whether the exercise effects on OC are also sex-specific. We tested whether the responses of OC and its forms to acute High Intensity Interval Exercise (HIIE) and High Intensity Interval Training (HIIT) differed between males and females. Secondly, we examined whether sex hormones vary with OC forms within sexes to understand if these are driving factor in any potential sex differences. METHODS: Total OC (tOC), undercarboxylated OC (ucOC), and carboxylated OC (cOC) were measured in serum of 96 healthy participants from the Gene SMART cohort (74 males and 22 females) at rest, immediately after, and 3 h after a single bout of HIIE, and at rest, 48 h after completing a four week HIIT intervention. Baseline testosterone and estradiol were also measured for a subset of the cohort (Males = 38, Females = 20). Linear mixed models were used to a) uncover the sex-specific effects of acute exercise and short-term training on OC forms and b) to examine whether the sex hormones were associated with OC levels. RESULTS: At baseline, males had higher levels of tOC, cOC, and ucOC than females (q < 0.01). In both sexes tOC, and ucOC increased to the same extent after acute HIIE. At baseline, in males only, higher testosterone was associated with higher ucOC (ß = 3.37; q < 0.046). Finally, tOC and ucOC did not change following 4 weeks of HIIT. CONCLUSION/DISCUSSION: While there were no long-term changes in OC and its forms. tOC and ucOC were transiently enhanced after a bout of HIIE similarly in both sexes. This may be important in metabolic signalling in skeletal muscle and bone suggesting that regular exercise is needed to maintain these benefits. Overall, these data suggest that the sex differences in exercise adaptations do not extend to the bone turnover marker, OC.

Association of paediatric mastocytosis with a polymorphism resulting in an amino acid substitution (M541L) in the transmembrane domain of c-KIT.

BACKGROUND: The receptor tyrosine kinase c-KIT plays a key role in normal mast cell development. Point mutations in c-KIT have been associated with sporadic or familial mastocytosis. OBJECTIVES: Two unrelated pairs of apparently identical twins affected by cutaneous mastocytosis attending the Mastocytosis Clinic at the Royal Children's Hospital, Melbourne, provided an opportunity to assess the possible contribution of c-KIT germline mutations or polymorphisms in this disease. METHODS: Tissue biopsy, blood and/or buccal swab specimens were collected from 10 children with mastocytosis. To detect germline mutations/polymorphisms in c-KIT, we studied all coding exons by denaturing high pressure liquid chromatography. Exons showing mismatches were examined by direct sequencing. The influence of the substitution identified was further examined by expressing the variant form of c-KIT in factor-dependent FDC-P1 cells. RESULTS: In both pairs of twins, a heterozygous ATG to CTG transition in codon 541 was observed, resulting in the substitution of a methionine residue in the transmembrane domain by leucine (M541L). In each case, one parent was also heterozygous for this allele. Expression of M541L KIT in FDC-P1 cells enabled them to grow in human KIT ligand (stem cell factor, SCF) but did not confer factor independence. Compared with cells expressing wild-type KIT at a similar level, M541L KIT-expressing cells displayed enhanced growth at low levels of SCF, and heightened sensitivity to the KIT inhibitor, imatinib mesylate. CONCLUSIONS: The data suggest that the single nucleotide polymorphism resulting in the substitution M541L may predispose to paediatric mastocytosis.

Reproductive experience and expression of dopamine D(2) receptor mRNA: a possible mechanism for reduced prolactin secretion in primiparous rats.

Reproductive experience (i.e. pregnancy and lactation) leads to reduced levels of circulating prolactin in both women and rats. Stimulation of prolactin secretion by dopamine antagonists is also blunted following reproductive experience in both species. Whereas a parity-induced reduction in haloperidol-stimulated prolactin secretion is evident in ovariectomised rats, it is unknown whether a similar attenuation of prolactin secretion is present in reproductively experienced, cycling pro-oestrous rats. The present study examined this possibility. Moreover, to determine possible mechanisms involved in parity-mediated changes in prolactin secretion, both dopamine utilisation within the arcuate nucleus/median eminence and expression of dopamine D(2) receptor mRNA (short and long forms) in the anterior pituitary were measured across the afternoon of pro-oestrous in reproductively experience and inexperienced females. Prolactin secretion was lower on the afternoon of pro-oestrous in primiparous females compared to age-matched, nulliparous controls. In addition, haloperidol-stimulated prolactin secretion was reduced in ovariectomised, reproductively experienced females. Although no differences in dopamine utilisation were observed as a function of reproductive experience, parity did affect the expression of both forms of D(2) receptor mRNA in the anterior pituitary. Compared with nulliparous controls, primiparous females had increased D(2 long) mRNA expression at 12.00 h on pro-oestrous as well as increased D(2 short) mRNA expression at 14.00 h. Because the ratio of D(2 long)/D(2 short) can significantly effect lactotroph proliferation and prolactin secretion, a shift in relative expression of the two D(2) receptor isoforms within the anterior pituitary of parous females may help account for the reduction in prolactin secretion that occurs following reproductive experience.

Sex- and age-specific differences in relaxin family peptide receptor expression within the hippocampus and amygdala in rats.

Relaxin is an essential pregnancy-related hormone with broad peripheral effects mediated by activation of relaxin-like family peptide 1 receptors (RXFP1). More recent studies suggest an additional role for relaxin as a neuropeptide, with RXFP1 receptors expressed in numerous brain regions. Neurons in an area of the brainstem known as the nucleus incertus (NI) produce relaxin 3 (RLN3), the most recently identified neuropeptide in the relaxin family. RLN3 has been shown to activate both RXFP1 and relaxin-like family peptide receptor 3 (RXFP3) receptor subtypes. Studies suggest wide-ranging neuromodulatory effects of both RXFP1 and RXFP3 activation, although to date the majority of studies have been conducted in young males. In the current study, we examined potential sex- and age-related changes in RLN3 gene expression in the NI as well as RXFP1 and RXFP3 gene expression in the dorsal hippocampus (HI), ventral hippocampus (vHI) and amygdala (AMYG) using young adult (9-12weeks) and middle-aged (9-12months) male and female rats. In addition, regional changes in RXFP1 and RXFP3 protein expression were examined in the CA1, CA2/CA3 and dentate gyrus (DG) as well as within basolateral (BLA), central (CeA), and medial (MeA) amygdaloid nuclei. In the NI, RLN3 showed an age-related decrease in males. In the HI, only the RXFP3 receptor showed an age-related change in gene expression, however, both receptor subtypes showed age-related changes in protein expression that were region specific. Additionally, while gene and protein expression of both receptors increased with age in AMYG, these effects were both region- and sex-specific. Finally, overall males displayed a greater number of cells that express the RXFP3 protein in all of the amygdaloid nuclei examined. Cognitive and emotional processes regulated by activity within the HI and AMYG are modulated by both sex and age. The vast majority of studies exploring the influence of sex on age-related changes in the HI and AMYG have focused on sex hormones, with few studies examining the role of neuropeptides. The current findings suggest that changes in relaxin family peptides may contribute to the significant sex differences observed in these brain regions as a function of aging.

Central infusions of the recombinant human prolactin receptor antagonist, S179D-PRL, delay the onset of maternal behavior in steroid-primed, nulliparous female rats.

The expression of maternal behavior in the newly parturient rat is under endocrine regulation. Blocking endogenous PRL secretion with bromocriptine delays the normal rapid expression of maternal care shown toward foster young in steroid-primed virgin female rats. The recent development of the PRL receptor antagonist S179D-PRL, a mutant of human PRL in which the serine residue at the 179 position is replaced with aspartate, provides a potentially useful tool to examine the role of PRL in neural processing. In the present report, three experiments were conducted that examined the effects of this PRL antagonist on the induction of maternal behavior. In each experiment, ovariectomized, nulliparous rats were treated sequentially with SILASTIC capsules implanted sc with progesterone (days 1-11) and estradiol (days 11-17), a treatment that stimulates a rapid onset of maternal behavior in virgin rats. On day 11, females were implanted with Alzet miniosmotic pumps connected to cannulae directed unilaterally at the lateral ventricle (Exp 1) or bilaterally at the medial preoptic area (MPOA; Exp 2 and 3). Pumps contained either doses of S179D-PRL (0.115 or 1.15 mg/ml; Exp 1 and 2), wild-type human PRL (1.15 mg/ml; Exp 3), or the saline vehicle (Exp 1-3). Testing for maternal behavior began on day 12, a day after pump insertion, and animals were tested daily for 6 days. Latencies to contact, retrieve, and group foster test young were recorded. Administration of both the high and low doses of S179D-PRL infused into the lateral ventricle (Exp 1) or MPOA (Exp 2) significantly delayed the onset of maternal behavior. In contrast, MPOA infusions of the control hormone, wild-type human PRL, in Exp 3 did not delay the onset of maternal behavior. These findings support the concept that the effects of S179D-PRL are caused by its actions as a PRL receptor antagonist rather than by a nonspecific effect of the protein. Overall, these results demonstrate the effectiveness of S179D-PRL acting at the level of the central nervous system (and, more specifically, within the MPOA) to regulate maternal behavior, a PRL-mediated response.

New antiarrhythmic agents. 6. Quantitative structure-activity relationships of aminoxylidides.

The synthesis and pharmacological evaluation of primary and tertiary aminoxylidides with the amino group in the 2-7 position of the acyl chain are described. 2,6-Xylidine was acylated with haloacyl halides and converted to the target compounds by direct amination or by the Gabriel procedure. Alternatively, 2,6-xylidine was coupled with keto acids, and the ketoxylidides were converted to the amines by reductive amination. The target compounds were evaluated in mice both for antiarrhythmic efficacy against chloroform-induced tachycardia and for central nervous system toxicity. Experimentally determined values of partition coefficients and pKa values were used for quantitative structure-activity analyses. While the antiarrhythmic activity could be described as a function of log P alone, the CNS toxicity was best described as a function of both log P and pKa. The results suggest that antiarrhythmic potency can be increased by increasing lipophilicity, while the therapeutic index can be improved by increasing the pKa.

New antiarrhythmic agents. 5. alpha-Aminoaceto-2,6-xylidides with functionalized amide alkyl substituents.

The synthesis of aminoaceto-2',6'-xylidides substituted on the amide nitrogen with 2-(diethylamino)ethyl, 2-aminoethyl, 2-hydroxyethyl, and 2-ethoxyethyl groups is described. The 2-aminoethyl derivatives were prepared by treatment of N-(2-phthalimidoethyl)-2',6'-xylidine with chloroacetyl chloride, followed by treatment with either potassium phthalmide or diethylamine. Hydrazinolysis of the phthalimides liberated the free amines. The remaining target compounds were produced by alkylation of lidocaine or of 2-phthalimidoaceto-2',6'-xylidide with the appropriate halide and sodium hydride, followed by hydrazinolysis where necessary. All target compounds were evaluated for antiarrhythmic efficacy against chloroform-induced ventricular tachycardia, as well as for acute CNS toxicity in mice. Most of the target compounds were more potent than the corresponding secondary amides and had improved therapeutic margins toward CNS toxicity. The diamines N-(2-aminoethyl)-2-aminoaceto-2',6'-xylidide (13) and N-(2-aminoethyl)--2-(diethylamino)aceto-2',6'-xylidide (29) are especially promising in this respect. Several compounds were tested as spinal anesthetics.

New antiarrhythmic agents. 2. Amide alkyl alpha-amino xylidides.

The synthesis of a series of N-alkyl 2-amino 2',6'-xylidides is described. The method involved coupling of the N-alkyl-2',6'-xylidine with the appropriate 2-haloacyl halide, followed by ammonolysis. Alternatively, alkylation of the 2-phthalimido 2',6'-xylidide with NaH and the alkyl halide followed by hydrazinolysis was used. All compounds were evaluated for their ability to protect mice against chloroform-induced ventricular fibrillation. The compounds were generally more potent antifibrillatory agents than the corresponding secondary amides. All were more potent than tocainide and several showed less CNS toxicity. Five compounds were further evaluated in dogs with ventricular arrhythmias resulting from myocardial infarction. N-Ethyl-2-aminoaceto-4'-propoxy-2',6'-xylidide was as potent as lidocaine and produced less CNS toxicity.

New antiarrhythmic agents. 3. Primary beta-amino anilides.

The synthesis and pharmacologic evaluation of primary beta-amino anilides, as well as comparisons with tocainide, lidocaine, and its beta homologue, are described. Substituted anilines were acylated with 3-bromoacyl chlorides and converted to the title compounds by direct amination or via 3-phthalimido anilides and subsequent hydrazinolysis. Alternatively, anilines were acylated with substituted acryloyl chlorides and the amines prepared by addition of ammonia to the double bond. The target compounds were evaluated for their ability to protect against chloroform-induced fibrillation in mice. All were found to have some antifibrillatory activity; several were more potent than tocainide, a compound in clinical trials as an oral antiarrhythmic drug. Four compounds were tested for their effects against ventricular arrhythmias in dogs with myocardial infarction. 3-Amino-2',6'-butyroxylidide (38) was found to be more potent and less CNS toxic than tocainide.

New antiarrhythmic agents. 1. Primary alpha-amino anilides.

Thirty-two alpha-amino anilides with various substituents in the aromatic ring and in the alpha position are described. Their abilities to protect mice against chloroform-induced fibrillation and to elicit toxicity were determined. Substitution of an alkyl or aryl group in the alpha position enhanced the antifibrillatory activity. In most cases, increased potency was accompanied by increased toxicity. Eleven compounds were tested in dogs with surgically induced myocardial infarction; most showed antiarrhythmic activity. 2-Aminopropiono-2',6'-xylidide, tocainide, was chosen for clinical investigation.

Endogenous opioid facilitation of maternal memory in rats.

In rats, contact with pups at parturition establishes a form of maternal memory that enables female rats to respond rapidly to pups in the future. Treatment of pregnant female rats with the long-lasting micro opioid receptor antagonist, beta-funaltrexamine (beta-FNA), prior to parturition interfered with the establishment of maternal memory. Similar treatment 3 hr postpartum resulted in disrupted retention of maternal memory that appeared nonspecific, with both drug- and vehicle-treated rats displaying a deficit. However, infusion of the opioid antagonist 24 hr postpartum had no effect on the retention of maternal memory tested 7 days later. These findings indicate that the establishment of maternal memory is mediated by endogenous opioid activity around the time of parturition.

Independent mediation of unconditioned motor behavior by striatal D1 and D2 receptors in rats depleted of dopamine as neonates.

The effects of systemic administration of DA receptor antagonists suggest that unconditioned motor behavior in rats depleted of DA as neonates continues to be dependent upon dopaminergic transmission, yet the specific contribution of D1 and D2 receptors to these behaviors has been altered. The purpose of the present study was to determine whether these depletion-induced receptor changes are occurring at the level of striatal DA terminals and their targets. The ability of bilateral intrastriatal injections (0.5 microliter) of DA receptor antagonists to induce motoric deficits was determined in adult rats treated with vehicle or 6-OHDA (100 micrograms, intraventricular) on postnatal day 3. Administration of the D1-like antagonist SCH 23390 (0.5-2.0 micrograms) or the D2-like antagonist clebopride (1.0-4.0 micrograms) induced dose-dependent akinesia, catalepsy, and somatosensory neglect in vehicle-treated controls. In contrast, neither antagonist produced deficits in rats depleted of forebrain DA as neonates. However, combined administration of SCH 23390 + clebopride induced similar akinesia, catalepsy, and somatosensory neglect in both controls and DA depleted animals. Animals depleted of DA were more sensitive than controls to the low doses of this combined D1 + D2 antagonism. These results demonstrate that activation of striatal DA receptors remains necessary for unconditioned motor behavior in rats depleted of DA as neonates. However, the specific contributions of D1- and D2-like receptors to these behaviors differ between intact animals and those depleted of DA as neonates. The ability of endogenous DA acting at either D1 or D2 receptors to support spontaneous motor behavior in rats depleted of DA as neonates may contribute to their relative sparing from parkinsonian deficits.

Co-activation of D1- and D2-like receptors is unnecessary for stimulated motor behavior in rats depleted of dopamine during development.

The motoric effects of the D1-like agonist SKF 38393 (5.0 or 20.0 mg/kg) and the D2-like agonist quinpirole (0.2, 1.0, or 3.0 mg/kg) were determined in adult rats treated with 6-OHDA (100 micrograms) or its vehicle on postnatal Day 3. Quinpirole, but not SKF 38393, produced stereotypy and modest motor activity in vehicle-treated rats. These effects of quinpirole were blocked by either the D1-like antagonist SCH 23390 (0.2 or 0.4 mg/kg) or the D2-like antagonist clebopride (10.0 mg/kg). In contrast, administration of either D1- or D2-like agonists enhanced stereotypy and motor behavior in animals depleted of dopamine with 6-OHDA. However, in these animals, only the D1-like antagonist was able to block D1-induced behaviors and only the D2-like antagonist was able to block D2-induced behaviors. A separate group of adult rats, treated with 6-OHDA (200 micrograms) on postnatal Day 20, was studied to determine whether these effects depended upon age at the time of DA depletion. Animals depleted on Day 20 resembled animals depleted on Day 3 in that D2-, but not D1-like antagonists, blocked D2 agonist-induced responses. These results demonstrate that in animals depleted of DA during development, qualitative changes in D1/D2 receptor interactions result in the ability of each receptor subtype to independently activate stereotypy and motor behavior.

D1- and D2-receptor mediation of motoric behavior in rats depleted of DA as neonates: effects of age and size of depletion.

The D1/D2 mediation of motor behavior in rats is qualitatively altered following large forebrain dopamine (DA) depletions on postnatal day 3. These animals are markedly subsensitive, relative to controls or animals depleted of DA as adults, to the motoric deficits produced by individual D1- or D2-like antagonists but are impaired following combined D1 +D2 antagonists. In order to determine the extent of DA depletion necessary to produce this subsensitivity to individual antagonists, we compared the motoric effects of D1 and D2 antagonists in adult animals sustaining a wide range of DA depletions on day 3. Only animals with striatal depletions of > or = 95% demonstrated this subsensitivity to individual antagonists. Moreover, since important changes in DA receptor ontogeny occur during the first postnatal week, we compared the ability of the D1-like antagonist, SCH 23390 (0.2 mg/kg), or the D2-like antagonists, clebopride (10.0 mg/kg) and haloperidol (1.0 mg/kg), to induce akinesia or catalepsy in adults depleted of DA on either day 1 or on day 3. Rats depleted of striatal DA (> 95%) at either age exhibited similar subsensitivity to D1 or D2 antagonists. These findings suggest that large DA depletions are necessary to alter the roles of D1 and D2 receptors in the expression of motor behavior and that this plasticity is comparable in animals depleted on day 1 or day 3.

Opioid receptor antagonism during early lactation results in the increased duration of nursing bouts.

High levels of mu opioid receptor activation during the postpartum period result in the disruption of ongoing maternal behavior. The role of physiological levels of endogenous opioids on the mediation of maternal behavior in postpartum females, however, has not been closely examined. The purpose of the present experiments was to examine the function of endogenous opioids during early and mid-lactation by treating postpartum females with the opioid antagonist naloxone and monitoring their behavioral interactions with pups. Although this treatment did not lead to any qualitative differences in the maternal behaviors measured (pup retrieval and grooming, nest building, grouping of pups, or crouching over pups), there was a quantitative difference in the amount of time the females spent with pups on the nest and actively nursing pups. Naloxone, given either systemically or centrally (intracerebroventricularly), resulted in prolonged nursing and nesting bouts. This effect, however, was only observed during the early lactation time point (postpartum days 5-7). Females tested later in lactation (postpartum days 10-12 or 12-14) did not display the increased nursing or nesting bouts in response to the antagonist. These data indicate that central opioids play a role in the duration of nursing bouts during early lactation.

Tocainide conjugation in humans: novel biotransformation pathway for a primary amine.

The metabolism of tocainide, an experimental antiarrhythmic drug, was studied in humans. Urinary excretion of unchanged drug was 28-55% in 24 hr after oral dosing. Urine hydrolysis with hydrochloric acid or beta-glucuronidase increased tocainide recovery to 55-79%. Saccharo-1,4-lactone inhibited the beta-glucuronidase-mediated tocainide recovery increase. Adjustment of urine to pH 13 produced a compound identified as 3-(2,6-xylyl)-5-methylhydantoin. Evidence suggests that it was derived from the same metabolite that formed the additional tocainide after acid or beta-glucuronidase treatment. Tocainide carbamoyl O-beta-D-glucuronide is the structure proposed for the metabolite. The suggested pathway for its formation involves the addition of carbon dioxide to the amino nitrogen of tocainide followed by uridine diphosphate-glucuronic acid conjugation.