Role of brain transmigrating neutrophils in depression-like behavior during systemic infection.

Peripheral inflammation induces transmigration of interleukin (IL)-1ß-expressing neutrophils to the brain. We investigated the possibility that this presents a new route of immune-to-brain communication by assessing their role in sickness behaviors relevant for mood disorders. Mice treated with lipopolysaccharide (LPS) developed despair-like behavior, and administration of an anti-polymorphonuclear antibody abolished LPS-induced despair-like and asocial behaviors, which correlated with the levels of IL-1ß expression in the brain. These behavioral changes were directly mediated by the energy-regulating hormone, leptin. Increasing the concentration of endogenous leptin during obesity exacerbated, whereas its neutralization using a specific antiserum attenuated sickness behaviors and importantly the neutrophil transmigrating process. Our results indicate a role for peripheral neutrophils in conveying inflammatory signals to the brain, which appears to be dependent on the energy status of the organism. This constitutes a novel mechanism of immune-to-brain communication relevant to mood disorders.

Effect of obesity on the acute inflammatory response in pregnant and cycling female rats.

Nonpregnant female rats have a lower inflammatory response to lipopolysaccharide (LPS) than males and, at late stages of gestation, the fever response to this immunogen is almost completely suppressed. We have shown in males that obesity exacerbates sickness responses to pathogenic stimuli. In the present study, we investigated whether obesity would have a similar effect in females and reverse some of the suppressive effects of pregnancy on the innate immune response. Lean and diet-induced obese adult Wistar rats were randomly separated into either cycling or mated groups. On day 18 of pregnancy or in the metestrous/dioestrous phase in cycling rats, a single injection of LPS (100 µg/kg) was administered and rats were sacrificed 8h or 24 h later. In pregnant females, LPS induced a higher increase in body temperature in obese rats only at the 24-h time point and lower hypothalamic interleukin (IL)-1ß expression and higher circulating levels of IL-1 receptor antagonist (ra) than their cycling counterparts. Conversely, there was no suppression of inflammatory signals in the white adipose tissue of pregnant rats. At 24 h post LPS, the cell surface marker CD11c and IL-6 mRNA expression were increased in white adipose tissue from obese rats regardless of reproductive state, whereas IL-1ra was highest in the LPS-treated obese pregnant group. In cycling females, LPS induced a higher fever response in obese rats accompanied by higher circulating levels of IL-6 and IL-1ra, as well as an increase in circulating leptin only in the obese cycling group. In the hypothalamus, obese rats showed significantly higher expression of nuclear factor-IL-6 in at the 8-h time point. Collectively, these results show that diet-induced obesity in females is associated with a similar pattern of response to that previously observed in males. On the other hand, obesity had limited effects in pregnant rats, with the exception of white adipose tissue.

Changes in dendritic spine density on layer 2/3 pyramidal cells within the cingulate cortex of late pregnant and postpartum rats.

A rapid upregulation of astrocytic protein expression within area 2 of the cingulate cortex (Cg2) of the maternal rat occurs within 3h postpartum and persists throughout lactation. Previous studies have shown that similar changes in astrocytic proteins can signal changes in local synapses and dendritic spines. Thus, here we used the Golgi-Cox impregnation technique to compare spine density in layer 2 and 3 pyramidal cells of Cg2, the CA1 region of the hippocampus and the parietal cortex (ParCx) among metestrus, late pregnant (LP), 3-hour postpartum (3H PP) and 16-day postpartum rats (D16 PP). Rats in the 3H PP group had higher numbers of dendritic spines/10 µm on the apical dendrites of pyramidal neurons in both Cg2 and CA1 than the other groups, which did not differ. A similar pattern was observed in basilar dendrites but this failed to reach significance. In Cg2, Sholl analysis revealed that rats in the D16 PP group had a significantly greater extent of dendritic arborization in the basilar region than any other group. These data suggest that the changes in astrocytic proteins that occur in Cg2 in the postpartum period are associated with neuronal plasticity in pyramidal layers 2 and 3.

Effects of parturition on immediate early gene protein expression within the brains of female rats.

The mother-infant interaction that occurs immediately postpartum period has important consequences including changes in protein expression in the astrocytes within cingulate cortex area 2 (Cg2). Because increased expression of basic fibroblast growth factor (bFGF) and glial fibrillary acidic protein (GFAP) has been associated with increased neuronal activity we used immediate early gene expression to evaluate the effects of parturition plus interaction with pups during and immediately after delivery to investigate patterns of neural activation in a number of brain areas including Cg2. In the first experiment, we compared levels of immunoreactivity of two immediate early genes: c-Fos and egr-1, among three groups of animals: Cycling, Late Pregnant, and rats perfused 1.5 h postpartum. The average number of Fos and egr-1-ir cells/section were calculated for the Parietal Cortex (ParCx), nucleus accumbens (NAc), medial amygdala (MEA), medial preoptic area (MPOA), supraoptic area (SON) and Cg2. In a second experiment, Fos-ir induction was compared between cycling rats and rats at hour 3 postpartum. Contrary to our hypothesis no changes in expression of either immediate early gene were observed in Cg2. In Experiment 1 however, an upregulation in both early genes was seen in the ParCx, and, of Fos-ir only in the MPOA of postpartum animals. A decrease in Fos-ir was seen in the NAc of late pregnant animals and no significant differences were seen in either immediate early gene expression within the MEA. Interestingly, areas that showed a significant increase in neuronal activation project to Cg2. The possibility of an interaction between these changes and glial cells in Cg2 is discussed.

Steroid hormones and maternal experience interact to induce glial plasticity in the cingulate cortex.

Neocortical plasticity is not usually associated with changes in reproductive function. However, we have shown a six to 10-fold increase in the number of astrocytes labeled with glial fibrillary acidic protein (GFAP) and astrocytic basic fibroblast growth factor or FGF-2 (bFGF) in the cingulate cortex area 2 (Cg2) in postpartum rats, indicative of changes in connectivity in this area. In the present studies, we investigated the necessary and sufficient stimuli for these changes to occur. We show that 3 h of maternal experience combined with a hormonal treatment that mimics late pregnancy induces the astrocytic changes in Cg2 in virgin rats. The extent of these changes was similar to those of postpartum females. Sensitized virgin females did not show any astrocytic changes after 3 h of maternal behavior, suggesting that a similar amount of maternal experience alone is not sufficient to increase astrocytic bFGF- and GFAP-immunoreactivity in Cg2. Consistent with these data, eliminating early maternal experience by removing pups immediately postpartum abolishes the increased bFGF and GFAP protein expression in the cingulate cortex. These results suggest that maternal experience and hormonal state interact to produce astrocytic remodeling in the Cg2. The current results are consistent with a role for the cingulate cortex in maternal responsivity as suggested by early lesion studies in rats and more recent imaging studies in humans.

The slippery slope: prediction of successful weight maintenance in anorexia nervosa.

BACKGROUND: Previous research has found that many patients with anorexia nervosa (AN) are unable to maintain normal weight after weight restoration. The objective of this study was to identify variables that predicted successful weight maintenance among weight-restored AN patients. METHOD: Ninety-three patients with AN treated at two sites (Toronto and New York) through in-patient or partial hospitalization achieved a minimally normal weight and were then randomly assigned to receive fluoxetine or placebo along with cognitive behavioral therapy (CBT) for 1 year. Clinical, demographic and psychometric variables were assessed after weight restoration prior to randomization and putative predictors of successful weight maintenance at 6 and 12 months were examined. RESULTS: The most powerful predictors of weight maintenance at 6 and 12 months following weight restoration were pre-randomization body mass index (BMI) and the rate of weight loss in the first 28 days following randomization. Higher BMI and lower rate of weight loss were associated with greater likelihood of maintaining a normal BMI at 6 and 12 months. An additional predictor of weight maintenance was site; patients in Toronto fared better than those in New York. CONCLUSIONS: This study found that the best predictors of weight maintenance in weight-restored AN patients over 6 and 12 months were the level of weight restoration at the conclusion of acute treatment and the avoidance of weight loss immediately following intensive treatment. These results suggest that outcome might be improved by achieving a higher BMI during structured treatment programs and on preventing weight loss immediately following discharge from such programs.

Fluctuations in astrocytic basic fibroblast growth factor in the cingulate cortex of cycling, ovariectomized and postpartum animals.

In the current studies we investigated the timing of onset and the conditions needed for the maintenance of the upregulation of basic fibroblast growth factor (bFGF) and glial fibrillary acidic protein (GFAP) in the cingulate cortex area 2 (Cg2) that occurs in postpartum animals. We have previously shown that this upregulation is present from day 4 to day 24, and is not seen late in pregnancy (days 21-22). In the current studies, we demonstrate that bFGF and GFAP are both upregulated in Cg2 as early as 3 h postpartum, and are maintained until at least day 24 postpartum in animals deprived of pup stimulation for 8 days prior to perfusion. bFGF and GFAP immunoreactivity returns to prepartum levels by 5-6 weeks post-weaning, and the typical postpartum increase is not further enhanced in multiparous rats. We also show that, although there are significant changes in levels of bFGF immunoreactivity across the phases of the estrous cycle, peak cycling levels remain much lower than those observed in lactating rats. Possible stimuli involved in the induction of bFGF and GFAP in Cg2, and the potential relevance of these changes to the maternal state are discussed.

Inhibition of nitric oxide synthase within the medial preoptic area impairs pup retrieval in lactating rats.

Central suppression of nitric oxide (NO) production by administering 250 microg of Nitro-superw--subL-Argenine Methyl Ether (L-NAME), an inhibitor of NO synthase, into the 3rd ventricle disrupts both pup retrieval and maternal aggression in postpartum rats. In these studies, the authors examined the ability of varying doses of L-NAME to produce these effects on maternal behavior. Doses of L-NAME that were shown to be ineffective when injected into the 3rd ventricle were administered bilaterally into the medial preoptic area (MPOA) of rats on Day 4 postpartum. To assess the specificity of L-NAME's effect within the MPOA, the authors bilaterally injected Nitro-superw--subD-Argenine Methyl Ether (D-NAME), an inactive isomer of L-NAME, into the MPOA. When administered intracerebroventricularly, the 2 highest doses of L-NAME used, 250 microg and 200 microg, disrupted retrieval behavior and maternal aggression. Bilateral injections of L-NAME into the MPOA at doses of 20 microg and 40 microg/side also disrupted pup retrieval, and D-NAME injections into the MPOA had no effect on the maternal behaviors measured. All rats in these experiments showed normal maternal behavior 24 hr after drug administration. These results suggest that NO acts within the MPOA to facilitate retrieval behavior.

Upregulation of astrocytic basic fibroblast growth factor in the cingulate cortex of lactating rats: time course and role of suckling stimulation.

Previous work from our laboratory has shown that there is a much higher level of bFGF and GFAP immunoreactivity in area 2 of the cingulate cortex (Cg2) of rats on day 16 of lactation than in cycling or late pregnant females. To examine the time course of this change, in the first of the current studies, we compared bFGF and GFAP immunoreactivity in the brains of lactating females on postpartum day 4 (PP4), day 10 (PP10), day 16 (PP16), and day 24 (PP24) with that of cycling and ovariectomized (OVX) females. In the second study, we investigated whether the maintenance of these changes in bFGF and GFAP depended on suckling stimulation by removing litters on day 1 or day 16 postpartum and examining the brains of the dams on day 4 (Pr4) or day 24 (Pr24) postpartum, respectively. bFGF and GFAP immunoreactivity within Cg2 and the medial preoptic area (MPOA) were measured. In both experiments astrocytic bFGF and GFAP surface density in the Cg2 varied significantly across groups. All postpartum rats, regardless of stage of lactation or presence of the litter, had significantly higher levels of bFGF and GFAP immunoreactivity than cycling animals. Thus, the maintenance of this upregulation in bFGF and GFAP immunoreactivity does not depend on suckling stimulation. Consistent with our previous report, astrocytic bFGF was also elevated in the MPOA of PP16 animals. These data suggest a robust, long-lasting, postpartum change in bFGF and GFAP immunoreactivity in Cg2 and a role for this area of the cortex in the physiological and behavioral adaptations that accompany reproductive experience.

Differential effects of reproductive and hormonal state on basic fibroblast growth factor and glial fibrillary acid protein immunoreactivity in the hypothalamus and cingulate cortex of female rats.

Morphological changes in astrocytes occur in a number of brain regions including the hypothalamus and hippocampal regions as a function of hormonal and reproductive state. Because basic fibroblast growth factor has been shown to play an important role in morphological changes in astrocytes, we investigated whether basic fibroblast growth factor immunoreactivity would also be influenced by reproductive state and circulating gonadal steroids. To do this we compared astrocytic basic fibroblast growth factor and glial fibrillary acid protein immunoreactivity in hypothalamic nuclei and the cingulate cortex, area 2 among groups of cycling, late pregnant and lactating rats as well as in ovariectomized and ovariectomized hormone-replaced females. Significant differences in both basic fibroblast growth factor and glial fibrillary acid protein immunoreactivity were observed across groups in the supraoptic nucleus, parvocellular paraventricular nucleus, medial preoptic area of the hypothalamus and cingulate cortex 2. The pattern of change in basic fibroblast growth factor and glial fibrillary acid protein immunoreactivity varied across regions both in direction and magnitude. For example, although in the supraoptic nucleus ovariectomized rats had lower levels of basic fibroblast growth factor-ir than cycling females, this pattern was reversed within cingulate cortex. Overall the results of this study suggest that reproductive and hormonal states are associated with robust changes in basic fibroblast growth factor and glial fibrillary acid protein immunoreactivity in a number of brain areas but that the changes observed vary in magnitude as well as direction from one brain region to another.

Central nitric oxide synthase inhibition disrupts maternal behavior in the rat.

Blocking nitric oxide (NO) production, by 3rd ventricle administration of a nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 250 microg/5 microl, postpartum [pp]) decreased milk ejections in Day 10 pp rats. On Day 4 pp, L-NAME treatment eliminated pup retrieval and at both stages of lactation suppressed maternal aggression. Fewer rats treated with L-NAME on Day 10 pp retrieved 4-day-old pups than controls, although all nursed older litters. Following exposure to a mobile intruder, Fos expression was lower in the medial preoptic area and the bed nucleus of the stria terminalis in L-NAME-treated rats than in controls but was lower in the medial amygdala only following exposure to an anaesthetized intruder. Thus, the elevated levels of NO observed in lactation may contribute to the mechanism(s) that mediate maternal behavior and aggression.

NMDA receptors and voltage-dependent calcium channels mediate different aspects of acquisition and retention of a spatial memory task.

Activity dependent calcium entry into neurons can initiate a form of synaptic plasticity called long-term potentiation (LTP). This phenomenon is considered by many to be one possible cellular mechanism underlying learning and memory. The calcium entry that induces this phenomenon can occur when N-methyl-D-aspartate receptors (NMDARs) and/or voltage-dependent calcium channels (VDCCs) are activated. While much is known about synaptic plasticity and the mechanisms that are triggered by activation of these two Ca(2+) channels, it is unclear what roles they play in learning. To better understand the role activation of these channels may play in learning we systemically administered pharmacological antagonists to block NMDARs, VDCCs, or both during training trials and retention tests in a radial arm maze task. Wistar rats injected with the NMDAR antagonist MK-801 (0.1mg/kg) were impaired in the acquisition of this task. In contrast, rats injected with verapamil (10mg/kg), an antagonist to VDCCs, acquired the task at the same rate as control animals, but were impaired on a 10-day retention test. A group of animals injected with both antagonists were unable to learn the task. The results suggest that each of the calcium channels and the processes they trigger are involved in a different stage of memory formation or expression.

Food restriction during lactation results in prolonged hyposensitivity to the positive-feedback effects of oestradiol.

Food restriction prolongs lactational infertility in rats. Here, we investigated whether an attenuated response to the positive-feedback effects of oestrogen on luteinizing hormone release contributed to this effect. The ability of oestrogen to induce surges in luteinizing hormone in ad libitum fed and food-restricted dams at different times of lactation was compared. The results showed that, on day 20 postpartum, ad libitum fed dams showed luteinizing hormone surges after oestrogen treatment, but food-restricted dams did not. Ovariectomy or RU486 treatment restored the ability of oestrogen to induce luteinizing hormone surges in food-restricted dams, and chronic progesterone exposure reduced oestrogen-induced surges of luteinizing hormone in ad libitum fed ovariectomized dams. Food restriction also resulted in a reduced ability of oestrogen to induce progesterone receptor immunoreactivity, but did not reduce the number of oestrogen receptors (ERalpha) in the anteroventralperiventricular area. As with the surge in luteinizing hormone, the effects of food restriction on oestrogen induction of progesterone receptors were mediated by progesterone. Together, these results suggest that the ability of food restriction to extend the length of lactational diestrus is mediated, in part, by a decrease in sensitivity to the positive-feedback effects of oestrogen. This results from high circulating concentrations of progesterone which apparently reduce the ability of oestrogen to induce progesterone receptor expression.

Prolactin and oxytocin interaction in the paraventricular and supraoptic nuclei: effects on oxytocin mRNA and nitric oxide synthase.

We investigated the contribution of prolactin and oxytocin to the increase in staining for NADPH-d and oxytocin mRNA in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) observed at the end of pregnancy, or following a steroid-priming regimen that mimics the hormonal profile of late pregnant females. Ovariectomized rats received chronic implants of silastic capsules containing oestrogen and progesterone followed by progesterone removal. In experiment 1, oxytocin antagonist (OTA) was administered to rats to investigate whether intranuclear oxytocin release was necessary for NADPH-d staining. In experiments 2a and b, rats received concurrent treatment with bromocryptine (0.5 mg/day) to suppress endogenous prolactin release, and either systemic prolactin (0.5 mg once daily), or prolactin (2 micro g/ micro l), or vehicle infused twice a day into the third ventricle, or chronic oxytocin infusion (24 ng/day) for 3 days following progesterone removal. Brains were then processed for NADPH-d histochemistry. In experiment 3, the interaction of prolactin and oxytocin on oxytocin mRNA within the SON and PVN was examined. NADPH-d staining in the SON and PVN was reduced by the highest dose of the OTA, and by bromocryptine treatment. Central prolactin and oxytocin replacement completely restored NADPH-d staining in bromocryptine-treated rats. Finally, both bromocryptine and the OTA suppressed oxytocin mRNA expression and prolactin replacement restored expression levels to that of controls. Together, these data suggest that the increased capacity to produce nitric oxide in the SON and PVN during late pregnancy is dependent on prolactin stimulating oxytocin gene mRNA and hence intranuclear oxytocin release.

Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa.

Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN). These candidate genes were evaluated for sequence variation and for linkage and association of this sequence variation to AN in family and case : control data sets. Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs. Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls. Linkage analysis of these candidate gene SNPs with 33 microsatellite markers in families including relative pairs concordantly affected with restricting AN (N=37) substantially increased the evidence for linkage of this region to restricting AN to an NPL score of 3.91. Statistically significant genotypic, allelic, and haplotypic association to AN in the case : control design was observed at HTR1D and OPRD1 with effect sizes for individual SNPs of 2.63 (95% CI=1.21-5.75) for HTR1D and 1.61 (95% CI=1.11-2.44) for OPRD1. Using genotype data on parents and AN probands, three SNPs at HTR1D were found to exhibit significant transmission disequilibrium (P&<0.05). The combined statistical genetic evidence suggests that HTR1D and OPRD1 or linked genes may be involved in the etiology of AN.

Pups presence eliminates the stress hyporesponsiveness of early lactating females to a psychological stress representing a threat to the pups.

Blunted neuroendocrine responses to stress are reported in lactating females after exposure to various stressors. However, many of the stimuli used in these studies have little ethological relevance for maternal protection of the litter in a threatening environment. The question that arises is whether the relevance of the stressor to the infant is critical in the 'gating' of the neuroendocrine response. We hypothesized that the presence of pups with their mothers at the time of exposure to an intruder or a predator odour is an effective way to increase the emotional salience of the psychological stressor, thus eliminating the stress hyporesponsiveness in lactating females. We first compared neuroendocrine responses [corticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus of the hypothalamus (PVN) and central nucleus of the amygdala (CeA), plasma adrenocorticotropic hormone (ACTH) and corticosterone] between early (EL, PPD3-5), late (LL, PPD 15) lactating and virgin (V) females to a male intruder in the home cage. We next investigated the effect of pups' presence at the time of stressor exposure on the magnitude of the hormonal response to a male intruder in the home cage or to a predator odour (fox urine) in a novel environment. In the male intruder paradigm, levels of CRF mRNA expression in the PVN and CeA were lower in LL compared to EL or V females and plasma ACTH and corticosterone secretion was not as elevated in LL compared to EL females. Aggression towards the intruder was high in EL females in the presence of their pups and a positive correlation was found with the integrated ACTH response. Aggression rapidly declined after pup separation (2.5 h or 48 h) or in LL nursing females. In EL females, the presence of the pups with their mothers (EL + pups) at the time of stress significantly increased plasma ACTH and corticosterone responses to either male intruder or predator odour compared to EL females without their pups for 2.5 h or 48 h (EL - pups). Plasma ACTH response to fox urine in EL + pups females was comparable to that of virgin females, suggesting that increasing the salience of emotionally relevant stimuli by keeping the pups present in the cage could eliminate the hyporesponsiveness detected for EL females without their pups. These studies indicate the critical role of the pups in modulating the maternal response to stressors that represent a threat for the litter. We hypothesize that the amygdala, because of its ability to process olfactory stimuli and stimuli with affective properties, might play an essential role in 'gating' the neuroendocrine response to stress during lactation.

Chronic neuropeptide Y Y5 receptor stimulation suppresses reproduction in virgin female and lactating rats.

Continuous infusion of neuropeptide Y (NPY) disrupts cyclicity and delays the onset of puberty in female rats indicating that NPY can suppress reproduction. Central application of NPY also reliably increases food intake in rats. States with heavy demands on energy resources where reproduction is also inhibited, such as lactation, are similarly accompanied by elevations in central NPY expression. In previous studies, we have shown that, compared to lactating rats fed ad libitum, food-restricted lactating rats exhibit a longer period of lactational diestrus that is correlated with increased central NPY expression. These studies link NPY to the inhibition of reproduction that is mediated by low availability of energy resources. Here, we examine the effect of chronic 7-day infusion of the mixed Y1/Y4/Y5 agonist (Leu31, Pro34) NPY and selective agonists to the Y2 (NPY13-36) and Y5 (D-Trp32 NPY and D-Trp34 NPY) receptors on food intake and the oestrous cycle of virgin female rats. We also investigated the effect of chronic infusion from day 8-15 postpartum (pp) of D-Trp32 NPY and D-Trp34 NPY on food-intake and the length of lactational diestrus in lactating rats fed ad libitum. In virgin females, infusion of (Leu31, Pro34) NPY and both the Y5 agonists lengthened the period between consecutive oestrus days while the Y2 agonist NPY13-36 was without effect. Selective Y5 receptor activation alone caused an increase in food intake in virgin females. In lactating females, D-Trp32 NPY extended the length of lactational diestrus, while D-Trp34 NPY had no effect on this parameter. These data suggest that Y5 receptor activation suppresses the reproductive axis in both virgin and lactating rats and that Y5 receptor activation enhances food-intake in virgin females.

Y1 receptor activation is involved in the effect of exogenous neuropeptide Y on pup growth and the early termination of lactational diestrus in the postpartum rat.

The effect of chronic administration of exogenous neuropeptide Y (NPY) and specific NPY receptor agonists and antagonists on reproductive function was examined in lactating rats. As previously demonstrated in our laboratory, chronic (7-day) intracerebroventricular (i.c.v.) NPY infusion (6 microg/day) from days 8-15 postpartum (pp) caused a significant decrease in milk production and an early termination of lactational diestrus. Similar application of the mixed Y1/Y4/Y5 receptor agonist (Leu31, Pro34) NPY (at 3, 6 and 9 microg/day) reproduced the effect of chronic NPY infusion on milk production in a dose-independent manner. Consistent with this effect, the potent Y1 antagonist/Y4 agonist, 1229U91, given concomitantly with NPY eliminated the decline in milk production. The Y2 receptor agonist, NPY13-36, had no effect on milk production at any of the doses used. Length of lactational diestrus was reduced following administration of the Y2 agonist at 18 microg/day but not at 9 microg or 27 microg/day whereas (Leu31, Pro34) NPY infusion had no effect on this parameter at any of the doses used. However, the group that was treated with NPY plus 1229U91 exhibited the usual length of lactational diestrus, indicating that there is at least some Y1 involvement in the effects of NPY on lactational infertility. To test the possibility that the effects of NPY infusion are mediated through changes in circulating prolactin and progesterone, plasma concentrations of these hormones were measured on day 15 pp in NPY-, (Leu31, Pro34) NPY- and vehicle-treated females. NPY-infused females had lower plasma prolactin concentrations than vehicle-infused dams but progesterone concentrations were similar across groups. Overall, these data indicate that chronic exogenous NPY-infusion in lactating females disrupts milk production and shortens lactational diestrus, most likely through reducing prolactin secretion, and that this effect is mediated via Y1 receptor activity.

What treatments patients seek after inpatient care: a follow-up of 24 patients with anorexia nervosa.

BACKGROUND: To determine the kind of treatment patients with anorexia nervosa (AN) seek for their eating disorder following hospitalization. METHOD: Twenty-four women previously treated in the Toronto General Hospital were interviewed to determine the nature and amount of treatment received following discharge. RESULTS: Mean age: 31 years (SD=9.18). Mean body mass index (BMI) at assessment: 19.97 (SD=4.00). All had seen at least one or more professionals, mainly family doctors and psychiatrists, within the first 6 months. Mean hours of treatment: 85. Eighty-eight per cent had taken psychotropic medication (most commonly antidepressants). Symptomatic and asymptomatic patients did not differ in amount of treatment received. CONCLUSIONS: Regardless of their symptom state, AN patients continue to use the health system heavily following weight restoration. Their aftercare is thus essential for ongoing maintenance treatment and to prevent relapse, and training primary-care physicians to provide it may be one way to contain health care costs.